Your SlideShare is downloading. ×
0
Narissara Suratannon, MD.
Topic included..
   Pathology of asthma
       Anatomical change
       Multicellular inflammation
   Which are factor...
Asthma
   A disorder of the conducting airways
   Through variety of provocation (different
    pathways)…produce the sa...
Pathology
   Epithelial desquamation
   Thickening of lamina reticularis
   Increased numbers of
    myofibroblasts
  ...
Picture from Middleton
Stephen Holgate.JACI 2007:120;1233-44
Normal airway epithelium compared with mildly symptomatic atopic asthma



                                               ...
The reason for that..
   1. Fragility of epithelium
   2. Defective of repairment
   3. Tight junctions cannot fully devel...
Increase destruction :
            Fragility of epithelium
   More severe in allergic than non-allergic forms
   Greater...
Plane of separation between
    columnar and basal cells:       Creola bodies: slough
disruption of desmosomal linkages   ...
Immunofluorescence with antibodies directed to ZO-1
  and occludin confirmed poorly developed TJs in
     asthmatic compar...
Filaggrin




2008;122:
689-93




                        Regan et al.JACI 2008;122:689-93
At least in a subset of those with asthma, the filaggrin
gene defect may be the fundamental predisposing factor
not only f...
Expose to Injurious agents &
   allergens: disrupted TJs

         Tobacco smoke extract
           Respiratory viruses
Pr...
Expose to Injurious agents &
          allergens: other mechanisms

   Some chemical and biological agents insult tissue
...
Int Arch Allergy Immunol 1999;118:437–439
Int Arch Allergy Immunol 1999;118:437–439
Defective repair of epithelium
   Normal patients : mitotic activity in remaining epithelial cells by
    regeneration of...
Asthmatic patients : repair by simple, stratified
    squamous epithelium or goblet cells
Airway Epithelium
   As fragility and impaired proliferation; the epithelium
    is chronically injuried and unable to re...
Epithelial cells: as an effector cells
   Physiochemical barrier

   Regulated recruitment, activation and differentiati...
Chemokines
   CXC or α Chemokines
       ELR (Glu-Leu-Arg) containing CXC :
        predominantly chemoattractant for ne...
IL-8 (CXCL8) Potent chemoattractant of neutrophils




Eotaxin (CCL11) Chemoattractant of eosinophils = CCR3

RANTES (CCL5...
J Immunol 2005;174:8183–90
J Immunol 2005;174:8183–90
Thymic stromal lymphopoietin is releasedby human epithelial
   cells in responseto microbes, trauma, or inflammation
     ...
A Novel Cytokine : TSLP




                   Stephen T. Holgate.JACI 2007;120:1233-44
A Novel Cytokine : TSLP
   TSLP : IL-7 like cytokine
   Correlations between TSLP expression, TARC/
    CCL17,MDC/CCL22
...
The bronchial epithelium is highlighted as
    a key site for asthma pathogenesis




                                    ...
Hyalinization and thickening of
lamina reticularis




                                   RBM




                        ...
Basal membrane
   Initiated close to disease onset
   The extent of thickness does not relate to severity,
    duration,...
Lamina Reticularis
   Found only in humans and primates
   Reticulin fibers (collagen type I, III, VI), tenascin, hepari...
Smooth muscle
   Hyperplasia : larger airways (more characterized)
   Hypertrophy : smaller airways
   Cause from conti...
Mucous secreting elements
   Submucosal gland enlargement and goblet cell
    hyperplasia : histological hallmarks
   Nu...
ST Holgate. Clin Exp Allergy 2008;38:872-97
Cellular Infiltration
   Multicellular process :
       Eosinophils (mainly)
       Neutrophils                 Recruit...
Mast cells
   Mucosal mast cells : Tryptase MCs
   Connective tissue mast cells : Chymase tryptase MCs

