Clase fenómeno de raynaud iavm 2013

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Revision Etiopatogenia de Fenomeno de Raynaud

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Clase fenómeno de raynaud iavm 2013

  1. 1. Fenómeno de Raynaud Patogenia y Diagnóstico Diferencial Ignacio AlfredoValerio Morales Médico Residente en Reumatología martes, 10 de septiembre de 13
  2. 2. Fenómeno de Raynaud Historia http://www.historiadelamedicina.org/raynaud.html Maurice Auguste Gabriel Raynaud (1834 - 1881) 1862 Anatomía patológica Francesa 1862 Tesis doctoral 1866 Profesor de Curso Sainte-Périne, Saint Antoine (ejército) Varios artículos 1876 Medalla de oro del Cólera Estudios en Gangrenas 1929 Thomas Lewis martes, 10 de septiembre de 13 Nació el 5 de julio de 1834 en París. Su padre era Jacques Auguste, profesor en el Colegio real Bourbon. Su madre era Félicité Marie Vernois. Estudió medicina en París con la ayuda de su tío, el conocido profesor Ange-Gabriel-Maxime Ver- nois (1809-1877). Se doctoró en 862 con la tesis De l’asphyxie locale et de la gangrène symétrique des extrémités. Ese mismo año se doctoró también en letras con la tesis Les Médecins au temps de Molière, thèse pour le doctorat, présentée à la Faculté des lettres En 1865 fue médico del bureau central e impartió el curso de clínica médica en el Hôtel-Dieu, en sustitución de Piorry (865-66). En 1866 fue encargado de curso complementario sobre enfermedades mentales y nerviosas. Al año siguiente fue profesor suplente de patología interna sustituyendo a Monneret. En 1868 fue médico de los Hospitales: Sainte-Périne, Saint-Antoine (872), Lariboisière (872) y Charité (880). En 1870 impartió un curso sobre las enfermedades de la armada. Tras una revisión escrupulosa y puesta al día de las gangrenas, Raynaud señala más adelante: “...Je me propose de démontrer quíl existe une variété de gangrène sèche, affectant les ex- trémités, qu’il est impossible d’expliquer par une oblitération vasculaire ; variété caracté- risée surtout par une remarquable tendance à la symétrie, en sorte qu’elle affecte toujours des parties similaires, les deux membres supé- rieurs ou inférieurs, ou les quatre à la fois ; plus dans certains cas, le nez et les oreilles ; et je chercherai à prouver que cette espèce de grangène a sa cause dans un vice d’inervation des vaisseaux capillaires, qu’il me restera à préciser... “ En el texto se exponen como ejemplo diferentes historias clínicas o casos detallados cuando predo- mina el elemento nervioso, en su forma benigna, en su forma grave, cuando hay lesiones del aparato circulatorio demostradas en la autopsia, etc. En el capítulo tercero se refiere Raynaud a la sintomatología, diagnóstico, pronóstico, causas, naturaleza de la enfermedad y tratamiento. Acompañan al texto una serie de grabados. Murió joven a consecuencia de sus padecimientos cardíacos el 29 de junio de 1888 en París.
  3. 3. Fenómeno de Raynaud Historia http://www.historiadelamedicina.org/raynaud.html Maurice Auguste Gabriel Raynaud (1834 - 1881) 1862 Anatomía patológica Francesa 1862 Tesis doctoral 1866 Profesor de Curso Sainte-Périne, Saint Antoine (ejército) Varios artículos 1876 Medalla de oro del Cólera Estudios en Gangrenas 1929 Thomas Lewis martes, 10 de septiembre de 13 Nació el 5 de julio de 1834 en París. Su padre era Jacques Auguste, profesor en el Colegio real Bourbon. Su madre era Félicité Marie Vernois. Estudió medicina en París con la ayuda de su tío, el conocido profesor Ange-Gabriel-Maxime Ver- nois (1809-1877). Se doctoró en 862 con la tesis De l’asphyxie locale et de la gangrène symétrique des extrémités. Ese mismo año se doctoró también en letras con la tesis Les Médecins au temps de Molière, thèse pour le doctorat, présentée à la Faculté des lettres En 1865 fue médico del bureau central e impartió el curso de clínica médica en el Hôtel-Dieu, en sustitución de Piorry (865-66). En 1866 fue encargado de curso complementario sobre enfermedades mentales y nerviosas. Al año siguiente fue profesor suplente de patología interna sustituyendo a Monneret. En 1868 fue médico de los Hospitales: Sainte-Périne, Saint-Antoine (872), Lariboisière (872) y Charité (880). En 1870 impartió un curso sobre las enfermedades de la armada. Tras una revisión escrupulosa y puesta al día de las gangrenas, Raynaud señala más adelante: “...Je me propose de démontrer quíl existe une variété de gangrène sèche, affectant les ex- trémités, qu’il est impossible d’expliquer par une oblitération vasculaire ; variété caracté- risée surtout par une remarquable tendance à la symétrie, en sorte qu’elle affecte toujours des parties similaires, les deux membres supé- rieurs ou inférieurs, ou les quatre à la fois ; plus dans certains cas, le nez et les oreilles ; et je chercherai à prouver que cette espèce de grangène a sa cause dans un vice d’inervation des vaisseaux capillaires, qu’il me restera à préciser... “ En el texto se exponen como ejemplo diferentes historias clínicas o casos detallados cuando predo- mina el elemento nervioso, en su forma benigna, en su forma grave, cuando hay lesiones del aparato circulatorio demostradas en la autopsia, etc. En el capítulo tercero se refiere Raynaud a la sintomatología, diagnóstico, pronóstico, causas, naturaleza de la enfermedad y tratamiento. Acompañan al texto una serie de grabados. Murió joven a consecuencia de sus padecimientos cardíacos el 29 de junio de 1888 en París.
  4. 4. Fenómeno de Raynaud Historia Maurice Auguste Gabriel Raynaud (1834 - 1881) 1862 1929 Thomas Lewis 1930 Fenómeno de Raynaud vs Enfermedad de Raynaud 1950 Puede tener Enfermedad Subyacente asociada. <<Allen&Brown>> http://www.historiadelamedicina.org/raynaud.html martes, 10 de septiembre de 13 Thomas Lewis proposed in 1929 that RP was due to “local fault,” rather than a defect in the central nervous system in the 1930s by Allen and Brown2~ who divided RS into Raynaud's phenomenon and Raynaud's disease on the basis of the absence or presence of an associated disease. However, as early as the 1950s, it was recognized that Raynaud's phenomenon may precede an underlying disease by many years.
  5. 5. Fenómeno de Raynaud Historia Maurice Auguste Gabriel Raynaud (1834 - 1881) 1862 1929 Thomas Lewis 1930 Fenómeno de Raynaud vs Enfermedad de Raynaud 1950 Puede tener Enfermedad Subyacente asociada. <<Allen&Brown>> http://www.historiadelamedicina.org/raynaud.html martes, 10 de septiembre de 13 Thomas Lewis proposed in 1929 that RP was due to “local fault,” rather than a defect in the central nervous system in the 1930s by Allen and Brown2~ who divided RS into Raynaud's phenomenon and Raynaud's disease on the basis of the absence or presence of an associated disease. However, as early as the 1950s, it was recognized that Raynaud's phenomenon may precede an underlying disease by many years.
  6. 6. Fenómeno de Raynaud Introducción “Trastorno isquémico episódico en los dedos de las manos y los pies, manifestado por palidez, cianosis y rubor de la piel, en respuesta a estímulos como el frío o el estrés emocional” J. Am. Acad. Dermatol. 59 (2008) 633–653 martes, 10 de septiembre de 13 Episodic color changes of the hands and feet in response to cold or stress, known as Raynaud Phenomenon (RP), are a frequent complaint among patients presenting to pediatric rheumatology clinics. The first description of vasomotor instability triggered by cold exposure, or “local asphyxia of the extremities,” is ascribed to A.G. Maurice Raynaud, a French medical student, whose name has become synonymous with this disorder.1 Despite 150 years of clinical observation and basic research, only recently have significant inroads been established to explain the biological basis for this condition and to establish evidence-based therapeutic interventions Thomas Lewis proposed in 1929 that RP was due to “local fault,” rather than a defect in the central nervous system.
