• characterized by a sequence of host phenotypic and metabolicresponses to systemic inflammation that includes changes in ...
the systemic inflammatory response to injury includes two general phases:                        acute pro-inflammatory p...
definition of terms       infection       - identifiable source of microbial insult       SIRS            - two or more ...
central nervous systemregulation of inflammation
afferent signals to the brain                         circulatory pathway                                 hormone releas...
hormonal response to      injury
hormone signaling pathways      hormones are chemical signals that are released to modulate the function of target cells ...
Hypothalamic RegulationHormones Regulated by the         Corticotropin-releasing hormoneHypothalamus, Pituitary, and      ...
adrenocorticotropic hormone (ACTH) synthesized and released by the anterior pituitary gland       in healthy humans, ACT...
cortisol a glucocorticoid hormone released by the adrenal cortex in response to ACTH its release is increased during tim...
glucocorticoids have immunosuppressive properties       immunologic changes associated with glucocorticoid administratio...
macrophage migration–                  growth hormone (GH)inhibiting factor (MIF)                 a neuro-hormone express...
catecholamines hormones secreted by the chromaffin cells of the adrenal medulla and function as neurotransmitters inthe C...
aldosterone                       Insulin a mineralocorticoid released     secreted by the islets of Langerhans in the p...
acute phase proteins non-specific biochemical markers produced byhepatocytes in response to tissue injury, infectionor in...
cytokines                                   tumor necrosis factor alpha (TNF) a class of protein signalingcompounds that ...
Interleukin-1 (two subtypes: 1L-1alpha and            Interleukin-21L-1 beta)       IL-1 alpha is primarily membrane     ...
Interleukin-4 (IL-4)                           Interleukin-6 (IL-6) released by activated helper T cells and      releas...
interleukin-8                              Interleukin-10 (IL-10) synthesized bymacrophages as well as         an anti-i...
Interleukin-12                                             Interleukin-13 (IL-13) a regulator of cell mediated immunity  ...
Interleukin-15 (IL-15) synthesized in many cell types,                                          Interleukin-18 (IL-18)inc...
kallikrein-kinin system a group of proteins that contribute to inflammation, blood pressure control, coagulation, and pai...
Heat Shock Proteins a group of intracellular proteins that areincreasingly expressed during times of stress,such as burn ...
Reactive Oxygen Species are small molecules that are highly reactive due to the presence of unpaired outerorbit electrons...
Eicosanoids                                                eicosanoids mostly generate a proinflammatory derived primari...
Fatty acid metabolites                                         Omega-3 fatty acids      omega-6 fatty acids             ...
Serotonin                                   Histamine a monoamineneurotransmitter (5-                                   ...
G-protein receptors (GPRs) a large family of transmembrane receptors that bind amultitude of ligands (e.g., epinephrine, ...
Ligand-gated ion channels (LGICs) are transmembrane receptors that allowthe rapid influx of ions (e.g., sodium,calcium, p...
Receptor tyrosine kinases(RTKs) are transmembrane receptors thatare involved in cell signaling forseveral growth factors,...
The Janus kinases (JAKs) represent a family of tyrosine kinases thatmediate signal transduction of severalcytokines, incl...
Suppressor of cytokine signaling (SOCS)molecules are a group of cytokine-induced proteins thatfunction as a negative feed...
Mitogen-Activated Protein Kinases pathways mediated through mitogen-activated proteinkinase (MAPK) contribute to inflamma...
Nuclear factor B (NF-B) a transcription factor that has a central role in regulatingthe gene products expressed after inf...