   Histamine, P...
Mast cells
   Microlocalization of mast cells is a critical event in
    development of asthmatic phenotype
   Airway sm...
Mucosal layers   Submucosal layers




                            NEJM 2002;346:1699-705
Interaction between mast cells
         and airway smooth muscle
   SCF (c-kit ligand) : produced by epithelium, smooth
 ...
Eosinophils
• Very prominent cell
 in allergic asthma
• IL-3, GM-CSF, eotaxin
 : early derivation
• IL-5 : maturation and
...
Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 8
Alveolar macrophages and dendritic cells
 The most numerous cells in the airway
  lumen in normal and asthma patients
 2...
Alveolar macrophages and dendritic cells
   Anti-inflammatory cytokines : IL-10
   Th1 cytokines : IL-12
   Th2 cytokin...
Lymphocytes
   Severity of asthma can be reflected by the activation
    stage; CD25
   Th2 cytokines :center role in se...
Neutrophils
   Commonly found in airway of healthy patients
   Neutrophilic asthma
   During viral induced exacerbation...
Neutrophils mediate asthma pathogenesis
through…
 1. Potent proinflammatory functions : TNF-α, IL-1,
    IL-8, GM-CSF, G-C...
Heterogenity of asthma; according to
BAL
   Eosinophilic asthma
   Neutrophilic asthma
   Mixed inflammatory
    asthma...
Neutrophillic asthma
   Patients who die sudden from asthma, severe asthma,
    corticosteroid dependent

   Tends to be...
Neutrophillic asthma
   In response to involving pathogens; epithelial signals
    were sent to recruit inflammatory cell...
Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
Take Home Message
   Asthma is a heterogenous disease which has the
    same manifestations of
       Airway hyperespons...
Take Home Message
   Pathology
       Epithelial disruption : Creola bodies
       Homogenous thickening of lamina reti...
Asthma Pathogenesis
Asthma Pathogenesis
Upcoming SlideShare
Loading in...5
×

Asthma Pathogenesis

6,919

Published on

Published in: Health & Medicine, Technology
0 Comments
7 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
6,919
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
519
Comments
0
Likes
7
Embeds 0
No embeds

No notes for slide

Transcript of "Asthma Pathogenesis"