  7. 7. Fenómeno de Raynaud Introducción “Trastorno isquémico episódico en los dedos de las manos y los pies, manifestado por palidez, cianosis y rubor de la piel, en respuesta a estímulos como el frío o el estrés emocional” J. Am. Acad. Dermatol. 59 (2008) 633–653 martes, 10 de septiembre de 13 Episodic color changes of the hands and feet in response to cold or stress, known as Raynaud Phenomenon (RP), are a frequent complaint among patients presenting to pediatric rheumatology clinics. The first description of vasomotor instability triggered by cold exposure, or “local asphyxia of the extremities,” is ascribed to A.G. Maurice Raynaud, a French medical student, whose name has become synonymous with this disorder.1 Despite 150 years of clinical observation and basic research, only recently have significant inroads been established to explain the biological basis for this condition and to establish evidence-based therapeutic interventions Thomas Lewis proposed in 1929 that RP was due to “local fault,” rather than a defect in the central nervous system.
  8. 8. Fenómeno de Raynaud Epidemiología Distribución mundial Afecta 3-5% de la población Incidencia 2.2% Fem / 1.5% Masc. Zonas de clima frío* Prevalencia: Fem 1,8-30% / Hombre 4-14% Gemelos Homocigotos 38% Gemelos Heterocigotos 18% Prevalencia: 80-90% de Niños y Adultos con Esclerosis sistémica o EMTC ...y en 10 a 45% de LES... ,,,33% Sjögren... ...20% Dermato o polimiositis ...12.3 - 20% Artritis Reumatoide. Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48 martes, 10 de septiembre de 13 New onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatological evaluation.
  9. 9. Fenómeno de Raynaud Epidemiología Distribución mundial Afecta 3-5% de la población Incidencia 2.2% Fem / 1.5% Masc. Zonas de clima frío* Prevalencia: Fem 1,8-30% / Hombre 4-14% Gemelos Homocigotos 38% Gemelos Heterocigotos 18% Prevalencia: 80-90% de Niños y Adultos con Esclerosis sistémica o EMTC ...y en 10 a 45% de LES... ,,,33% Sjögren... ...20% Dermato o polimiositis ...12.3 - 20% Artritis Reumatoide. Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48 martes, 10 de septiembre de 13 New onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatological evaluation.
  10. 10. Fenómeno de Raynaud Epidemiología Factores de Riesgo Historia Familiar en 25% Sexo Femenino Clima Frío Ocupacion:Vibración Edad en hombres ETOH y Estado Marital en Mujeres Betabloqueadores,TRH Hipertensión arterial Consumo de Tabaco Edad Promedio de presentación 14 años 27% Despúes de los 40 años Inicio - 2 años - 12.6% tendrá enfermedad de tejido conectivo SSc en 15 a 20% si hay Anormalidades capilares de uña + AutoAc al presentarse el FdR Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 martes, 10 de septiembre de 13
  11. 11. Fenómeno de Raynaud Epidemiología Factores de Riesgo Historia Familiar en 25% Sexo Femenino Clima Frío Ocupacion:Vibración Edad en hombres ETOH y Estado Marital en Mujeres Betabloqueadores,TRH Hipertensión arterial Consumo de Tabaco Edad Promedio de presentación 14 años 27% Despúes de los 40 años Inicio - 2 años - 12.6% tendrá enfermedad de tejido conectivo SSc en 15 a 20% si hay Anormalidades capilares de uña + AutoAc al presentarse el FdR Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 martes, 10 de septiembre de 13
  12. 12. Clasificación Fenómeno de Raynaud Clasificación martes, 10 de septiembre de 13
  13. 13. Fenómeno de Raynaud Clasificación F.#Raynaud# Primario# Secundario# Lancet2001;357:2042–48 martes, 10 de septiembre de 13 Raynaud’s phenomenon is classified as primary (formerly Raynaud’s disease) if there is no known underlying illness and secondary (formerly Raynaud’s syndrome) if there is an associated disorder detected upon assessment; the distinction is important, because prognosis, severity, and treatment can all be affected. Many non-inflammatory processes and most systemic rheumatic diseases can be associated with Raynaud’s phenomenon. However, the most frequent association is with systemic sclerosis (scleroderma). Actual prevalence data are incomplete, although Raynaud’s phenomenon is thought to occur in more than 90% of patients with scleroderma, 10–45% with systemic lupus, a third of patients with primary Sjögren’s syndrome, 20% with dermatomyositis or polymyositis, and 10–20% with rheumatoid arthritis.18
  14. 14. Fenómeno de Raynaud Clasificación F.#Raynaud# Primario# Secundario# Lancet2001;357:2042–48 martes, 10 de septiembre de 13 Raynaud’s phenomenon is classified as primary (formerly Raynaud’s disease) if there is no known underlying illness and secondary (formerly Raynaud’s syndrome) if there is an associated disorder detected upon assessment; the distinction is important, because prognosis, severity, and treatment can all be affected. Many non-inflammatory processes and most systemic rheumatic diseases can be associated with Raynaud’s phenomenon. However, the most frequent association is with systemic sclerosis (scleroderma). Actual prevalence data are incomplete, although Raynaud’s phenomenon is thought to occur in more than 90% of patients with scleroderma, 10–45% with systemic lupus, a third of patients with primary Sjögren’s syndrome, 20% with dermatomyositis or polymyositis, and 10–20% with rheumatoid arthritis.18
  15. 15. Fenómeno de Raynaud Clasificación F.#Raynaud# Primario# Secundario# Lancet2001;357:2042–48 martes, 10 de septiembre de 13 Raynaud’s phenomenon is classified as primary (formerly Raynaud’s disease) if there is no known underlying illness and secondary (formerly Raynaud’s syndrome) if there is an associated disorder detected upon assessment; the distinction is important, because prognosis, severity, and treatment can all be affected. Many non-inflammatory processes and most systemic rheumatic diseases can be associated with Raynaud’s phenomenon. However, the most frequent association is with systemic sclerosis (scleroderma). Actual prevalence data are incomplete, although Raynaud’s phenomenon is thought to occur in more than 90% of patients with scleroderma, 10–45% with systemic lupus, a third of patients with primary Sjögren’s syndrome, 20% with dermatomyositis or polymyositis, and 10–20% with rheumatoid arthritis.18
  16. 16. Fenómeno de Raynaud Clasificación F.#Raynaud# Primario# Secundario# Riesgo de progresión a Enf.Tejido Conectivo 2% a 10 años + > 6.3% Landry et al. JVasc Surg 1996; 23: 76–78. Seropositividad Lancet2001;357:2042–48 martes, 10 de septiembre de 13 Raynaud’s phenomenon is classified as primary (formerly Raynaud’s disease) if there is no known underlying illness and secondary (formerly Raynaud’s syndrome) if there is an associated disorder detected upon assessment; the distinction is important, because prognosis, severity, and treatment can all be affected. Many non-inflammatory processes and most systemic rheumatic diseases can be associated with Raynaud’s phenomenon. However, the most frequent association is with systemic sclerosis (scleroderma). Actual prevalence data are incomplete, although Raynaud’s phenomenon is thought to occur in more than 90% of patients with scleroderma, 10–45% with systemic lupus, a third of patients with primary Sjögren’s syndrome, 20% with dermatomyositis or polymyositis, and 10–20% with rheumatoid arthritis.18
  17. 17. Fenómeno de Raynaud Clasificación Primario vs Secundario Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48 martes, 10 de septiembre de 13 Vascular dysfunction in primary RP is, by definition, fully reversible, whereas secondary RP may combine defective function and structural abnormalities. SSc-associated RP fundamentally differs from primary RP because of its associated vasculopathy, involving fibrous intimal proliferation with associated intravascular thrombi.
  18. 18. Fenómeno de Raynaud Clasificación Primario vs Secundario DisfunciónVascular primaria totalmente reversible = Primario Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48 martes, 10 de septiembre de 13 Vascular dysfunction in primary RP is, by definition, fully reversible, whereas secondary RP may combine defective function and structural abnormalities. SSc-associated RP fundamentally differs from primary RP because of its associated vasculopathy, involving fibrous intimal proliferation with associated intravascular thrombi.
  19. 19. Fenómeno de Raynaud Clasificación Primario vs Secundario DisfunciónVascular primaria totalmente reversible = Primario Vasculopatía - Fibrosis - -Proliferación - Trombosis = Secundario (SS) Reumatol Clin. 2006;2 Supl 3:S10-5 Reumatol Clin. 2008;4(2):59-66 / Lancet 2001; 357: 2042–48 martes, 10 de septiembre de 13 Vascular dysfunction in primary RP is, by definition, fully reversible, whereas secondary RP may combine defective function and structural abnormalities. SSc-associated RP fundamentally differs from primary RP because of its associated vasculopathy, involving fibrous intimal proliferation with associated intravascular thrombi.