systemic inflammatory response syndrome (SIRS)
systemic inflammatory response syndrome (SIRS)
systemic inflammatory response syndrome (SIRS)
systemic inflammatory response syndrome (SIRS)
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systemic inflammatory response syndrome (SIRS)

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REFERENCE shwartz surgery
prepared by dr.kucha

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systemic inflammatory response syndrome (SIRS)

  1. 1. • characterized by a sequence of host phenotypic and metabolicresponses to systemic inflammation that includes changes in heartrate, respiratory rate, blood pressure, temperature regulation, andimmune cell activation
  2. 2. the systemic inflammatory response to injury includes two general phases:  acute pro-inflammatory phase  characterized by activation of cellular processes designed to restore tissue function and eradicate invading microorganisms  anti-inflammatory phase  counter-regulatory phase  serve to modulate the pro-inflammatory phase preventing excessive pro- inflammatory activities as well as restoring homeostasis
  3. 3. definition of terms  infection - identifiable source of microbial insult  SIRS - two or more of following criteria are met: - temperature ≥38°C (100.4°F) or ≤36°C (96.8°F) - heart rate ≥90 beats per minute - respiratory rate ≥20 breaths per minute or PaCO2 ≤32 mmHg or mechanical ventilation - white blood cell count ≥12,000/L or ≤4000/L or 10% band forms  sepsis - identifiable source of infection + SIRS  severe sepsis - sepsis + organ dysfunction  septic shock - sepsis + cardiovascular collapse (requiring vasopressor support)
  4. 4. central nervous systemregulation of inflammation
  5. 5. afferent signals to the brain circulatory pathway  hormone release into the systemic circulation  adrenocorticotropic hormone [ACTH], glucocorticoids afferent signal pathways  neuronal pathway  sympathetic response via the release of epinephrine, norepinephrine  parasympathetic response by inducing acethycholine release
  6. 6. hormonal response to injury
  7. 7. hormone signaling pathways  hormones are chemical signals that are released to modulate the function of target cells  polypeptides (e.g., cytokines, glucagon, and insulin)  amino acids (e.g., epinephrine, serotonin, and histamine)  fatty acids (e.g., glucocorticoids, prostaglandins, and leukotrienes)  hormone receptors are present on or within the target cells and allow signal transduction to progress intracellularly mostly through three major pathways:  receptor kinases such as insulin and insulin-like growth factor (IGF) receptors  guanine nucleotide-binding or G-protein receptors such as neurotransmitter and prostaglandin receptors  ligand-gated ion channels that permit ion transport when activated  on activation, the signal is then amplified through the action of secondary signaling molecules leading to downstream effects such as protein synthesis and further mediator release
  8. 8. Hypothalamic RegulationHormones Regulated by the Corticotropin-releasing hormoneHypothalamus, Pituitary, and Thyrotropin-releasing hormone Growth hormone–releasing hormoneAutonomic System Luteinizing hormone–releasing hormone Anterior Pituitary Regulation Adrenocorticotropic hormone Cortisol Thyroid-stimulating hormone Thyroxine Triiodothyronine Growth hormone Gonadotrophins Sex hormones Insulin-like growth factor Somatostatin Prolactin Endorphins Posterior Pituitary Regulation Vasopressin Oxytocin Autonomic System Norepinephrine Epinephrine Aldosterone Renin-Angiotensin System Insulin Glucagon Enkephalins
  9. 9. adrenocorticotropic hormone (ACTH) synthesized and released by the anterior pituitary gland  in healthy humans, ACTH release follows a circadian rhythms  its greatest elevation occurs at night until the hours immediately before sunrise  during times of stress this diurnal pattern becomes blunted because ACTH release is elevated in proportion to the severity of injury  important stimuli for ACTH release in the injured patient  corticotropin-releasing hormone  pain  anxiety  vasopressin  angiotensin II  cholecystokinin  vasoactive intestinal polypeptide  catecholamines  proinflammatory cytokines a principal regulator of steroid synthesis conditions of excess ACTH stimulation result in adrenocorticalhypertrophy