  1. 1. Narissara Suratannon, MD.
  2. 2. Topic included..  Pathology of asthma  Anatomical change  Multicellular inflammation  Which are factors contributed to asthma pathogenesis (Filaggrin , TLSP, TARC,..?)  Distinct type of asthma : neutrophilic inflammation
  3. 3. Asthma  A disorder of the conducting airways  Through variety of provocation (different pathways)…produce the same result of  Airway hyperesponsiveness :  Contract too much, too easily spontaneously and in response to exogenous/endogenous stimuli  Variable airflow obstruction  Multi-cellular inflammation Stephen T. Holgate.Clin Exp Aller 2008:38;872-97
  4. 4. Pathology  Epithelial desquamation  Thickening of lamina reticularis  Increased numbers of myofibroblasts  Evidence of airway remodeling  Hypertrophy and hyperplasia of airway smooth muscle  Mucous gland hyperplasia  Angiogenesis Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  5. 5. Picture from Middleton
  6. 6. Stephen Holgate.JACI 2007:120;1233-44
  7. 7. Normal airway epithelium compared with mildly symptomatic atopic asthma Picture from Middleton
  8. 8. The reason for that.. 1. Fragility of epithelium 2. Defective of repairment 3. Tight junctions cannot fully developed 4. Loss of antioxidant function 5. Cytokines that damaged epithelium
  9. 9. Increase destruction : Fragility of epithelium  More severe in allergic than non-allergic forms  Greater loss : greater degree of airway responsiveness  Reduced with glucocorticoid therapy  Creola bodies  Epithelial cells from asthmatic airways, are unable to form effective TJs fully measurement of transepithelial resistance indicating increased leakiness Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  10. 10. Plane of separation between columnar and basal cells: Creola bodies: slough disruption of desmosomal linkages clumps of epithelial cells Picture from Middleton
  11. 11. Immunofluorescence with antibodies directed to ZO-1 and occludin confirmed poorly developed TJs in asthmatic compared with normal cultures Stephen Holgate.JACI 2007:120;1233-44
  12. 12. Filaggrin 2008;122: 689-93 Regan et al.JACI 2008;122:689-93
  13. 13. At least in a subset of those with asthma, the filaggrin gene defect may be the fundamental predisposing factor not only for the development of eczema but also asthma
  14. 14. Expose to Injurious agents & allergens: disrupted TJs Tobacco smoke extract Respiratory viruses Proteolytically active allergens eg.Der p1 Oxidants (can break perijunctional actin) Stephen Holgate.JACI 2007:120;1233-44
  15. 15. Expose to Injurious agents & allergens: other mechanisms  Some chemical and biological agents insult tissue damaging through the generation of reactive oxygen species  Lack some of antioxidative capacity (Comhair SA et al.2007)  superoxide dismutase and glutathione peroxidase  Enhanced release of proinflammatory cytokines in response to diesel exhaust particle exposure Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  16. 16. Int Arch Allergy Immunol 1999;118:437–439
  17. 17. Int Arch Allergy Immunol 1999;118:437–439
  18. 18. Defective repair of epithelium  Normal patients : mitotic activity in remaining epithelial cells by regeneration of normal ciliated and goblet cells : entired process 2 wks!  By stimulate intrinsic repair pathways with engagement of EGFRs by autocrine secretion of appropriate EGF family eg. EGF, heparin- binding EGF-like growth factor to drive cell migration, proliferation  Asthmatic epithelial cells : reduced expression of proliferative markers such as Ki67 (nuclear expression of cell cycle markers) and upregulation of cell cyclin inhibitor,nuclear p21wat Stephen Holgate.JACI 2007:120;1233-44
  19. 19. Asthmatic patients : repair by simple, stratified squamous epithelium or goblet cells
  20. 20. Airway Epithelium  As fragility and impaired proliferation; the epithelium is chronically injuried and unable to repair properly  Leakiness of epithelium leading to greater access of inhaled allergens, pollutants and irritants  Consider asthma as a disease of impaired barrier function  Next assessment : gene regulation comparing asthmatic with normal epithelial cells Stephen Holgate.Clin Exp Allergy 2008:38;872-97
