inflammation - modified for nursing.pptx

The best power point for presentation

1. Inflammation and tissue healing 12/29/2022 1

2. Outline Definition Nomenclature Etiology Cardinal signs Phases: Vascular and Cellular Acute vs chronic Tissue healing Types of healing(mechanism) 12/29/2022 2

3. Inflammation The survival of all organisms requires that they eliminate foreign invaders, such as infectious pathogens, and damaged tissues. These functions are mediated by a complex host response called inflammation 12/29/2022 3

4. What is inflammation? Inflammation – Protective response intended to eliminate the initial cause of cell injury and the necrotic cells and tissues arising from the injury accomplishes its protective mission by diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes and toxins) 4 12/29/2022

5. Cont… Without inflammation, infections would go unchecked and wounds would never heal. Serves to bring defense & healing mechanisms to the site of injury Could be harmful 12/29/2022 5

6. Nomenclature - itis Appendicitis Cellulitis Meningitis Pneumonitis Nephritis Myocarditis 12/29/2022 6

7. Etiologies Microbial infections--pneumonia, skin infections, etc. Physical agents: burns, trauma--like cuts, radiation Chemicals: toxins and caustic substances like battery acid Others: immunologic reactions-- rheumatoid arthritis 12/29/2022 7

8. 5 cardinal clinical signs of inflammation(external manifestations) rubor redness tumor swelling calor heat dolor pain Virchow added a fifth--loss of function 12/29/2022 8

9. 9 Acute inflammation The immediate and early response to an injurious agent Influx of neutrophils Chronic inflammation Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously Influx of lymphocytes and macrophages 12/29/2022

10. Acute inflammation -Has two major components -Vascular changes and cellular events 10 12/29/2022

11. Cont… 1.Vascular changes : Changes in Vascular Caliber and Flow begin rapidly after infection or injury but may develop at variable rates, depending on the nature and severity of the original inflammatory stimulus. transient vasoconstriction(lasting for seconds) arteriolar vasodilation 12/29/2022 11

12. Cont… As the microvasculature becomes more permeable, protein-rich fluid moves into the extravascular tissues → hemoconentration → stasis → margination of leukocytes 12/29/2022 12

13. 13 12/29/2022

14. Cont… The major local manifestations of acute inflammation, compared to normal. Vascular dilation and increased blood flow (causing erythema and warmth), Extravasation and deposition of plasma fluid and proteins (edema), and Leukocyte emigration and accumulation in the site of injury. 12/29/2022 14

15. Cont… Increased Vascular Permeability Early phase-the fluid is transudate transudation is soon eclipsed by increasing vascular permeability that allows the movement of protein-rich fluid and even cells (called an exudate ) into the interstitium. 12/29/2022 15

16. How do endothelial cells become permeable? Endothelial cell contraction Junctional retraction Direct endothelial injury (immediate sustained response) Leukocyte-dependent endothelial injury Increased transcytosis of fluid Leakage from new vessels 16 12/29/2022

17. Endothelial cell contraction postcapillary venules is the most common cause of increased vascular permeability . It is a reversible process elicited by histamine, bradykinin, leukotrienes, and many other chemical mediators(immediate transient response),short lived(15-30min) 12/29/2022 17

18. Direct endothelial injury (immediate sustained response ) Endothelial cell necrosis and detachment Result of severe injury or burn Occurs immediately and lasts until vessel repaired 18 12/29/2022

19. Leukocyte-dependent endothelial injury Occurs at sites of leukocyte accumulation Due to leukocyte activation which releases proteolytic enzymes and toxic oxygen 19 12/29/2022

20. Cont… 12/29/2022 20

21. Cont… 2.Cellular events Margination and Rolling Adhesion and Transmigration Migration into interstitial tissue 12/29/2022 21

22. Margination Normal flow - RBCs and WBCs flow in the center of the vessel A cell poor plasma is flowing adjacent to endothelium As blood flow slows, WBCs collect along the endothelium  Margination 22 12/29/2022

23. Endothelial Activation The underlying stimulus causes release of mediators which activate the endothelium causing selectins and other mediators to be moved quickly to the surface 23 12/29/2022

24. Selectins Selectins bind selected sugars Se lected + Lectins (sugars) = Selectins Some selectins are present on endothelial cells (E- Selectin ) Some selectins are present on leukocytes (L- Selectin ) Some selectins are present on platelets (P- Selectin ) Weak & transient binding Results in rolling 24 12/29/2022