  10. 10. cortisol a glucocorticoid hormone released by the adrenal cortex in response to ACTH its release is increased during times of stress and may be chronically elevated in certain diseaseprocesses  e.g. burn-injured patients may exhibit elevated levels for 4 weeks actions:  it potentiates the hyperglycemic actions of glucagon and epinephrine  it acts on liver enzymes by decreasing glycogenesis while increasing gluconeogenesis  it facilitates the breakdown of protein and amino acids in skeletal muscles and mediates the release of lactate which are substrates used by the liver for gluconeogenesis  it stimulates the release of free fatty acids, triglycerides, and glycerol in adipose tissue to increase circulating energy stores  may impair wound healing because cortisol reduces transforming growth factor beta (TGF-) and insulin-like growth factor I (IGF-I) in the wound  can be partially ameliorated by the administration of vitamin A
  11. 11. glucocorticoids have immunosuppressive properties  immunologic changes associated with glucocorticoid administration include:  thymic involution  depressed cell-mediated immune responses reflected by decreases in T-killer and natural killer cell function  T-lymphocyte blastogenesis  mixed lymphocyte responsiveness  graft-versus-host reactions  delayed hypersensitivity responses  it inhibits leukocyte migration to sites of inflammation by inhibiting the expression of adhesion molecules  it inhibits monocyte intracellular killing of bacteria while maintaining chemotactic and phagocytic properties  it inhibits neutrophil superoxide reactivity, suppress chemotaxis, and normalize apoptosis signaling mechanisms but maintain neutrophil phagocytic function
  12. 12. macrophage migration– growth hormone (GH)inhibiting factor (MIF)  a neuro-hormone expressed primarily by the pituitary gland that has both: a neuro-hormone that is stored and  metabolic (promotes protein synthesis and insulinsecreted by the anterior pituitary resistance, and enhances the mobilization of fat stores)and by intracellular pools within andmacrophages  immunomodulatory effects a counter-regulatory mediator  its secretion is upregulated by hypothalamic GH–releasing hormone and downregulated by somatostatin  during times of stress, MIF modulates the inflammatory response by inhibiting the insulin-like growth factor (IGF) immunosuppressive effect of  has anabolic effects, including increased protein synthesis cortisol on immunocytes and and lipogenesis thereby increasing their  in the liver, it stimulates protein synthesis and activity against foreign glycogenesis pathogens  in adipose tissue, it increases glucose uptake and lipid utilization  in skeletal muscles, it mediates glucose uptake and protein synthesis
  13. 13. catecholamines hormones secreted by the chromaffin cells of the adrenal medulla and function as neurotransmitters inthe CNS  most common catecholamines are epinephrine, norepinephrine, and dopamine, which have metabolic, immunomodulatory, and vasoactive effects act on both alpha and beta receptors, which are widely distributed on several cell types, including vascularendothelial cells, immunocytes, myocytes, adipose tissue, and hepatocytes  epinephrine  induces a catabolic hyperglycemia through hepatic gluconeogenesis and glycogenolysis as well as by peripheral lipolysis and proteolysis  promotes insulin resistance in skeletal muscle  has immunomodulatory properties mediated primarily through the activation of beta2 receptors on immunocytes  inhibit the release of inflammatory cytokines, including TNF, interleukin-1, and interleukin-6, while also enhancing the release of the anti-inflammatory mediator interleukin-10  increases leukocyte demargination with resultant neutrophilia and lymphocytosis exert several hemodynamic effects, including increased cardiac oxygen demand, vasoconstriction, andincreased cardiac output used to treat systemic hypotension during septic shock increase the secretion of thyroid hormone, parathyroid hormones, and renin, but inhibit the release ofaldosterone
  14. 14. aldosterone Insulin a mineralocorticoid released  secreted by the islets of Langerhans in the pancreasby the zona glomerulosa of theadrenal cortex  it mediates an overall host anabolic state through hepatic  secretion is stimulated glycogenesis and glycolysis, peripheral glucose uptake, by ACTH, angiotensin II, lipogenesis, and protein synthesis decreased intravascular volume, and  hyperglycemia during critical illness has hyperkalemia immunosuppressive effects:  glycosylation of immunoglobulins it increases intravascular  decreased phagocytosisvolume by acting on the renal  respiratory burst of monocytesmineralocorticoid receptor ofthe distal convoluted tubules  an increased risk for infectionto retain sodium and eliminatepotassium and hydrogen ions  insulin therapy to manage hyperglycemia has grown in favor and has been shown to be associated with both decreased mortality and a reduction in infectious complications in select patient populations