  21. 21. Epithelial cells: as an effector cells  Physiochemical barrier  Regulated recruitment, activation and differentiation of inflammatory cells in response to exogenous stimuli that cause epithelial damage from those cells remain  Upregulated expression of ICAM-1  Proinflammatory cytokines (IL-1ß, TNF-α, IL-6)  Cytokines (GM-CSF, G-CSF, IL-4, -13,-9, -5, -10, -11, -16, TGFß)  Peptide mediators – endothelin-1 and -3 (bronchoconstriction) Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  22. 22. Chemokines  CXC or α Chemokines  ELR (Glu-Leu-Arg) containing CXC : predominantly chemoattractant for neutrophils  Non-ELR CXC : induced by IFN  CC or ß chemokines : chemoattractants for eosinophils, basophils, monocytes, dendritic cells, lymphocytes
  23. 23. IL-8 (CXCL8) Potent chemoattractant of neutrophils Eotaxin (CCL11) Chemoattractant of eosinophils = CCR3 RANTES (CCL5) Predominant chemoattractant of eosinophils TARC (CCL17) Chemoattractant for Th2 lymphocytes = CCR4
  24. 24. J Immunol 2005;174:8183–90
  25. 25. J Immunol 2005;174:8183–90
  26. 26. Thymic stromal lymphopoietin is releasedby human epithelial cells in responseto microbes, trauma, or inflammation and potently activates mast cells Allakhverdi et al.JEM 2003:204(2);253–258
  27. 27. A Novel Cytokine : TSLP Stephen T. Holgate.JACI 2007;120:1233-44
  28. 28. A Novel Cytokine : TSLP  TSLP : IL-7 like cytokine  Correlations between TSLP expression, TARC/ CCL17,MDC/CCL22  Th2-polarization is more closely under the control of TSLP at the epithelium where the airways inter act with the environment  Altered responses to this interaction in asthmatics may reflect inherent abnormalities of the epithelium itself, such as altered responses to vira l infection Ying et al.J Immunol 2005;174:8183–90
  29. 29. The bronchial epithelium is highlighted as a key site for asthma pathogenesis Stephen T. Holgate. JACI 2007;120:1233-44
  30. 30. Hyalinization and thickening of lamina reticularis RBM Picture from Middleton
  31. 31. Basal membrane  Initiated close to disease onset  The extent of thickness does not relate to severity, duration, fatality, responsiveness to control and does not progressive  Basal lamina (true basement membrane)  Lamina reticularis/ reticular basement membrane Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  32. 32. Lamina Reticularis  Found only in humans and primates  Reticulin fibers (collagen type I, III, VI), tenascin, heparin sulfate and serum-derived components  Homogenous hyaline in appearance  Myofibroblast numbers beneath RBM correlating with extent of collagen thickness  Relate with epithelial secreting EGF familiy agents after epithelial injury Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  33. 33. Smooth muscle  Hyperplasia : larger airways (more characterized)  Hypertrophy : smaller airways  Cause from continuous irritation by mediators, repeated episodes of bronchoconstriction, loss of inhibitory control with unopposed myogenic activity, EGF can induce airway smooth muscle mitogenesis  Correlate with fatal asthma more than long-standing process  Increase muscle mass : marked increase resistence to airway flow that may become life threatening Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  34. 34. Mucous secreting elements  Submucosal gland enlargement and goblet cell hyperplasia : histological hallmarks  Numbers of goblet cells that secrete viscus mucus increases, with a parallel reduction in cilated cells  Goblet cells occurred in the more peripheral airways which are normally devoid of goblet cells  IL-4, IL-9, IL-13, TNF-α EGF play a significant role  Mucus (adhere and continuity with goblet cell apex) mixed with inflammatory exudative plugs in the airways in fatal asthma Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  35. 35. ST Holgate. Clin Exp Allergy 2008;38:872-97
  36. 36. Cellular Infiltration  Multicellular process :  Eosinophils (mainly)  Neutrophils Recruited from circulation  CD4+ T lymphocytes  Mast cells : activated resident cells in airways  Macrophages and dendrtitic cells : both resident cells and recruitment to the lung  NKT cells?? Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  37. 37. Mast cells  Mucosal mast cells : Tryptase MCs  Connective tissue mast cells : Chymase tryptase MCs  Histamine, PGD2, LTC4 : induce bronchoconstriction mucous secretion, mucosal edema  Cytokines (IL-4, IL-5, IL-13) : IgE synthesis, Th2 differentiation, eosinophilic inflammation  TNF-α, TGF-ß, FGF, tryptase, chymase - activated fibroblasts : airway remodelling Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  38. 38. Mast cells  Microlocalization of mast cells is a critical event in development of asthmatic phenotype  Airway smooth muscle TC mast cells infiltration in asthma, not in eosinophilic bronchitis : enhanced contractility  Also contributing to fibrogenesis and an increase in smooth muscle “remodelling response” Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  39. 39. Mucosal layers Submucosal layers NEJM 2002;346:1699-705