25. 25 12/29/2022

26. 26 SLOWING CONCENTRATION Margination Rolling Adhesion Transmigration 12/29/2022

27. 27 12/29/2022

28. Rolling Selectins transiently bind to receptors PMNs bounce or roll along  Rolling 28 12/29/2022

29. 29 12/29/2022

30. Adhesion Mediated by integrins ICAM-1 and VCAM-1 Intracellular adhesion molecule, vascular adhesion molecule 30 12/29/2022

31. 31 12/29/2022

32. Transmigration Mediated/assisted by PECAM-1 & ICAM-1 ( Integrins ) Diapedesis (cells crawling) Primary in venules Collagenases degrade BM  Permeability platelet endothelial cell adhesion molecule 1(PECAM-1) 32 12/29/2022

33. 33 12/29/2022

34. Chemotaxis Movement toward the site of injury along a chemical gradient Chemotactic factors include Complement components (20 serum proteins) Arachadonic acid (AA) metabolites Soluble bacterial products Chemokines , cytokines 34 12/29/2022

35. Cont… Leukocyte Activation Stimuli include microbes, products of necrotic cells, and several mediators leukocyte express on their surface different kinds of receptors that sense the presence of microbes Leukocyte activation results in many enhanced functions 12/29/2022 35

36. Phagocytosis Phagocytosis (engulf and destroy): consists of three distinct but interrelated steps Recognition & attachment Leukocytes bind and ingest most microorganisms and dead cells via specific surface receptors, which recognize either components of the microbes and dead cells, or host proteins, called opsonins , that coat microbes and target them for phagocytosis (a process called opsonization ) 36 12/29/2022

37. Cont… The most important opsonins are antibodies of the immunoglobulin G ( IgG ) class that bind to microbial surface antigens, breakdown products of the complement protein C3, and plasma carbohydrate-binding lectins called collectins , which bind to microbial cell-wall sugar groups. 12/29/2022 37

38. Cont… Engulfment Killing/degradation O 2 dep: Reactive O 2 species(ROS) ,phagocytosis stimulates the oxidative burst O 2 indep: Bactericidal permeability agents, lysozyme, elastase, lactoferrin,major basic protein(MBP) 12/29/2022 38

39. 12/29/2022 39

40. Leukocyte-induced tissue injury Lysosomal enzymes are released into the extracellular space during phagocytosis causing cell injury and matrix degradation Activated leukocytes release reactive oxygen species and products of arachidonic acid metabolism which can injure tissue and endothelial cells These events underlie many human diseases (e.g. Rheumatoid arthritis) 40 12/29/2022

41. Cont… Defects in Leukocyte Function Genetic or aquired increased susceptibility to infections Genetic defects are rare 12/29/2022 41

42. Leukocyte adhesion deficiency 1 (LAD-1) Recurrent bacterial infections Inflammatory lesions lack neutrophil infiltrate High numbers of neutrophils in the circulation Neutrophils from patients can roll but do not stick  chain of CD11/CD18 sub unit of integrins 42 12/29/2022

43. Chediak-Higashi Syndrome Defect in fusion of phagosome with phagolysosome 43 12/29/2022

44. Chronic Granulomatous Disease Defect in NADPH oxidase system Marked decrease in ability to kill microorganisms 44 12/29/2022

45. Outcome of acute inflammation 12/29/2022 45

46. MORPHOLOGIC PATTERNS OF ACUTE INFLAMMATION Depends on severity, the cause and the particular tissue involved Serous inflammation: is characterized by the outpouring of a watery, relatively protein-poor fluid that, depending on the site of injury, derives either from the serum or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. 12/29/2022 46

47. Fibrinous inflammation occurs as a consequence of more severe injuries, resulting in greater vascular permeability that allows large molecules (such as fibrinogen) to pass the endothelial barrier A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura. 12/29/2022 47

48. Cont… Can result in resolution (removal by fibrinolytic system) or organization (in the ingrowth of fibroblasts and blood vessels) leading to scarring Suppurative (purulent) inflammation is manifested by the presence of large amounts of purulent exudate (pus) consisting of neutrophils, necrotic cells, and edema fluid. 12/29/2022 48

49. Abscesses are focal collections of pus that may be caused by seeding of pyogenic organisms into a tissue or by secondary infections of necrotic foci. An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by necrosis of cells and sloughing (shedding) of inflammatory necrotic tissue 12/29/2022 49

50. occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most commonly encountered in (1) Inflammatory necrosis of the mucosa of the mouth, stomach, intestines, or genitourinary tract; and (2) Tissue necrosis and subcutaneous inflammation of the lower extremities in older persons who have circulatory disturbances that predispose to extensive necrosis. 12/29/2022 50

51. Chemical Mediators of Inflammation: Each phase of Inflammation is orchestrated by several chemical mediators – cytokines. Most mediators induce their effects by binding to specific receptors on target cells Can have very few targets or widespread effects Mediators may stimulate target cells to release secondary effector molecules. Different mediators may have similar actions 12/29/2022 51

52. Cont… The actions of most mediators are tightly regulated. Once activated and released from the cell, mediators quickly decay (e.g., arachidonic acid metabolites), are inactivated by enzymes (e.g., kininase inactivates bradykinin ), are eliminated (e.g., antioxidants scavenge toxic oxygen metabolites), or are inhibited (complement-inhibitory proteins). 12/29/2022 52

53. Cont… 53 12/29/2022

54. Cont… Cell-Derived Mediators The two vasoactive amines histamine and serotonin are stored as preformed molecules in mast cells and other cells and are among the first mediators to be released in acute inflammatory reactions 12/29/2022 54

55. Vasoactive amines Histamine Found in mast cells, basophils and platelets Released in response to stimuli Promotes arteriolar dilation and venular endothelial contraction results in widening of interendothelial cell junctions with increased vascular permeability Serotonin Vasoactive effects similar to histamine Found in platelets Released when platelets aggregate 55 12/29/2022

56. Preformed histamine is released from mast cell granules in response to a variety of stimuli: (1) physical injury such as trauma or heat; (2) immune reactions involving binding of IgE antibodies to Fc receptors on mast cells (3) C3a and C5a fragments of complement, the so-called anaphylatoxins 12/29/2022 56

57. (4) leukocyte-derived histamine-releasing proteins; (5) neuropeptides (e.g., substance P); and (6) certain cytokines (e.g., IL-1 and IL-8). 12/29/2022 57

58. Arachidonic Acid (AA) Arachidonic Acid (AA) Metabolites: Prostaglandins, Leukotrienes , and Lipoxins AA is a component of cell membrane phospholipids Where is it located? The breakdown of AA into its metabolites produces a variety of biologic effects 58 12/29/2022

59. Arachidonic acid metabolites Metabolites of AA - short-range hormones AA metabolites act locally at site of generation Rapidly decay or are destroyed 59 12/29/2022

60. Arachidonic Acid AA is released from the cell membrane by phospholipases which have themselves been activated by various stimuli and/or inflammatory mediators AA metabolism occurs via two major pathways named for the enzymes that initiate the reactions; lipoxygenase and cyclooxygenase 60 12/29/2022

61. 61 AA metabolites (eicosanoids) Cyclooxygenases synthesize Prostaglandins Thromboxanes Lipoxygenases synthesize Leukotrienes Lipoxins 12/29/2022

62. 12/29/2022 62

63. Platelet-Activating Factor (PAF) Another phospholipid-derived mediator released by phospholipases Induces aggregation of platelets Causes vasoconstriction and bronchoconstriction 100 to 1,000 times more potent than histamine in inducing vasodilation and vascular permeability Enhances leukocyte adhesion, chemotaxis, degranulation and the oxidative burst 63 12/29/2022

64. Cytokines Polypeptides that are secreted by cells Act to regulate cell behaviors Autocrine, paracrine or endocrine effects These “biological response modifiers” are being actively investigated for therapeutic use in controlling the inflammatory response. 64 12/29/2022

65. Cont…. major cytokines in acute inflammation are TNF and IL-1, as well as a group of chemoattractant cytokines called chemokines. Other cytokines that are more important in chronic inflammation include interferon-γ (IFN-γ) and IL-12 12/29/2022 65

66. 66 12/29/2022

67. Nitric Oxide NO is a soluble free radical gas Made by nitric oxide synthetase (NOS) in endothelium (eNOS), macrophages ,cardiac myocytes,hepatocytes(iNOS), and specific neurons in the brain (nNOS) Broad range of functions and effects that are short range Vasodilatation by relaxing smooth muscle.  platelet aggregation Inhibits mast cells Regulates leukocyte recruitment 67 12/29/2022