  15. 15. acute phase proteins non-specific biochemical markers produced byhepatocytes in response to tissue injury, infectionor inflammation  c-reactive protein  a marker of pro-inflammatory response in many clinical settings, including appendicitis, vasculitis, and ulcerative colitis  do not show diurnal variations and are not modulated by feeding acute phase protein levels may be unreliable asan index of inflammation in the setting of hepaticinsufficiency
  16. 16. cytokines tumor necrosis factor alpha (TNF) a class of protein signalingcompounds that are  primarily synthesized by macrophages,essential for both innate and monocytes, and T cells, which are abundant inadaptive immune responses peritoneum and splanchnic tissues mediate a broad sequence  rapidly mobilized in response to stressors suchof cellular responses, as injury and infection, and is a potent mediatorincluding cell migration, DNA of the subsequent inflammatory responsereplication, cell turnover,and immunocyte  has a very brief half-life, but the activityproliferation of TNF elicits many metabolic and immunomodulatory activities at the site of injury and  stimulates muscle breakdown andinfection, they mediate the cachexia through increasederadication of invading catabolism, insulin resistance, andmicro-organisms and also redistribution of amino acids topromote wound healing hepatic circulation as fuel substrates  an exaggerated pro-  mediates coagulation activation, inflammatory cytokine cell migration, and macrophage response to phagocytosis, and enhances the inflammatory stimuli expression of adhesion molecules, may result in prostaglandin E2 , platelet- hemodynamic activating factor, glucocorticoids, instability (i.e., septic and eicosanoids shock) and metabolic derangements (i.e., muscle wasting)
  17. 17. Interleukin-1 (two subtypes: 1L-1alpha and Interleukin-21L-1 beta)  IL-1 alpha is primarily membrane  primarily a promoter of T-lymphocyte associated and functions through cellular proliferation and differentiation, contact immunoglobulin production, and gut barrier  IL-1 beta is readily detectable in soluble integrity form and mediates an inflammatory sequence similar to that of TNF  has a short half-life of <10 minutes, IL-2 is not readily detectable after acute injury primarily synthesized by monocytes,macrophages, endothelial cells, fibroblasts, and  IL-2 binds to IL-2 receptors, which areepidermal cells expressed on leukocytes released in response to inflammatory stimuli,  IL-2 receptor blockade inducesincluding cytokines (TNF, IL-2, interferon- [IFN-]) immunosuppressive effects and can beand foreign pathogens pharmacologically used for organ transplantation an endogenous pyrogen because it acts on thehypothalamus by stimulating prostaglandin activity  attenuated IL-2 expression observedand thereby mediates a febrile response during major injury or blood transfusion may contribute to the relatively immunosuppressed state of the surgical patient
  18. 18. Interleukin-4 (IL-4) Interleukin-6 (IL-6) released by activated helper T cells and  released by macrophages and stimulated bystimulates the differentiation of T cells, inflammatory mediators such as endotoxin, TNF,and also stimulates T-cell proliferation and and IL-1B-cell activation  after injury, IL-6 levels in the circulation are important in antibody-mediated detectable by 60 minutes, peak between 4 and 6immunity and in antigen presentation hours, and can persist for as long as 10 days  induces class switching of  plasma levels of IL-6 are proportional to differentiating B lymphocytes to the degree of injury during surgery produce predominantly  high plasma IL-6 levels have been immunoglobulin G4 and associated with mortality during intra- immunoglobulin E, which are abdominal sepsis important immunoglobulins in allergic and antihelmintic responses  has counter-regulatory effects on the inflammatory cascade through the inhibition of has anti-inflammatory effects on TNF and IL-1macrophages, exhibited by an attenuatedresponse to pro-inflammatory mediators  promotes the release of soluble tumor necrosissuch as IL-1, TNF, interleukin-6, and factor receptors and IL-1 receptor antagonists,interleukin-8 and stimulates the release of cortisol appears to increase macrophagesusceptibility to the anti-inflammatoryeffects of glucocorticoids