  40. 40. Interaction between mast cells and airway smooth muscle  SCF (c-kit ligand) : produced by epithelium, smooth muscle, fibroblasts  CXCL8/CXCL10 produced by airway smooth muscle interact with CXCR3/CXCR2 on mast cells (recruitment, enhanced mediator secretion)  Reverse reaction : mast cells secrete CCL19, stimulate airway smooth muscle through CCR7 stimulate muscle migration and contribute to smooth muscle hyperplasia Stephen Holgate.Clin Exp Allergy 2008:38;872-97
  41. 41. Eosinophils • Very prominent cell in allergic asthma • IL-3, GM-CSF, eotaxin : early derivation • IL-5 : maturation and recruitment into the airways Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 89
  42. 42. Trivedi and Lloyd.Cell. Mol. Life Sci. 2007:64;1269 – 8
  43. 43. Alveolar macrophages and dendritic cells  The most numerous cells in the airway lumen in normal and asthma patients  2 important roles  Inflammatory cytokines  Proinflammatory cytokines :MIP-1α (CCL3), TNF- α, GM-CSF  Chemokines : CXCL8, CCL5, CCL11  Eicosanoids : prostaglandins, LTB4 Stephen Holgate.Clin Exp Allergy 2008:38;872-97
  44. 44. Alveolar macrophages and dendritic cells  Anti-inflammatory cytokines : IL-10  Th1 cytokines : IL-12  Th2 cytokines : CCL17 and CCL22 in response to allergen challenge  Role as APCs when interact with local inflammatory cytokines eg. TSLP : Th2 polarization Stephen Holgate.Clin Exp Allergy 2008:38;872-97
  45. 45. Lymphocytes  Severity of asthma can be reflected by the activation stage; CD25  Th2 cytokines :center role in secreting IL-4, IL-5, IL-13  Th1/Th2 imbalance should not be viewes as pathognomonic for asthma  Th1 shift does not lead to fewer asthma symptoms  In severe asthma, we found elevation levels of IFN-Ɣ in serum and BAL fluid  Role of T-regulatory cells?? : little evidence Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  46. 46. Neutrophils  Commonly found in airway of healthy patients  Neutrophilic asthma  During viral induced exacerbations  Role in asthma is still undefined  Reflect of disease severity?  A consequence of corticosteroid treatment Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  47. 47. Neutrophils mediate asthma pathogenesis through… 1. Potent proinflammatory functions : TNF-α, IL-1, IL-8, GM-CSF, G-CSF 2. Innate immune activation  Epithelium of neutrophilic asthma express higher levels of TLR2,4, CD 14 and surface protein A which may occur in response to increase in airway endotoxin, bacterial colonization and respiratory viruses 3. Role in airway remodeling via capacity of release TGF-ß, VEGF (in asthmatic patients) Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  48. 48. Heterogenity of asthma; according to BAL  Eosinophilic asthma  Neutrophilic asthma  Mixed inflammatory asthma  Paucigranulocytic asthma
  49. 49. Neutrophillic asthma  Patients who die sudden from asthma, severe asthma, corticosteroid dependent  Tends to be older and a more aggressive disease with more tissue destruction and airway remodelling  Similar in terms of gender, atopy, smoking and lung function  Distinct immune and inflammatory mechanisms involving innate immune dysfunction Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  50. 50. Neutrophillic asthma  In response to involving pathogens; epithelial signals were sent to recruit inflammatory cells  If the responses are not insufficient to eliminate microbes; chronic persistent inflammation occurred and can damage host tissue  Evidence that innate immunity was stimulated  Endotoxin levels esp. from H. influenza and P. aeruginosa were increased Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  51. 51. Stephen Holgate et al.Middleton’s Allergy Principles & Practice.7’th edition P.893-915
  52. 52. Take Home Message  Asthma is a heterogenous disease which has the same manifestations of  Airway hyperesponsiveness :  Variable airflow obstruction  Multi-cellular inflammation  Epithelium seems to be a key regulator of asthma  Filaggrin gene polymorphisms have increased risks of developing asthma in atopic eczema patients
  53. 53. Take Home Message  Pathology  Epithelial disruption : Creola bodies  Homogenous thickening of lamina reticularis  Airway remodelling  Mast cells infiltrated at airway smooth muscle  TARC and TSLP : Th2 polarization  To know more about asthma pathogenesis could contribute to know the target points of treatment
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×