  20. 20. Fisiopatogenia Fenómeno de Raynaud Patogenia martes, 10 de septiembre de 13
  21. 21. Fenómeno de Raynaud Patogenia Fisiopatogenia & Fenómeno de Raynaud Primario martes, 10 de septiembre de 13
  22. 22. Fenómeno de Raynaud Patogenia GENÉTICA ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646 martes, 10 de septiembre de 13 The most significant evidence of linkage was seen for D6S261, which satisfies the Lander and Kruglyak criteria for suggestive linkage Only one potential candidate gene, the Beta subunit of the muscle acetylcholine receptor, was found to map to within the 5 areas of possible linkage. Outside these areas were 2 further candidate genes, the serotonin 1B and 1E receptors linkage at D6S261. The fact that 5 areas of possible linkage have been found indicates that primary RP may be an oligogenic condition, although the findings in some of the areas may be false positive Using the likelihood ratio test to compare the 2 models, HoLOD and HeLOD were found to significantly differ at D9S156 (P < 0.0003), D17S1791 (P < 0.007), and D7S664 (P < 0.04), indicating evidence of genetic heterogeneity at these loci. This finding indicates that the genetic basis to primary RP may vary between individuals. Objective. To identify chromosomal regions con- taining genes involved in the susceptibility to primary Raynaud’s phenomenon (RP). Methods. Six extended families with multiple individuals affected with primary RP (n = 37) were examined for linkage in a 2-stage, whole-genome screen, using a total of 298 microsatellite markers. Results. Multipoint, nonparametric linkage analysis identified 5 areas of possible linkage, with a nominal level of significance of P < 0.05. Analysis of a finer map of markers in these regions defined the regions of linkage as 21.4 cM on 6q13–6q23.3 (D6S261; P < 0.0004), 10.2 cM on 7p22–7p15 (D7S664; P < 0.014), 1.6 cM on 9p23–9p22 (D9S156; P < 0.0075), 5.1 cM on 17p13.1–17p12 (D17S1791; P < 0.036), and 11.8 cM on Xp11.4–Xp11.23 (DXS8054; P < 0.006). Three potential candidate genes map to these regions: the B subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors. Conclusion. These results provide evidence of the presence and location of genes that are involved in the genetic susceptibility to primary RP.
  23. 23. Fenómeno de Raynaud Patogenia GENÉTICA ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646 martes, 10 de septiembre de 13 The most significant evidence of linkage was seen for D6S261, which satisfies the Lander and Kruglyak criteria for suggestive linkage Only one potential candidate gene, the Beta subunit of the muscle acetylcholine receptor, was found to map to within the 5 areas of possible linkage. Outside these areas were 2 further candidate genes, the serotonin 1B and 1E receptors linkage at D6S261. The fact that 5 areas of possible linkage have been found indicates that primary RP may be an oligogenic condition, although the findings in some of the areas may be false positive Using the likelihood ratio test to compare the 2 models, HoLOD and HeLOD were found to significantly differ at D9S156 (P < 0.0003), D17S1791 (P < 0.007), and D7S664 (P < 0.04), indicating evidence of genetic heterogeneity at these loci. This finding indicates that the genetic basis to primary RP may vary between individuals. Objective. To identify chromosomal regions con- taining genes involved in the susceptibility to primary Raynaud’s phenomenon (RP). Methods. Six extended families with multiple individuals affected with primary RP (n = 37) were examined for linkage in a 2-stage, whole-genome screen, using a total of 298 microsatellite markers. Results. Multipoint, nonparametric linkage analysis identified 5 areas of possible linkage, with a nominal level of significance of P < 0.05. Analysis of a finer map of markers in these regions defined the regions of linkage as 21.4 cM on 6q13–6q23.3 (D6S261; P < 0.0004), 10.2 cM on 7p22–7p15 (D7S664; P < 0.014), 1.6 cM on 9p23–9p22 (D9S156; P < 0.0075), 5.1 cM on 17p13.1–17p12 (D17S1791; P < 0.036), and 11.8 cM on Xp11.4–Xp11.23 (DXS8054; P < 0.006). Three potential candidate genes map to these regions: the B subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors. Conclusion. These results provide evidence of the presence and location of genes that are involved in the genetic susceptibility to primary RP.
  24. 24. Fenómeno de Raynaud Patogenia GENÉTICA ARTHRITIS & RHEUMATISM , 43,(7),2000, pp 1641–1646 martes, 10 de septiembre de 13 The most significant evidence of linkage was seen for D6S261, which satisfies the Lander and Kruglyak criteria for suggestive linkage Only one potential candidate gene, the Beta subunit of the muscle acetylcholine receptor, was found to map to within the 5 areas of possible linkage. Outside these areas were 2 further candidate genes, the serotonin 1B and 1E receptors linkage at D6S261. The fact that 5 areas of possible linkage have been found indicates that primary RP may be an oligogenic condition, although the findings in some of the areas may be false positive Using the likelihood ratio test to compare the 2 models, HoLOD and HeLOD were found to significantly differ at D9S156 (P < 0.0003), D17S1791 (P < 0.007), and D7S664 (P < 0.04), indicating evidence of genetic heterogeneity at these loci. This finding indicates that the genetic basis to primary RP may vary between individuals. Objective. To identify chromosomal regions con- taining genes involved in the susceptibility to primary Raynaud’s phenomenon (RP). Methods. Six extended families with multiple individuals affected with primary RP (n = 37) were examined for linkage in a 2-stage, whole-genome screen, using a total of 298 microsatellite markers. Results. Multipoint, nonparametric linkage analysis identified 5 areas of possible linkage, with a nominal level of significance of P < 0.05. Analysis of a finer map of markers in these regions defined the regions of linkage as 21.4 cM on 6q13–6q23.3 (D6S261; P < 0.0004), 10.2 cM on 7p22–7p15 (D7S664; P < 0.014), 1.6 cM on 9p23–9p22 (D9S156; P < 0.0075), 5.1 cM on 17p13.1–17p12 (D17S1791; P < 0.036), and 11.8 cM on Xp11.4–Xp11.23 (DXS8054; P < 0.006). Three potential candidate genes map to these regions: the B subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors. Conclusion. These results provide evidence of the presence and location of genes that are involved in the genetic susceptibility to primary RP.