  19. 19. interleukin-8 Interleukin-10 (IL-10) synthesized bymacrophages as well as  an anti-inflammatory cytokine synthesizedother cell lines such as primarily by monocytes; however, it is alsoendothelial cells released by other lymphocytes stimulates the release of  inhibits the secretion of pro-inflammatoryIFN- and functions as a cytokines, including TNF and IL-1, partly throughpotent chemo-attractant the downregulation of NF-B and therebyfor neutrophils functions as a negative feedback regulator of the inflammatory cascade elevated plasma hasbeen associated with  increased plasma levels of IL-10 also have beendisease severity and end associated with mortality and disease severityorgan dysfunction during after traumatic injurysepsis  significantly contribute to the underlying immunosuppressed state during sepsis through the inhibition and subsequent anergy of immunocytes
  20. 20. Interleukin-12 Interleukin-13 (IL-13) a regulator of cell mediated immunity  exerts many of the same immunomodulatory released by activated phagocytes, effects as does IL-4including monocytes, macrophages,  inhibits monocyte release of TNF, IL-1, IL-neutrophils, and dendritic cells, and is 6, and IL-8, while increasing the secretionincreasingly expressed during of IL-1R antagonistendotoxemia and sepsis  has no identifiable effect on T lymphocytes and stimulates lymphocytes to increase only has influence on selected B-lymphocytesecretion of IFN- with the co-stimulus of populationsinterleukin-18 and also stimulates naturalkiller cell cytotoxicity and helper T cell  increased IL-13 expression is observed duringdifferentiation septic shock and mediates neutropenia, monocytopenia, and leukopenia IL-12 release is inhibited by IL-10  IL-12 deficiency inhibits  ihibits leukocyte interaction with activated phagocytosis in neutrophils endothelial surfaces
  21. 21. Interleukin-15 (IL-15) synthesized in many cell types, Interleukin-18 (IL-18)including macrophages and skeletalmuscle after endotoxin  formerly IFN-–inducing factor, is synthesizedadministration primarily by macrophages stimulates natural killer cell  activates NF-B through an Myeloid differentiationactivation as well as B-cell and T-cell primary response gene (88) (MyD88)-dependentproliferation and thus functions as a pathway with subsequent proinflammatoryregulator of cellular immunity mediator release has immunomodulatory effects  mediates hepatotoxicity associated with Fas ligandsimilar to those of IL-2, in part due and TNFto shared receptor subunits  the viral skin pathogen molluscum contagiosum acts as a potent inhibitor of secretes an IL-18BP–like protein, which neutralizeslymphocyte apoptosis by enhancing IL-18 and thereby inhibits the inflammatorythe expression of anti-apoptotic responsemolecules such as Bcl-2
  22. 22. kallikrein-kinin system a group of proteins that contribute to inflammation, blood pressure control, coagulation, and painresponses  prekallikrein is activated to produce the serine protease kallikrein, which subsequently plays a role in the coagulation cascade  stimuli for the activation of prekallikrein are Hageman factor, trypsin, plasmin, factor XI, glass surfaces, kaolin, and collagen  kallikrein metabolizes high molecular weight kininogen to form bradykinin  kinins mediate several physiologic processes:  vasodilation  increased capillary permeability  tissue edema  pain pathway activation  inhibition of gluconeogenesis  increased bronchoconstriction  kinins also increase renal vasodilation and consequently reduce renal perfusion pressure  decreased renal perfusion leads to activation of the renin-angiotensin-aldosterone system, which acts on the nephron to actively resorb sodium and subsequently increase intravascular volume bradykinin and kallikrein levels are increased during gram-negative bacteremia, hypotension,hemorrhage, endotoxemia, and tissue injury  the degree of elevation in the levels of these mediators has been associated with the magnitude of injury and mortality
