1. Innate Immunity: Inflammation Chapter 6 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

2. 2 Immunity First line of defense First line of defense Innate resistance Innate resistance Second line of defense Second line of defense Inflammation Inflammation Third line of defense Third line of defense Adaptive (acquired) immunity Adaptive (acquired) immunity

3. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 3 First Line of Defense Physical and mechanical barriers Physical and mechanical barriers Skin Skin Linings of the gastrointestinal, genitourinary, and respiratory tracts Linings of the gastrointestinal, genitourinary, and respiratory tracts Sloughing off of cells Sloughing off of cells Coughing and sneezing Coughing and sneezing Flushing Flushing Vomiting Vomiting Mucus and cilia Mucus and cilia

4. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 4 First Line of Defense Biochemical barriers Biochemical barriers Synthesized and secreted saliva, tears, earwax, sweat, and sebum Synthesized and secreted saliva, tears, earwax, sweat, and sebum Antimicrobial peptides Antimicrobial peptides Cathelicidins, defensins (α defensins in neutrophil granules), and collectins (lungs) Cathelicidins, defensins (α defensins in neutrophil granules), and collectins (lungs) Normal bacterial flora Normal bacterial flora Vaginal: lactobacillus Vaginal: lactobacillus Intestinal: produce ammonia, phenols, indols, etc. that inhibit colonization by pathogens Intestinal: produce ammonia, phenols, indols, etc. that inhibit colonization by pathogens

5. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 5 Second Line of Defense Inflammatory response Inflammatory response Causes Causes Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Local manifestations Local manifestations Vascular response Vascular response Blood vessel dilation, increased vascular permeability and leakage, WBC adherence to the inner walls of the vessels and migration through the vessels Blood vessel dilation, increased vascular permeability and leakage, WBC adherence to the inner walls of the vessels and migration through the vessels

6. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 6 Inflammation Goals Goals Limit and control the inflammatory process Limit and control the inflammatory process Prevent and limit infection and further damage Prevent and limit infection and further damage Control bleeding Control bleeding Interact with components of the adaptive immune system Interact with components of the adaptive immune system Prepare the area of injury for healing Prepare the area of injury for healing

7. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 7 Plasma Protein Systems Protein systems Protein systems Complement system Complement system Coagulation system Coagulation system Kinin system Kinin system All contain inactive enzymes (proenzymes) All contain inactive enzymes (proenzymes) Sequentially activated Sequentially activated First proenzyme is converted to an active enzyme First proenzyme is converted to an active enzyme Substrate of the activated enzyme becomes the next component in the series Substrate of the activated enzyme becomes the next component in the series

8. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 8 Plasma Protein Systems Complement system Complement system Can destroy pathogens directly Can destroy pathogens directly Activates or collaborates with every other component of the inflammatory response Activates or collaborates with every other component of the inflammatory response Pathways Pathways Classical Classical Lectin Lectin Alternative Alternative

9. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 9 Plasma Protein Systems Coagulation (clotting) system Coagulation (clotting) system Forms a fibrinous meshwork at an injured or inflamed site Forms a fibrinous meshwork at an injured or inflamed site Prevents the spread of infection Prevents the spread of infection Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity Forms a clot that stops bleeding Forms a clot that stops bleeding Provides a framework for repair and healing Provides a framework for repair and healing Main substance is an insoluble protein called fibrin Main substance is an insoluble protein called fibrin

10. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 10 Plasma Protein Systems Kinin system Kinin system Functions to activate and assist inflammatory cells Functions to activate and assist inflammatory cells Primary kinin is bradykinin Primary kinin is bradykinin Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis

11. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 11 Plasma Protein Systems

12. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 12 Cellular Mediators of Inflammation Cellular components Cellular components Granulocytes, platelets, monocytes, and lymphocytes Granulocytes, platelets, monocytes, and lymphocytes Cell surface receptors Cell surface receptors Pattern recognition receptors (PRRs) Pattern recognition receptors (PRRs) Pathogen-associated molecular patterns (PAMPs) Pathogen-associated molecular patterns (PAMPs) Toll-like receptors Toll-like receptors Complement receptors Complement receptors Scavenger receptors Scavenger receptors

13. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 13 Mast Cells Cellular bags of granules located in loose connective tissues close to blood vessels Cellular bags of granules located in loose connective tissues close to blood vessels Skin, digestive lining, respiratory tract Skin, digestive lining, respiratory tract Activation Activation Physical injury, chemical agents, immunologic processes, Toll-like receptors Physical injury, chemical agents, immunologic processes, Toll-like receptors Chemical release in two ways Chemical release in two ways Degranulation and synthesis of lipid-derived chemical mediators Degranulation and synthesis of lipid-derived chemical mediators

14. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 14 Mast Cell Degranulation Histamine Histamine Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules Retraction of endothelial cells lining the capillaries Retraction of endothelial cells lining the capillaries Receptors Receptors H 1 receptor (proinflammatory) H 1 receptor (proinflammatory) H 2 receptor (anti-inflammatory) H 2 receptor (anti-inflammatory)

15. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 15 Histamine Receptors Receptors H 1 receptor H 1 receptor Proinflammatory Proinflammatory Present in smooth muscle cells of the bronchi Present in smooth muscle cells of the bronchi H 2 receptor H 2 receptor Anti-inflammatory Anti-inflammatory Present on parietal cells of the stomach mucosa Present on parietal cells of the stomach mucosa Induces the secretion of gastric acid Induces the secretion of gastric acid

16. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 16 Mast Cells

17. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 17 Mast Cell Degranulation Chemotactic factors Chemotactic factors Neutrophil chemotactic factor Neutrophil chemotactic factor Attracts neutrophils Attracts neutrophils Eosinophil chemotactic factor of anaphylaxis (ECF-A) Eosinophil chemotactic factor of anaphylaxis (ECF-A) Attracts eosinophils Attracts eosinophils

18. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 18 Mast Cell Synthesis of Mediators: Late Response Leukotrienes Leukotrienes Product of arachidonic acid from mast cell membranes Product of arachidonic acid from mast cell membranes Similar effects to histamine in later stages Similar effects to histamine in later stages Prostaglandins Prostaglandins Similar effects to leukotrienes; they also induce pain Similar effects to leukotrienes; they also induce pain Platelet-activating factor Platelet-activating factor Similar effect to leukotrienes and platelet activation Similar effect to leukotrienes and platelet activation

19. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 19 Mast Cells

20. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 20 Phagocytosis Process by which a cell ingests and disposes of foreign material Process by which a cell ingests and disposes of foreign material Production of adhesion molecules Production of adhesion molecules Margination (pavementing) Margination (pavementing) Adherence of leukocytes to endothelial cells Adherence of leukocytes to endothelial cells Diapedesis Diapedesis Emigration of cells through the endothelial junctions Emigration of cells through the endothelial junctions

21. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 21 Phagocytosis

22. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 22 Phagocytosis Steps Steps Opsonization, recognition, and adherence Opsonization, recognition, and adherence Engulfment Engulfment Phagosome formation Phagosome formation Fusion with lysosomal granules Fusion with lysosomal granules Destruction of the target Destruction of the target

23. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 23 Phagocytes Neutrophils Neutrophils Also referred to as polymorphonuclear neutrophils (PMNs) Also referred to as polymorphonuclear neutrophils (PMNs) Predominate in early inflammatory responses Predominate in early inflammatory responses Ingest bacteria, dead cells, and cellular debris Ingest bacteria, dead cells, and cellular debris Cells are short lived and become a component of the purulent exudate Cells are short lived and become a component of the purulent exudate

24. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 24 Phagocytes Monocytes and macrophages Monocytes and macrophages Monocytes produced in bone marrow, enter circulation, and migrate to the inflammatory site, where they develop into macrophages Monocytes produced in bone marrow, enter circulation, and migrate to the inflammatory site, where they develop into macrophages Macrophages typically arrive at inflammatory site 3 to 7 days after neutrophils Macrophages typically arrive at inflammatory site 3 to 7 days after neutrophils Macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, and secretory products Macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, and secretory products

25. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 25 Phagocytes Eosinophils Eosinophils Mildly phagocytic Mildly phagocytic Duties Duties Defense against parasites and regulation of vascular mediators Defense against parasites and regulation of vascular mediators Basophils Basophils Role uncertain Role uncertain

26. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 26 Phagocytes Natural killer (NK) cells Natural killer (NK) cells Function: recognize and eliminate cells infected with viruses and some function in eliminating cancer cells Function: recognize and eliminate cells infected with viruses and some function in eliminating cancer cells Platelets Platelets Activation results in degranulation and interaction with components of the coagulation system Activation results in degranulation and interaction with components of the coagulation system

27. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 27 Cytokines Interleukins Interleukins Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation Many types Many types Examples Examples IL-1 is a proinflammatory cytokine IL-1 is a proinflammatory cytokine IL-10 is an anti-inflammatory cytokine IL-10 is an anti-inflammatory cytokine

28. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 28 Cytokines Interferon Interferon Protects against viral infections Protects against viral infections Produced and released by virally infected host cells in response to viral double-stranded RNA Produced and released by virally infected host cells in response to viral double-stranded RNA Types Types INF-α and INF-ß INF-α and INF-ß Induce production of antiviral proteins Induce production of antiviral proteins INF-γ INF-γ Increases microbiocidal activity of macrophages Increases microbiocidal activity of macrophages

29. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 29 Cytokines

30. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 30 Cytokines Tumor necrosis factor-α Tumor necrosis factor-α Secreted by macrophages in response to PAMP and Toll-like receptor recognition (i.e., in response to pathogens) Secreted by macrophages in response to PAMP and Toll-like receptor recognition (i.e., in response to pathogens) Induces fever by acting as endogenous pyrogen Induces fever by acting as endogenous pyrogen Increases synthesis of inflammatory serum proteins Increases synthesis of inflammatory serum proteins Causes muscle wasting (cachexia) and intravascular thrombosis Causes muscle wasting (cachexia) and intravascular thrombosis

31. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 31 Chemokines Induce WBC chemotaxis Induce WBC chemotaxis Produced by macrophages, fibroblasts, endothelial cells Produced by macrophages, fibroblasts, endothelial cells

32. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 32 Results from vascular changes and corresponding leakage of circulating components into the tissue Results from vascular changes and corresponding leakage of circulating components into the tissue Heat Heat Redness Redness Swelling Swelling Pain Pain Local Manifestations of Inflammation

33. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 33 Vascular Response Transient vasoconstrictionseconds Transient vasoconstrictionseconds Vasodilation Vasodilation Increased capillary permeability Increased capillary permeability Exudation of fluid and cells Exudation of fluid and cells Cellular migration (margination/adherence, migration) Cellular migration (margination/adherence, migration)

34. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 34 Exudative Fluids Serous exudate Serous exudate Watery exudate: indicates early inflammation Watery exudate: indicates early inflammation Fibrinous exudate Fibrinous exudate Thick, clotted exudate: indicates more advanced inflammation Thick, clotted exudate: indicates more advanced inflammation Purulent exudate Purulent exudate Pus: indicates a bacterial infection Pus: indicates a bacterial infection Hemorrhagic exudate Hemorrhagic exudate Exudate contains blood: indicates bleeding Exudate contains blood: indicates bleeding

35. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 35 Systemic Manifestations of Inflammation Fever Fever Caused by exogenous and endogenous pyrogens Caused by exogenous and endogenous pyrogens Act directly on the hypothalamus Act directly on the hypothalamus Leukocytosis Leukocytosis Increased numbers of circulating leukocytes Increased numbers of circulating leukocytes Left shift, increase in immature cells (bands) Left shift, increase in immature cells (bands) Increased plasma protein synthesis Increased plasma protein synthesis Acute-phase reactants Acute-phase reactants C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc. C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc.

36. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 36 Control of Inflammation Carboxypeptidaseinhibits C3a and C5a Carboxypeptidaseinhibits C3a and C5a Histaminaseinhibits histamine Histaminaseinhibits histamine Arylsulfataseinhibits histamine Arylsulfataseinhibits histamine C-1 esterase inhibitorinhibits complement C-1 esterase inhibitorinhibits complement Kinins and clotting Kinins and clotting

37. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 37 Chronic Inflammation Inflammation lasting 2 weeks or longer Inflammation lasting 2 weeks or longer Often related to an unsuccessful acute inflammatory response Often related to an unsuccessful acute inflammatory response Other causes Other causes High lipid and wax content of microorganism High lipid and wax content of microorganism Ability to survive inside the macrophage Ability to survive inside the macrophage Toxins Toxins Chemicals, particulate matter, or physical irritants Chemicals, particulate matter, or physical irritants

38. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 38 Chronic Inflammation

39. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 39 Chronic Inflammation Characteristics Characteristics Dense infiltration of lymphocytes and macrophages Dense infiltration of lymphocytes and macrophages Granuloma formation Granuloma formation Epithelioid cell formation Epithelioid cell formation Giant cell formation Giant cell formation

40. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 40 Resolution and Repair Regeneration Regeneration Resolution Resolution Returning injured tissue to the original structure and function Returning injured tissue to the original structure and function Repair Repair Replacement of destroyed tissue with scar tissue Replacement of destroyed tissue with scar tissue Scar tissue Scar tissue Composed primarily of collagen to restore the tensile strength of the tissue Composed primarily of collagen to restore the tensile strength of the tissue

41. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 41 Resolution and Repair Débridement Débridement Cleaning up dissolved clots, microorganisms, erythrocytes, and dead tissue cells Cleaning up dissolved clots, microorganisms, erythrocytes, and dead tissue cells Healing Healing Filling in the wound Filling in the wound Sealing the wound (epithelialization) Sealing the wound (epithelialization) Shrinking the wound (contraction) Shrinking the wound (contraction)

42. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 42 Healing Primary intention Primary intention Wounds that heal under conditions of minimal tissue loss Wounds that heal under conditions of minimal tissue loss Secondary intention Secondary intention Wounds that require a great deal more tissue replacement Wounds that require a great deal more tissue replacement Open wound Open wound

43. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 43 Healing Reconstructive phase Reconstructive phase Fibroblast proliferation Fibroblast proliferation Collagen synthesis Collagen synthesis Epithelialization Epithelialization Contraction Contraction Myofibroblasts Myofibroblasts Cellular differentiation Cellular differentiation

44. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 44 Healing Maturation phase Maturation phase Continuation of cellular differentiation Continuation of cellular differentiation Scar tissue formation Scar tissue formation Scar remodeling Scar remodeling

45. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 45 Healing

46. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 46 Dysfunctional Wound Healing Dysfunction during inflammatory response Dysfunction during inflammatory response Hemorrhage Hemorrhage Fibrous adhesion Fibrous adhesion Infection Infection Excess scar formation Excess scar formation Wound sepsis Wound sepsis Hypovolemia Hypovolemia Hypoproteinemia Hypoproteinemia Anti-inflammatory steroids Anti-inflammatory steroids

47. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 47 Dysfunctional Wound Healing Dysfunction during reconstructive phase Dysfunction during reconstructive phase Impaired collagen matrix assembly Impaired collagen matrix assembly Keloid scar Keloid scar Hypertrophic scar Hypertrophic scar Impaired epithelialization Impaired epithelialization Anti-inflammatory steroids, hypoxemia, and nutritional deficiencies Anti-inflammatory steroids, hypoxemia, and nutritional deficiencies Impaired contraction Impaired contraction Contracture Contracture

48. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 48 Dysfunctional Wound Healing

49. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 49 Dysfunctional Wound Healing Wound disruption Wound disruption Dehiscence Dehiscence Wound pulls apart at the suture line Wound pulls apart at the suture line Excessive strain and obesity are causes Excessive strain and obesity are causes Increased risk of wound sepsis Increased risk of wound sepsis

50. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 50 Pediatrics Neonates have transiently depressed inflammatory and immune function Neonates have transiently depressed inflammatory and immune function Neutrophils not capable of efficient chemotaxis Neutrophils not capable of efficient chemotaxis Neonates express complement deficiency Neonates express complement deficiency Deficient in collectins and collectin-like proteins Deficient in collectins and collectin-like proteins

51. Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 51 Older Adults Impaired inflammation likely a result of chronic illness Impaired inflammation likely a result of chronic illness Diabetes, cardiovascular disease, etc. Diabetes, cardiovascular disease, etc. Chronic medication intake decreases the inflammatory response Chronic medication intake decreases the inflammatory response Healing response is diminished due to loss of the regenerative ability of the skin Healing response is diminished due to loss of the regenerative ability of the skin Infections are more common in older adults Infections are more common in older adults