  25. 25. Mecanismos Patogénicos Intravascular+ Neural+ Vascular+ Fenómeno de Raynaud Patogenia VasoconstricciónVasodilatación Rheumatology (Oxford) 45 (2006) iii33–35. N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291 martes, 10 de septiembre de 13 In broad terms, blood flow volume is regulated by an interactive system involving neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds. The inherent tone, or contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high basal tone in the coronary circulation to low or absent in the pulmonary circulation, and it can increase or decrease dramatically Numerous mechanisms participate in the regulation of vascular tone, including both intrinsic functions of vascular smooth muscle and endothelial cells, and extrinsic effects of nerves, adjacent tissues, circulating cells, and soluble factors
  26. 26. Mecanismos Patogénicos Intravascular+ Neural+ Vascular+ Fenómeno de Raynaud Patogenia VasoconstricciónVasodilatación Rheumatology (Oxford) 45 (2006) iii33–35. N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291 martes, 10 de septiembre de 13 In broad terms, blood flow volume is regulated by an interactive system involving neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds. The inherent tone, or contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high basal tone in the coronary circulation to low or absent in the pulmonary circulation, and it can increase or decrease dramatically Numerous mechanisms participate in the regulation of vascular tone, including both intrinsic functions of vascular smooth muscle and endothelial cells, and extrinsic effects of nerves, adjacent tissues, circulating cells, and soluble factors
  27. 27. Mecanismos Patogénicos Intravascular+ Neural+ Vascular+ Fenómeno de Raynaud Patogenia VasoconstricciónVasodilatación Respuesta vasomotora local excesiva: frío, calor y estrés emocional Rheumatology (Oxford) 45 (2006) iii33–35. N. Engl. J. Med. 347 (2002) 1001–1008./ Rheum. Dis. Clin. North. Am. 29 (2003) 275–291 martes, 10 de septiembre de 13 In broad terms, blood flow volume is regulated by an interactive system involving neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds. The inherent tone, or contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high basal tone in the coronary circulation to low or absent in the pulmonary circulation, and it can increase or decrease dramatically Numerous mechanisms participate in the regulation of vascular tone, including both intrinsic functions of vascular smooth muscle and endothelial cells, and extrinsic effects of nerves, adjacent tissues, circulating cells, and soluble factors
  28. 28. Fenómeno de Raynaud Patogenia Nat. Rev Rheumatol. 8, 469–479 (2012) Valerio-Morales IA 2013 VASCULAR INTRAVASCULARNEURAL OTROS martes, 10 de septiembre de 13
  29. 29. Fenómeno de Raynaud Patogenia Nat. Rev Rheumatol. 8, 469–479 (2012) Valerio-Morales IA 2013 VASCULAR INTRAVASCULARNEURAL OTROS Endotelio Prostaciclina NO Endotelina-1* Angiotensinogeno* *.-Profibrótico sobreexpresado en SSc Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos Músculo Liso martes, 10 de septiembre de 13
  30. 30. Vía autonómica Vía Sensorial Receptores alfa- adrenérgicos* Regulan(Vasos( 1-Simpático: (Norepi) 2- Parasimpático (Sustancia P,VIP, CGRP, NKA) 3- Sensitivas 4 - SNC Fenómeno de Raynaud Patogenia Nat. Rev Rheumatol. 8, 469–479 (2012) Valerio-Morales IA 2013 VASCULAR INTRAVASCULARNEURAL OTROS Endotelio Prostaciclina NO Endotelina-1* Angiotensinogeno* *.-Profibrótico sobreexpresado en SSc Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos Músculo Liso martes, 10 de septiembre de 13
  31. 31. Vía autonómica Vía Sensorial Receptores alfa- adrenérgicos* Regulan(Vasos( 1-Simpático: (Norepi) 2- Parasimpático (Sustancia P,VIP, CGRP, NKA) 3- Sensitivas 4 - SNC Fenómeno de Raynaud Patogenia Nat. Rev Rheumatol. 8, 469–479 (2012) Valerio-Morales IA 2013 VASCULAR INTRAVASCULARNEURAL OTROS Endotelio Prostaciclina NO Endotelina-1* Angiotensinogeno* *.-Profibrótico sobreexpresado en SSc Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos Músculo Liso + Adhesión plaquetaria/ activación Fibrinólisis Defectuosa! +Trombina +Viscosidad sanguínea Vasoconstrictores Serotonina TGF-B PDGF Profibrosis martes, 10 de septiembre de 13
  32. 32. Vía autonómica Vía Sensorial Receptores alfa- adrenérgicos* Regulan(Vasos( 1-Simpático: (Norepi) 2- Parasimpático (Sustancia P,VIP, CGRP, NKA) 3- Sensitivas 4 - SNC Fenómeno de Raynaud Patogenia Nat. Rev Rheumatol. 8, 469–479 (2012) Valerio-Morales IA 2013 VASCULAR INTRAVASCULARNEURAL OTROS Endotelio Prostaciclina NO Endotelina-1* Angiotensinogeno* *.-Profibrótico sobreexpresado en SSc Proliferación Contracción-relajación Agregación plaquetaria Baja Adhesión Leucos Músculo Liso + Adhesión plaquetaria/ activación Fibrinólisis Defectuosa! +Trombina +Viscosidad sanguínea Vasoconstrictores Serotonina TGF-B PDGF Profibrosis Endocrino: Estrógenos – R-Alfa adrenérgicos Hematológico:Viscosidad +, Deformabilidad - martes, 10 de septiembre de 13
  33. 33. Fenómeno de Raynaud Patogenia Nat. Rev Rheumatol. 8, 469–479 (2012) Valerio-Morales IA 2013 Dedos/Piel* Distal* +(Alfa1R)* Serotonina/ TXA* Isquemia/ Frío!ROS* Rho/Rho1K* Vía Rho-Kinasa -  Amplifica Respuesta del Músculo Liso al Frío -  Induce expresión de R- Alfa Adrenérgicos 2c -  Sensibiliza fibras contrátiles al Ca+ martes, 10 de septiembre de 13
  34. 34. Fenómeno de Raynaud Patogenia Factores Involucrados en la patogenia del Fenómeno de Raynaud Primario Reumatol Clin. 2006;2 Supl 3:S10-5 martes, 10 de septiembre de 13
  35. 35. Fenómeno de Raynaud Patogenia Factores Involucrados en la patogenia del Fenómeno de Raynaud Primario Reumatol Clin. 2006;2 Supl 3:S10-5 martes, 10 de septiembre de 13
  36. 36. Fenómeno de Raynaud Patogenia Factores Involucrados en la patogenia del Fenómeno de Raynaud Primario Reumatol Clin. 2006;2 Supl 3:S10-5 martes, 10 de septiembre de 13
  37. 37. Fenómeno de Raynaud Patogenia Factores Involucrados en la patogenia del Fenómeno de Raynaud Primario Reumatol Clin. 2006;2 Supl 3:S10-5 martes, 10 de septiembre de 13
  38. 38. Fenómeno de Raynaud Patogenia Factores Involucrados en la patogenia del Fenómeno de Raynaud Primario Reumatol Clin. 2006;2 Supl 3:S10-5 martes, 10 de septiembre de 13
  39. 39. Fenómeno de Raynaud Patogenia Factores Involucrados en la patogenia del Fenómeno de Raynaud Primario Reumatol Clin. 2006;2 Supl 3:S10-5 martes, 10 de septiembre de 13
  40. 40. Fenómeno de Raynaud Patogenia DisfunciónVascular & Espectro Esclerosis Sistémica martes, 10 de septiembre de 13 Systemic sclerosis (ssc) is a connective tissue and autoimmune disease of unknown etiology that affects various organ systems, including the lungs, heart, gastrointestinal tract and kidneys.1 the three major features of ssc are systemic vascular dysfunction, the presence of mononuclear cell infiltrates and connective tissue fibrosis
  41. 41. Fenómeno de Raynaud Patogenia & SSc Fibroblasto* Endotelio* miRNA* S.*Inmunológico* Estrés* Oxida=vo* Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010) martes, 10 de septiembre de 13 Cellular and molecular pathways underlying fibrosis in systemic sclerosis. Injury caused by viruses, autoantibodies, ischemia‐reperfusion or toxins triggers vascular damage and inflammation. Activated inflammatory cells secrete cytokines and growth factors. Endothelial injury results in generation of ROS, intravascular coagulation and platelet activation with release of serotonin, vasoactive mediators, thrombin and platelet‐derived growth factor, and sets in motion progressive vascular remodeling leading to luminal occlusion, reduced blood flow and tissue hypoxia. Secreted mediators, such as TGF‐β and Wnt10b, cause fibroblast activation and differentiation into myofibroblasts, which produce excess amounts of collagen, contract and remodel the connective tissue, and resist elimination by apoptosis. The stiff and hypoxic ECM of the fibrotic tissue further activates myofibroblasts. Injury also directly induces transdifferentiation of pericytes, epithelial cells and endothelial cells into myofibroblasts, expanding the tissue pool of matrix‐synthesizing, activated myofibroblasts. Abbreviations: CXCL12, CXC‐chemokine ligand 12; CXCR4, CXC‐chemokine receptor 4; ECM, extracellular matrix; IFN, interferon; ROS, reactive oxygen species; TGF‐β, transforming growth factor β; TH2 cell, type 2 helper T cell; TLR, Toll‐like receptor.
  42. 42. Fenómeno de Raynaud Patogenia & SSc Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010) martes, 10 de septiembre de 13 Cellular and molecular pathways underlying fibrosis in systemic sclerosis. Injury caused by viruses, autoantibodies, ischemia‐reperfusion or toxins triggers vascular damage and inflammation. Activated inflammatory cells secrete cytokines and growth factors. Endothelial injury results in generation of ROS, intravascular coagulation and platelet activation with release of serotonin, vasoactive mediators, thrombin and platelet‐derived growth factor, and sets in motion progressive vascular remodeling leading to luminal occlusion, reduced blood flow and tissue hypoxia. Secreted mediators, such as TGF‐β and Wnt10b, cause fibroblast activation and differentiation into myofibroblasts, which produce excess amounts of collagen, contract and remodel the connective tissue, and resist elimination by apoptosis. The stiff and hypoxic ECM of the fibrotic tissue further activates myofibroblasts. Injury also directly induces transdifferentiation of pericytes, epithelial cells and endothelial cells into myofibroblasts, expanding the tissue pool of matrix‐synthesizing, activated myofibroblasts. Abbreviations: CXCL12, CXC‐chemokine ligand 12; CXCR4, CXC‐chemokine receptor 4; ECM, extracellular matrix; IFN, interferon; ROS, reactive oxygen species; TGF‐β, transforming growth factor β; TH2 cell, type 2 helper T cell; TLR, Toll‐like receptor.