  23. 23. Heat Shock Proteins a group of intracellular proteins that areincreasingly expressed during times of stress,such as burn injury, inflammation, andinfection HSPs participate in many physiologicprocesses, including protein folding andprotein targeting bind both autologous and foreign proteinsand thereby function as intracellularchaperones for ligands such as bacterial DNAand endotoxin presumed to protect cells from thedeleterious effects of traumatic stress and,when released by damaged cells, alert theimmune system of the tissue damage
  24. 24. Reactive Oxygen Species are small molecules that are highly reactive due to the presence of unpaired outerorbit electrons can cause cellular injury to both host cells and invading pathogens through theoxidation of unsaturated fatty acids within cell membranes produced as a by-product of oxygen metabolism as well as by anaerobic processes potent oxygen radicals include:  oxygen  superoxide  hydrogen peroxide  hydroxyl radicals host cells are protected from the damaging effects of ROS through the activity ofendogenous antioxidants such as superoxide dismutase, catalase, and glutathioneperoxidase during times of stress or ischemia enzymatic clearance mechanisms are consumed,and on restoration of perfusion, the unbalanced production of ROS leads toreperfusion injury
  25. 25. Eicosanoids  eicosanoids mostly generate a proinflammatory derived primarily by oxidation of the membrane response with deleterious host effects and arephospholipid arachidonic acid (eicosatetraenoic acid) associated with acute lung injury, pancreatitis, and renal failure composed of subgroups, including prostaglandins,  leukotrienes are potent mediators ofprostacyclins, hydroxyeicosatetraenoic acids (HETEs), capillary leakage as well as leukocytethromboxanes, and leukotrienes adherence, neutrophil activation, bronchoconstriction, and vasoconstriction not stored within cells but are generated rapidly inresponse to many stimuli, including hypoxic injury,  eicosanoids also have several recognizeddirect tissue injury, endotoxin (lipopolysaccharide, or metabolic effectsLPS), norepinephrine, vasopressin, angiotensin II,  cyclooxygenase pathway products inhibitbradykinin, serotonin, acetylcholine, cytokines, and pancreatic -cell release of insulinhistamine  lipoxygenase pathway products stimulate -cell activity eicosanoid pathway activation also leads to the  prostaglandins such as prostaglandin E2formation of the anti-inflammatory compound lipoxin, can inhibit gluconeogenesis through thewhich inhibits chemotaxis and nuclear factor B (NF-B) binding of hepatic receptors and also canactivation inhibit hormone-stimulated lipolysis glucocorticoids, NSAIDs, and leukotriene inhibitorsblock the end products of eicosanoid pathways have a broad range of physiologic roles, includingneurotransmission, vasomotor regulation, and immunecell regulation
  26. 26. Fatty acid metabolites  Omega-3 fatty acids  omega-6 fatty acids  have specific anti-inflammatory effects, including inhibition of NF-B activity, TNF release from hepatic Kupffer  the primary source of cells, as well as leukocyte adhesion and migration lipids in commercially prepared enteral  the anti-inflammatory effects of omega-3 fatty acids on nutrition formulas chronic autoimmune diseases such as rheumatoid arthritis,  serve as precursors of psoriasis, and lupus have been documented in both animals inflammatory mediators and humans associated with injury  in experimental models of sepsis, omega-3 fatty and the stress response acids inhibit inflammation, ameliorate weight loss,  leukotrienes increase small-bowel perfusion, and may increase gut  prostaglandins barrier protection  platelet-  in human studies, omega-3 supplementation is activating factors associated with decreased production of TNF, interleukin-1, and interleukin-6 by endotoxin- stimulated monocytes  in a study of surgical patients, preoperative supplementation with omega-3 fatty acid was associated with reduced need for mechanical ventilation, decreased hospital length of stay, and decreased mortality with a good safety profile
  27. 27. Serotonin Histamine a monoamineneurotransmitter (5-  synthesized by the decarboxylation of the amino acidhydroxytryptamine) derived from histidinetryptophan  either rapidly released or stored in neurons, skin, synthesized by neurons in the gastric mucosa, mast cells, basophils, and plateletsCNS as well as byenterochromaffin cells of the GI  there are four histamine receptor (H) subtypes withtract and platelets varying physiologic roles  H1 binding mediates vasodilation, stimulates vasoconstriction, bronchoconstriction, intestinal motility, andbronchoconstriction, and myocardial contractilityplatelet aggregation  H2 binding stimulates gastric parietal cell acid secretion increases cardiac inotropy and  H3 is an autoreceptor found on presynapticchronotropy through histamine-containing nerve endings and leads tononadrenergic cyclic adenosine downregulation of histamine releasemonophosphate (cAMP)  H4 is expressed primarily in bone marrow,pathway eosinophils, and mast cells receptors are located in theCNS, GI tract, and monocytes
  28. 28. G-protein receptors (GPRs) a large family of transmembrane receptors that bind amultitude of ligands (e.g., epinephrine, bradykinin,leukotriene) and are involved in signal transduction duringthe inflammatory response extracellular ligands bind to GPR, which result in aconformational change and activation of associatedprotein two major second messengers of the G-protein pathwayare:  cAMP  calcium  increased intracellular cAMP can activate gene transcription through the activity of intracellular signal transducers such as protein kinase A  increased intracellular calcium can activate the intracellular signal transducer phospholipase C with further subsequent downstream effects  GPR binding also can promote the activity of protein kinase C, which can subsequently stimulate NF-B as well as other transcription factors
  29. 29. Ligand-gated ion channels (LGICs) are transmembrane receptors that allowthe rapid influx of ions (e.g., sodium,calcium, potassium, chloride) and are centralto the signal transduction ofneurotransmitters on ligand binding LGICs effectively converta chemical signal into an electrical signal the prototypical LGIC is the nicotinicacetylcholine receptor
  30. 30. Receptor tyrosine kinases(RTKs) are transmembrane receptors thatare involved in cell signaling forseveral growth factors, includingplatelet-derived growth factor,insulin-like growth factor, epidermalgrowth factor, and vascularendothelial growth factor on ligand binding, RTKs dimerizewith adjacent receptors, undergoautophosphorylation, and recruitsecondary signaling molecules (e.g.,phospholipase C) activation of RTK is important forgene transcription as well as cellproliferation and may haveinfluence in the development ofmany types of cancer
  31. 31. The Janus kinases (JAKs) represent a family of tyrosine kinases thatmediate signal transduction of severalcytokines, including IFN-, IL-6, IL-10, IL-12, andIL-13 JAKs bind to cytokines, and on ligand bindingand dimerization, activated JAKs recruit andphosphorylate signal transducer and activatorof transcription (STAT) molecules activated STAT proteins further dimerize andtranslocate into the nucleus and modulate thetranscription of target genes  the JAK/STAT system is a rapid pathway for membrane to nucleus signal transduction  the JAK/STAT pathway is inhibited by the action of phosphatase, the export of STATs from the nucleus, as well the interaction of antagonistic proteins
  32. 32. Suppressor of cytokine signaling (SOCS)molecules are a group of cytokine-induced proteins thatfunction as a negative feedback loop bydownregulating the JAK/STAT pathway exert an inhibitory effect partly by binding withJAK and thus competing with STAT a deficiency of SOCS activity may render a cellhypersensitive to certain stimuli, such asinflammatory cytokines and growth hormones
  33. 33. Mitogen-Activated Protein Kinases pathways mediated through mitogen-activated proteinkinase (MAPK) contribute to inflammatory signaling andregulation of cell proliferation and cell death MAPK pathways involve sequential stages of mediatorphosphorylation resulting in the activation ofdownstream effectors, including c-Jun N-terminal kinase(JNK), extracellular signal regulated protein kinase (ERK),and p38 kinase, with subsequent gene modulation dephosphorylation of MAPK pathway mediatorsinhibit their function
  34. 34. Nuclear factor B (NF-B) a transcription factor that has a central role in regulatingthe gene products expressed after inflammatory stimuli composed of two smaller polypeptides, p50 and p65 resides in the cytosol in the resting state primarilythrough the inhibitory binding of inhibitor of B (I-B) in response to an inflammatory stimulus such as TNF, IL-1, or endotoxin, a sequence of intracellular mediatorphosphorylation reactions leads to the degradation of I-Band subsequent release of NF-B  on release, NF-B travels to the nucleus and promotes gene expression  NF-B also stimulates the gene expression for I-B, which results in negative feedback regulation
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