  43. 43. Fenómeno de Raynaud Patogenia & SSc Trojanowska, M. Nat. Rev. Rheumatol. 6, 453–460 (2010) martes, 10 de septiembre de 13
  44. 44. Fenómeno de Raynaud Patogenia & SSc Gabrielli A et al. N Engl J Med 2009;360:1989-2003. martes, 10 de septiembre de 13 Figure 4. Lesions in Different Stages of Scleroderma.  As shown in Panel A, microvascular injury is one of the early events in the pathogenesis of scleroderma and is characterized by endothelial-cell damage, the proliferation of basal-lamina layers, occasional entrapment of peripheral-blood mononuclear cells in the vessel wall, and initial perivascular mononuclear-cell infiltrates. Endothelial cells show signs of increased programmed cell death. One or more reactive oxygen species (ROS)–generating triggering agents could be responsible for this stage. ROS may be generated inside the vascular lumen by peripheral-blood cells or within the vessel wall by macrophages, endothelial cells, vascular smooth-muscle cells, or adventitial fibroblasts in response to one or more noxious agents. Although low levels of ROS are necessary for normal vascular function, excessive production is responsible for functional and structural damage. As shown in Panel B, uncontrolled production of ROS activates local mesenchymal cells, inducing chemotaxis, proliferation, extracellular-matrix production, and the release of cytokines and growth factors that amplify the inflammatory focus. An autocrine circuitry (Ha-Ras–extracellular-signal–regulated kinases 1 and 2 [ERK1/2]/ROS) maintains ROS at levels that are high because of the reduced turnover of cytokine receptors. Structural and functional abnormalities of vessel walls and intravascular changes occur, leading to overt clinical symptoms. As shown in Panel C, the next stage is dominated by fibrosis, derangement of visceral-organ architecture, rarefaction of blood vessels, and consequently, hypoxia, which contributes to the maintenance of fibrosis. As shown in Panel D, once the single or multiple mechanisms responsible for mesenchymal-cell activation subside or recede or mesenchymal cells themselves undergo senescence or apoptosis, 81 the disease burns out. The clinical picture is dominated by internal-organ derangement. Triggering, amplifying, and maintenance factors are not necessarily confined to a single stage. Environmental, local, and genetic factors can influence the disease progression. In the inset, coupling of the NADPH oxidase to the glutathione (GSH) cycle is shown. Glucose metabolism, in particular G6PD, generates NADPH/H+, which is rapidly oxidized by NADPH oxidase enzymes to NADP+ H+-e-. H+ enters the GSH cycle: oxidized GSH (GSSG) is reduced by GSH reductase (GRH) to GSH, which is oxidized back to GSSG by GSH peroxidase. This enzyme uses as a preferred substrate H2O2 (2GSH+H2O2→GS–SG+2H2O), produced by SOD and superoxide generated by the NADPH oxidase cycle. GSH is synthesized from amino acids by the enzyme γ-glutamyl-cysteine synthetase, a rate-limiting reaction, which is tightly dependent on ATP. ATP depletion reduces GSH synthesis, increases peroxides, and unleashes the NADPH oxidase cycle, which generates a large excess of ROS, unbuffered by GSH.
  45. 45. Fenómeno de Raynaud Patogenia & SSc Indian Journal of Dermatology 2013; 58(4) martes, 10 de septiembre de 13 Si bien esta diapositiva explica de manera general la fisiopatogenia de la esclerosis sistémica, vamos a entrar en detalle en aquellos fenómenos descritos en la génesis y perpetuación del daño vascular y desrregulacion en Esclerosis sistémica, lo que nos llevará a abordar estos cuatro aspectos fundamentales involucrados en la vasculopatía de SSc.: Angiogénesis defectuosa Misma que debemos acoplar al ulterior desarrollo de fibrosis y la participación de las celulas mesenquimatosas, fibroblastos, matriz extracelular agregadas a los demás mecanismos esquematizados en la imagen.
  46. 46. Fenómeno de Raynaud Patogenia & SSc Angiogenesis defectuosa Vasculopatía-Fibrosis Cel. Mesenquimatosas Matriz Extracelular Indian Journal of Dermatology 2013; 58(4) martes, 10 de septiembre de 13 Si bien esta diapositiva explica de manera general la fisiopatogenia de la esclerosis sistémica, vamos a entrar en detalle en aquellos fenómenos descritos en la génesis y perpetuación del daño vascular y desrregulacion en Esclerosis sistémica, lo que nos llevará a abordar estos cuatro aspectos fundamentales involucrados en la vasculopatía de SSc.: Angiogénesis defectuosa Misma que debemos acoplar al ulterior desarrollo de fibrosis y la participación de las celulas mesenquimatosas, fibroblastos, matriz extracelular agregadas a los demás mecanismos esquematizados en la imagen.
  47. 47. ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Pericitos Stem Cell Miofibroblasto PLT T Fibroblasto B CP Fenómeno de Raynaud Patogenia & SSc martes, 10 de septiembre de 13 Como ya se comentó la SSc es unica dentro del espectro de las enfermedades reumáticas debido al depósito acelerado de colageno y fibrosis tisular. En esta diapositiva abordo los aspectos mas representativos en cuanto a la afectación vascular por SSc se refiere.
  48. 48. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  49. 49. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  50. 50. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  51. 51. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Microscopía electrónica: 1) Huecos 2)Vacuolización/apoptosis 3) Infiltrado perivascular inflamatorio 4) Fibroblastos y pericitos con prominentes RER 5) Fibrosis perivascular Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  52. 52. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Microscopía electrónica: 1) Huecos 2)Vacuolización/apoptosis 3) Infiltrado perivascular inflamatorio 4) Fibroblastos y pericitos con prominentes RER 5) Fibrosis perivascular Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  53. 53. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Microscopía electrónica: 1) Huecos 2)Vacuolización/apoptosis 3) Infiltrado perivascular inflamatorio 4) Fibroblastos y pericitos con prominentes RER 5) Fibrosis perivascular Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  54. 54. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Microscopía electrónica: 1) Huecos 2)Vacuolización/apoptosis 3) Infiltrado perivascular inflamatorio 4) Fibroblastos y pericitos con prominentes RER 5) Fibrosis perivascular Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  55. 55. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Microscopía electrónica: 1) Huecos 2)Vacuolización/apoptosis 3) Infiltrado perivascular inflamatorio 4) Fibroblastos y pericitos con prominentes RER 5) Fibrosis perivascular Fenotipo que Define Vasculopatía en esclerodermia: - Pérdida de Caderina endotelial - Sobreexpresión de RGS5 Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  56. 56. Fenómeno de Raynaud Patogenia & SSc CAPA MUSCULAR (MEDIA) ADVENTICIA ENDOTELIO: PDGF, Endoteilna-1, Selectinas, Integrinas, NO, Prostaciclina Microscopía electrónica: 1) Huecos 2)Vacuolización/apoptosis 3) Infiltrado perivascular inflamatorio 4) Fibroblastos y pericitos con prominentes RER 5) Fibrosis perivascular Fenotipo que Define Vasculopatía en esclerodermia: - Pérdida de Caderina endotelial - Sobreexpresión de RGS5 Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelial cells: The endothelium is a metabolically active tissue that, under normal circumstances, regulates regional blood flow, transportation of nutrients, regulating coagulation and fibrinolysis, and migration of blood cells while maintaining an antithrombotic lining in the vasculature. These important biologic functions are achieved through production of a complex array of molecules including vasodilators (e.g., nitric oxide and prostacyclin), vasoconstrictors (e.g., endo- thelin-1 and platelet-activating factor), and cell adhesion molecules (e.g., selectins and integrins). Electron micros- copy studies from skin biopsy specimens of patients demonstrate capillaries with thickening of the basement lamina and endothelial cells with a round or oval nucleus, cytoplasm filled with intermediate filaments, swelling of the mitochondria, smooth vesicles, and remnants of endoplasmic reticulum suggestive of damaged endothelial cells. The lumen of vessels was narrowed by endothelial cells, granular material, and platelets [77]. While light microscopy showed normal endothelial cells, other studies reported an increase in the number of cytoplasmic intermediate filaments, reduced numbers of micropincytic vesicles, and luminal surface blebs [79, 80]. These findings are reminiscent of cells undergoing apo- ptosis. Perivascular edema was noted. These investigators suggested that endothelial injury was an early event in scleroderma preceding other tissue changes because vascu- lar disease was seen in early skin lesions before tissue fibrosis. [3H]Thymidine labeling of dermal tissue demon- strates increased labeling of endothelial cells consistent with perturbation of this cell layer [81, 82]. Basement membrane of capillaries is thickened and displays evidence for increased fibronectin, collagen type IV, and laminin [78]. The main alterations seen by electron microscopy from studies of capillaries can be summarized as (1) gaps, vacuolization, and eventual destruction of endothelial cells, (2) reduplication of the basal lamina, (3) perivascular cellular infiltrates consisting of lymphocytes, plasma cells, macrophages, or monocytes, and (4) fibroblasts and pericytes with enlarged, rough endoplasmic reticulum accompanied by perivascular fibrosis [83]. These studies suggested that the endothelial cells are being injured in scleroderma, and there is a perivascular cellular reaction underway involving immune cells and fibroblasts, a vascular–cellular interaction that precedes the later stage of tissue fibrosis. Skin biopsies were studied to define the biological phenotype of scleroderma endothelial cells and the potential associated cause of the loss of capillaries. The molecules defining the scleroderma phenotype was the loss of vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation, and overexpression of antiangiogenic interferon alpha and overexpression of RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis
  57. 57. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Antiangiogenicos Proangiogenicos VEGF Procoagulates/ Fibrinolísis Vasodilatadores Vasoconstrictores Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 The downstream effects of blood vessel perturbation produce “biomarkers” of vascular damage. Endothelial cell injury results in an increased production of cytokines like endothelin-1 or impaired release of vasoactive molecules like nitric oxide (NO) and prostacyclin. This creates an imbalance of factors that regulate local blood flow and thus contributes to vascular instability seen in scleroderma. Activation of endothelial cells may also tip the balance of intravascular coagulation/fibrinolysis in favor of coagula- tion, alter release of vasoactive molecules, and trigger the release of growth, profibrotic, and angiogenic factors. The disturbance in the vascular tissue has been detected by measuring circulating markers of vascular disease [85]. Studies of the peripheral blood involving series of scleroderma patients demonstrate abnormalities in factors and other markers of vascular perturbation including: von Willebrand factor; circulating endothelin-1, soluble adhe- sion molecules, thrombospondin, thrombomodulin (TM), circulating endothelial cells, N-terminal pro-brain natriuretic peptide, antiendothelial cell antibodies, serum vascular endothelial growth factor (VEGF), endostatin, plasminogen activator, prostacyclin and thromboxane metabolites. Evidence for endothelial cell dysfunction using skin biopsy material is also reported. For example, studies of patient skin samples demonstrated platelet adhesion, decreased storage of factor VII-related antigen, and altered vessel morphology
  58. 58. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Antiangiogenicos Proangiogenicos VEGF Procoagulates/ Fibrinolísis Vasodilatadores Vasoconstrictores Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 The downstream effects of blood vessel perturbation produce “biomarkers” of vascular damage. Endothelial cell injury results in an increased production of cytokines like endothelin-1 or impaired release of vasoactive molecules like nitric oxide (NO) and prostacyclin. This creates an imbalance of factors that regulate local blood flow and thus contributes to vascular instability seen in scleroderma. Activation of endothelial cells may also tip the balance of intravascular coagulation/fibrinolysis in favor of coagula- tion, alter release of vasoactive molecules, and trigger the release of growth, profibrotic, and angiogenic factors. The disturbance in the vascular tissue has been detected by measuring circulating markers of vascular disease [85]. Studies of the peripheral blood involving series of scleroderma patients demonstrate abnormalities in factors and other markers of vascular perturbation including: von Willebrand factor; circulating endothelin-1, soluble adhe- sion molecules, thrombospondin, thrombomodulin (TM), circulating endothelial cells, N-terminal pro-brain natriuretic peptide, antiendothelial cell antibodies, serum vascular endothelial growth factor (VEGF), endostatin, plasminogen activator, prostacyclin and thromboxane metabolites. Evidence for endothelial cell dysfunction using skin biopsy material is also reported. For example, studies of patient skin samples demonstrated platelet adhesion, decreased storage of factor VII-related antigen, and altered vessel morphology
  59. 59. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Procoagulates/ Fibrinolísis Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Von Willebrand factor An increased Von Willebrand factor activity and factor VIII/von Willebrand factor (fVIII/vWf) antigen concentra- tions are reported in patients with scleroderma [86–89]. Higher circulating levels of both activities are thought to reflect in vivo endothelial injury [86]. Skin biopsies from patients were studied using immunohistochemistry demon- strating that vWf is leaked to the perivascular space/matrix and thus available for release into the systemic circulation [90]. Indicators of endothelial injury were further implied when patients with scleroderma were found to have abnormal levels of vWf, circulating levels of immune complexes, and oxidized lipoproteins
  60. 60. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Procoagulates/ Fibrinolísis VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ VwF$ Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Von Willebrand factor An increased Von Willebrand factor activity and factor VIII/von Willebrand factor (fVIII/vWf) antigen concentra- tions are reported in patients with scleroderma [86–89]. Higher circulating levels of both activities are thought to reflect in vivo endothelial injury [86]. Skin biopsies from patients were studied using immunohistochemistry demon- strating that vWf is leaked to the perivascular space/matrix and thus available for release into the systemic circulation [90]. Indicators of endothelial injury were further implied when patients with scleroderma were found to have abnormal levels of vWf, circulating levels of immune complexes, and oxidized lipoproteins
  61. 61. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Procoagulates/ Fibrinolísis Secundaria a Activación endotelial Liberan PDGF y TGF-Beta Beta-tromboglobulina, Tromboxano Quimioatracción leucocitaria Complejos plaqueta-Leucocito PLT Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Platelet activation It is apparent that in vivo platelet activation in sclero- derma is secondary to endothelial activation [103]. Activated platelets release a host of vasoactive and profibrotic factors that mediate vasoconstriction, platelet aggregation, leukocyte chemoattraction, activation of interstitial fibroblasts, and proliferation of myointimal cells. Among these platelet products, platelet-derived growth factor (PDGF) and TGF-β, in particular, are thought to play an important role in the biology of scleroderma by promoting increased production and deposition of extracellular matrix. Several studies give evidence for activation of platelets in scleroderma includ- ing elevated levels of circulating platelet aggregates, increased plasma levels of β-thromboglobulin, enhanced adhesion of scleroderma derived platelets, increased circulating microparticles containing platelet fragments, increased circulating platelet–leukocyte complexes, and increased urinary levels of thromboxane likely derive from activated platelets
  62. 62. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Procoagulates/ Fibrinolísis VwF$ VwF$ VwF$ Activación Plaquetaria Secundaria a Activación endotelial Liberan PDGF y TGF-Beta Beta-tromboglobulina, Tromboxano Quimioatracción leucocitaria Complejos plaqueta-Leucocito PLT Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Platelet activation It is apparent that in vivo platelet activation in sclero- derma is secondary to endothelial activation [103]. Activated platelets release a host of vasoactive and profibrotic factors that mediate vasoconstriction, platelet aggregation, leukocyte chemoattraction, activation of interstitial fibroblasts, and proliferation of myointimal cells. Among these platelet products, platelet-derived growth factor (PDGF) and TGF-β, in particular, are thought to play an important role in the biology of scleroderma by promoting increased production and deposition of extracellular matrix. Several studies give evidence for activation of platelets in scleroderma includ- ing elevated levels of circulating platelet aggregates, increased plasma levels of β-thromboglobulin, enhanced adhesion of scleroderma derived platelets, increased circulating microparticles containing platelet fragments, increased circulating platelet–leukocyte complexes, and increased urinary levels of thromboxane likely derive from activated platelets
  63. 63. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Procoagulates/ Fibrinolísis Interacciones: Cel-Cel Cel-Matriz E- Selectina / P-Selectina Mol. de Adhesión Celular 1 Integrinas: B-1 y B-4 ELAM-1/ sELAM-1 ICAM-1/ sICAM-1 VCAM-1 / sICAM-1 Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Adhesion molecules Another marker of vascular disease is the presence of adhesion proteins involved in cell–cell interaction and cell– matrix interactions that are found elevated in scleroderma skin, especially in perivascular infiltrates. Isolated microvascular endothelial cells express adhesion molecules E-selectin, intercellular adhesion molecule-1, and beta-1 and beta-4 integrin receptors in cell culture [113]. The endothelial leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule (VCAM-1), E-selectin, and P- selectin are found in endothelial cells in skin from patients with rapidly progressive scleroderma but not in normal skin. The soluble form of endothelial leukocyte adhesion molecule-1 (sELAM) is also reported elevated in scleroderma . Soluble intercellular adhesion molecule-1 and soluble interleukin-2 receptors were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volun- teers, providing evidence for activation of endothelial cells and CD3-positive cells, T cells in scleroderma patients. Several other reports confirm that increased circulating sICAM-1, sVCAM-1, P-selectin, and E-selectin occur in scleroderma compared to controls To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, sVCAM-1, soluble E-selectin, VEGF, and ET-1 were determined to be elevated in scleroderma patients who had significant organ involvement. Interestingly, a study of subtypes of scleroderma suggests that injury to the pulmonary and renal vascular may have distinct mechanisms. In patients with scleroderma renal crisis, the level of E-selectin, sVCAM-1, and sICAM-1 were elevated, but they were not consistently elevated in patients with pulmonary hypertension
  64. 64. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Procoagulates/ Fibrinolísis Moléculas de Adhesión Interacciones: Cel-Cel Cel-Matriz E- Selectina / P-Selectina Mol. de Adhesión Celular 1 Integrinas: B-1 y B-4 ELAM-1/ sELAM-1 ICAM-1/ sICAM-1 VCAM-1 / sICAM-1 Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Adhesion molecules Another marker of vascular disease is the presence of adhesion proteins involved in cell–cell interaction and cell– matrix interactions that are found elevated in scleroderma skin, especially in perivascular infiltrates. Isolated microvascular endothelial cells express adhesion molecules E-selectin, intercellular adhesion molecule-1, and beta-1 and beta-4 integrin receptors in cell culture [113]. The endothelial leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule (VCAM-1), E-selectin, and P- selectin are found in endothelial cells in skin from patients with rapidly progressive scleroderma but not in normal skin. The soluble form of endothelial leukocyte adhesion molecule-1 (sELAM) is also reported elevated in scleroderma . Soluble intercellular adhesion molecule-1 and soluble interleukin-2 receptors were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volun- teers, providing evidence for activation of endothelial cells and CD3-positive cells, T cells in scleroderma patients. Several other reports confirm that increased circulating sICAM-1, sVCAM-1, P-selectin, and E-selectin occur in scleroderma compared to controls To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, sVCAM-1, soluble E-selectin, VEGF, and ET-1 were determined to be elevated in scleroderma patients who had significant organ involvement. Interestingly, a study of subtypes of scleroderma suggests that injury to the pulmonary and renal vascular may have distinct mechanisms. In patients with scleroderma renal crisis, the level of E-selectin, sVCAM-1, and sICAM-1 were elevated, but they were not consistently elevated in patients with pulmonary hypertension
  65. 65. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Vasoconstrictores ET-1 ET-1 ET-1 Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelin-1 Endothelin-1 is a 21-amino-acid peptide with potent vasoconstrictive and proliferative effects that could mediate vascular injury and tissue fibrosis in scleroderma [92, 93]. Endothelin-1 released from the endothelial cells can act on vascular smooth muscle cells potentially inducing the expression of vascular myofibroblast. It can also act in an autocrine manner on the vascular endothelium itself. There are multiple sources of ET-1 in addition to endothelial cells including macrophages, epithelial cells, and mesenchymal cells. Enothelin-1 is elevated in the plasma of patients compared to controls, and it increases during cold exposure in selected scleroderma patients [94]. Endothelin-1 is found in association with high levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin in the blood of scleroderma patients [95–100]. The localiza- tion of ET-1 on specimens obtained by skin biopsies find that ET-1 deposits in the endothelial cells and dermal fibroblasts and has a positive correlation with the serum levels of ET-1 [101]. Another study found a significant increase of ET-1, tissue-type plasminogen, plasminogen activator inhibitor, transforming growth factor-beta, and β- thromboglobulin in patients with scleroderma suggesting both involvement of endothelial cells and associated platelet activation [102]. Elevated ET-1 is not only a biomarker of vascular disease, but may itself be causing abnormal vascular reactivity and mediating tissue fibrosis by its pro-fibrotic properties via activating TGF-β. Therefore, inhibiting ET-1 activity is considered an attractive target in treating scleroderma vascular disease
  66. 66. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA VasoconstrictoresENDOTELINA-1 ET-1 ET-1 ET-1 Fuentes de endotelina: - Cel. Endotelial - Macrofago - Cel. Epiteliales - Cel. Mesenquimales Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelin-1 Endothelin-1 is a 21-amino-acid peptide with potent vasoconstrictive and proliferative effects that could mediate vascular injury and tissue fibrosis in scleroderma [92, 93]. Endothelin-1 released from the endothelial cells can act on vascular smooth muscle cells potentially inducing the expression of vascular myofibroblast. It can also act in an autocrine manner on the vascular endothelium itself. There are multiple sources of ET-1 in addition to endothelial cells including macrophages, epithelial cells, and mesenchymal cells. Enothelin-1 is elevated in the plasma of patients compared to controls, and it increases during cold exposure in selected scleroderma patients [94]. Endothelin-1 is found in association with high levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin in the blood of scleroderma patients [95–100]. The localiza- tion of ET-1 on specimens obtained by skin biopsies find that ET-1 deposits in the endothelial cells and dermal fibroblasts and has a positive correlation with the serum levels of ET-1 [101]. Another study found a significant increase of ET-1, tissue-type plasminogen, plasminogen activator inhibitor, transforming growth factor-beta, and β- thromboglobulin in patients with scleroderma suggesting both involvement of endothelial cells and associated platelet activation [102]. Elevated ET-1 is not only a biomarker of vascular disease, but may itself be causing abnormal vascular reactivity and mediating tissue fibrosis by its pro-fibrotic properties via activating TGF-β. Therefore, inhibiting ET-1 activity is considered an attractive target in treating scleroderma vascular disease
  67. 67. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA VasoconstrictoresENDOTELINA-1 ET-1 ET-1 ET-1 Acciones de ET-1 en SSc: - Vasocontricción - Induce proliferación - Activación plaquetaria - Expresa sICAM-1 sVCAM - Induce TGF-Beta VCAM /ICAM' VCAM /ICAM' VCAM /ICAM' VCAM /ICAM' Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 Endothelin-1 Endothelin-1 is a 21-amino-acid peptide with potent vasoconstrictive and proliferative effects that could mediate vascular injury and tissue fibrosis in scleroderma [92, 93]. Endothelin-1 released from the endothelial cells can act on vascular smooth muscle cells potentially inducing the expression of vascular myofibroblast. It can also act in an autocrine manner on the vascular endothelium itself. There are multiple sources of ET-1 in addition to endothelial cells including macrophages, epithelial cells, and mesenchymal cells. Enothelin-1 is elevated in the plasma of patients compared to controls, and it increases during cold exposure in selected scleroderma patients [94]. Endothelin-1 is found in association with high levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin in the blood of scleroderma patients [95–100]. The localiza- tion of ET-1 on specimens obtained by skin biopsies find that ET-1 deposits in the endothelial cells and dermal fibroblasts and has a positive correlation with the serum levels of ET-1 [101]. Another study found a significant increase of ET-1, tissue-type plasminogen, plasminogen activator inhibitor, transforming growth factor-beta, and β- thromboglobulin in patients with scleroderma suggesting both involvement of endothelial cells and associated platelet activation [102]. Elevated ET-1 is not only a biomarker of vascular disease, but may itself be causing abnormal vascular reactivity and mediating tissue fibrosis by its pro-fibrotic properties via activating TGF-β. Therefore, inhibiting ET-1 activity is considered an attractive target in treating scleroderma vascular disease
  68. 68. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Baja expresión de β3 integrina PTX3 ENDOSTATINA Angiostatina μPA/μPA receptor + MMP-12 Kalistatina VEGF A la alza VEGFR-1 FGF2 TGF-β Activadores del plasminógeno Kininas/Kalikreina 9,11,12 a la baja Plasma& Tóxico& Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 There is both clinical and in vitro evidence for defective angiogenesis in scleroderma . For example, the finding of decreased capillary density in the skin and a low tissue expression of the β3 integrin complex, molecules important in facilitating the action of vascular endothelial growth factor, is consistent with disordered angiogenesis. Serum from scleroderma patients is toxic for endo- thelial cells and in vitro studies demonstrate inhibition of cell migration and vascular tube formation. Mononuclear cell support of angiogenesis is also abnormal in scleroderma. There are also several studies suggesting an imbalance of the production of proangiogenic and antiangiogenic factors, thus favoring a decreased ability to form new vessels. Giusti et al. identified genes involved in impaired angiogenesis by compared transcriptosomes of microvascular endothelial cells from normal subjects and patients with scleroderma. Scleroderma endothelial cells over-expressed proangiogenic transcripts but also up-regulated a variety of genes that have a negative effect on angiogenesis. These authors speculate from their data (including in vitro studies of endothelial cell invasion and migration) that stabilization of a proangiogenic pattern dictated by angiogenesis factors (e.g., VEGF) is blocked or altered by up-regulation of angiogenesis inhibitors such as the pent(r)axin-3 (PTX3), known to inhibit the proangiogenic effect of fibroblast growth factor-2 (FGF2). Paradoxically, despite clinical and laboratory evidence of defect angiogensis in scleroderma, there is an increase in VEGF, a key mediator of angiogensis and endothelial cell survival. Transforming growth factor β1 released from immune cells and tissue matrix can activate fibroblast and also promote angiogenesis. In fact, an in vitro study using skin biopsies cultured with chick embryo chorioallantoic membrane demonstrated that scleroderma samples increased vascular counts and promoted a dense mononuclear cell infiltrate when compared to normal skin, a finding consistent with increased proangiogenic factors in the scleroderma skin. High levels of VEGF were found in early in disease and in cases without digital ulcers suggesting that the VEGF was present to enhance vascular repair. VEGF exerts its function by binding to the tyrosine kinase receptors VEGFR1 (flt-1) and VEGFR2 (flk-1). Skin biopsies from the forearm of patients with scleroderma investigated the expression of VEGF, VEGFR- 2, and GLUT-1, the hypoxia-associated glucose transporter molecule. Increased GLUT-1 provides evidence for tissue hypoxia, and increased unbound VEGF suggest a source for increased blood levels of VEGF .
  69. 69. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA Angiogénesis Baja expresión de β3 integrina PTX3 ENDOSTATINA Angiostatina μPA/μPA receptor + MMP-12 Kalistatina VEGF A la alza VEGFR-1 FGF2 TGF-β Activadores del plasminógeno Kininas/Kalikreina 9,11,12 a la baja Plasma& Tóxico& Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 There is both clinical and in vitro evidence for defective angiogenesis in scleroderma . For example, the finding of decreased capillary density in the skin and a low tissue expression of the β3 integrin complex, molecules important in facilitating the action of vascular endothelial growth factor, is consistent with disordered angiogenesis. Serum from scleroderma patients is toxic for endo- thelial cells and in vitro studies demonstrate inhibition of cell migration and vascular tube formation. Mononuclear cell support of angiogenesis is also abnormal in scleroderma. There are also several studies suggesting an imbalance of the production of proangiogenic and antiangiogenic factors, thus favoring a decreased ability to form new vessels. Giusti et al. identified genes involved in impaired angiogenesis by compared transcriptosomes of microvascular endothelial cells from normal subjects and patients with scleroderma. Scleroderma endothelial cells over-expressed proangiogenic transcripts but also up-regulated a variety of genes that have a negative effect on angiogenesis. These authors speculate from their data (including in vitro studies of endothelial cell invasion and migration) that stabilization of a proangiogenic pattern dictated by angiogenesis factors (e.g., VEGF) is blocked or altered by up-regulation of angiogenesis inhibitors such as the pent(r)axin-3 (PTX3), known to inhibit the proangiogenic effect of fibroblast growth factor-2 (FGF2). Paradoxically, despite clinical and laboratory evidence of defect angiogensis in scleroderma, there is an increase in VEGF, a key mediator of angiogensis and endothelial cell survival. Transforming growth factor β1 released from immune cells and tissue matrix can activate fibroblast and also promote angiogenesis. In fact, an in vitro study using skin biopsies cultured with chick embryo chorioallantoic membrane demonstrated that scleroderma samples increased vascular counts and promoted a dense mononuclear cell infiltrate when compared to normal skin, a finding consistent with increased proangiogenic factors in the scleroderma skin. High levels of VEGF were found in early in disease and in cases without digital ulcers suggesting that the VEGF was present to enhance vascular repair. VEGF exerts its function by binding to the tyrosine kinase receptors VEGFR1 (flt-1) and VEGFR2 (flk-1). Skin biopsies from the forearm of patients with scleroderma investigated the expression of VEGF, VEGFR- 2, and GLUT-1, the hypoxia-associated glucose transporter molecule. Increased GLUT-1 provides evidence for tissue hypoxia, and increased unbound VEGF suggest a source for increased blood levels of VEGF .
  70. 70. Fenómeno de Raynaud Patogenia & SSc ENDOTELIO CAPA MUSCULAR (MEDIA) ADVENTICIA AngiogénesisAntiangiogénicos Proangiogénicos Baja expresión de β3 integrina PTX3 ENDOSTATINA Angiostatina μPA/μPA receptor + MMP-12 Kalistatina VEGF A la alza VEGFR-1 FGF2 TGF-β Activadores del plasminógeno Kininas/Kalikreina 9,11,12 a la baja Plasma& Tóxico& Clinic Rev Allerg Immunol (2009) 36:150–175 martes, 10 de septiembre de 13 There is both clinical and in vitro evidence for defective angiogenesis in scleroderma . For example, the finding of decreased capillary density in the skin and a low tissue expression of the β3 integrin complex, molecules important in facilitating the action of vascular endothelial growth factor, is consistent with disordered angiogenesis. Serum from scleroderma patients is toxic for endo- thelial cells and in vitro studies demonstrate inhibition of cell migration and vascular tube formation. Mononuclear cell support of angiogenesis is also abnormal in scleroderma. There are also several studies suggesting an imbalance of the production of proangiogenic and antiangiogenic factors, thus favoring a decreased ability to form new vessels. Giusti et al. identified genes involved in impaired angiogenesis by compared transcriptosomes of microvascular endothelial cells from normal subjects and patients with scleroderma. Scleroderma endothelial cells over-expressed proangiogenic transcripts but also up-regulated a variety of genes that have a negative effect on angiogenesis. These authors speculate from their data (including in vitro studies of endothelial cell invasion and migration) that stabilization of a proangiogenic pattern dictated by angiogenesis factors (e.g., VEGF) is blocked or altered by up-regulation of angiogenesis inhibitors such as the pent(r)axin-3 (PTX3), known to inhibit the proangiogenic effect of fibroblast growth factor-2 (FGF2). Paradoxically, despite clinical and laboratory evidence of defect angiogensis in scleroderma, there is an increase in VEGF, a key mediator of angiogensis and endothelial cell survival. Transforming growth factor β1 released from immune cells and tissue matrix can activate fibroblast and also promote angiogenesis. In fact, an in vitro study using skin biopsies cultured with chick embryo chorioallantoic membrane demonstrated that scleroderma samples increased vascular counts and promoted a dense mononuclear cell infiltrate when compared to normal skin, a finding consistent with increased proangiogenic factors in the scleroderma skin. High levels of VEGF were found in early in disease and in cases without digital ulcers suggesting that the VEGF was present to enhance vascular repair. VEGF exerts its function by binding to the tyrosine kinase receptors VEGFR1 (flt-1) and VEGFR2 (flk-1). Skin biopsies from the forearm of patients with scleroderma investigated the expression of VEGF, VEGFR- 2, and GLUT-1, the hypoxia-associated glucose transporter molecule. Increased GLUT-1 provides evidence for tissue hypoxia, and increased unbound VEGF suggest a source for increased blood levels of VEGF .

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