68. Reactive Oxygen Species ROS are synthesized via the NADPH oxidase (phagocyte oxidase) pathway and are released from neutrophils and macrophages that are activated by microbes, immune complexes, cytokines, and a variety of other inflammatory stimuli Kill microbes and destroy phagocytosed cells 12/29/2022 68

69. Cont… At higher levels damage tissues by varieties of ways endothelial damage, with thrombosis and increased permeability; protease activation and antiprotease inactivation, with a net increase in breakdown of the ECM; and direct injury to other cell types (e.g., tumor cells, erythrocytes, parenchymal cells). 12/29/2022 69

70. Plasma Protein-Derived Mediators Circulating proteins of three interrelated systems-the complement, kinin, and coagulation systems-are involved in several aspects of the inflammatory reaction. 12/29/2022 70

71. Chronic inflammation Inflammation of prolonged duration in which active inflammation, tissue injury and the healing proceed simultaneously Occurs in: Persistent infections – Tubercule , fungi, Treponemes Low toxicity Delayed hypersensitivity Granulomatous inflammation Prolonged exposure potentially toxic agents Silica Toxic plasma lipids  atherosclerosis Autoimmunity - RA, lupus   71 12/29/2022

72. Chronic inflammation is characterized by: Infiltration with mononuclear cells (macrophages, lymphocytes & plasma cells) Tissue destruction Repair involving angiogenesis and fibrosis Attempts at healing by connective tissue replacement of damaged tissue 72 12/29/2022

73. 73 Key macrophage events 1. Recruitment from circulation 2. Local Proliferation 3. Immobilization 4. Differentiation (microglia, kupffer , alveolar macrophage, osteoclasts). Macrophage prominent role due the large repertoire of products it can produce when activated Tox. O 2 Proteases Collagenases Chemotx factors Coag factors AA metabolites NO PDGF FGF TGF-  12/29/2022

74. 12/29/2022 74

75. Granulomatous Inflammation Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by focal accumulations of activated macrophages, which often develop an epithelial-like ( epithelioid ) appearance. It is encountered in a limited number of immunologically mediated, infectious and some noninfectious conditions. 12/29/2022 75

76. Cont… 76 Granuloma – focal collection of granulomatous inflammation Bacteria Tuberculosis Leprosy Parasites Schistosomiasis Fungi Histoplasmosis Blastomycosis Metal/Dust Silicosis Foreign body Splinter Suture Graft material 12/29/2022

77. Tissue repair Critical to the survival of an organism is the ability to repair the damage caused by toxic insults and inflammation 12/29/2022 77

78. Tissue repair = restoration of tissue architecture and function after an injury Occurs in two ways: Regeneration of injured tissue(replacement of damaged components) Replacement by connective tissue :a process termed healing which results scarring Usually, tissue repair involves both processes Involves cell proliferation , and interaction between cells and extracellular matrix 12/29/2022 78

79. Important background facts cellular proliferation growth factors the extracellular matrix The process of tissue repair regeneration scarring an illustration: skin wound healing why do good wounds go bad(factors affecting wound healing)? LECTURE OVERVIEW 12/29/2022 79

80. Lots of cells proliferate during tissue repair: injured tissue remnants vascular endothelial cells fibroblasts You need to know a few things about: the cell cycle the proliferative capacities of different tissues stem cells growth factors the extracellular matrix CELLULAR PROLIFERATION 12/29/2022 80

81. The Cell Cycle 12/29/2022 81

82. Continuously dividing (labile) tissues Stable tissues Permanent tissues Tissues of the body are divided into three groups: CELLULAR PROLIFERATION 12/29/2022 82

83. Continuously dividing (labile) tissues cells are continuously proliferating can easily regenerate after injury contain a pool of stem cells examples: bone marrow, skin, GI epithelium 12/29/2022 83

84. Stem cells in skin 12/29/2022 84

85. Stem cells in GI epithelium 12/29/2022 85

86. Stable tissues cells have limited ability to proliferate limited ability to regenerate (except liver!) normally in G , but can proliferate if injured examples: liver, kidney, pancreas 12/29/2022 86

87. Permanent tissues cells can’t proliferate can’t regenerate (so injury always leads to scar) examples: neurons, cardiac muscle 12/29/2022 87

88. The Cell Cycle and Different Cell Populations 12/29/2022 88

89. GROWTH FACTORS Very important in tissue repair. Actions: stimulate cell division and proliferation promote cell survival Huge list! Usually have “GF” in name: EGF TGF PDGF 12/29/2022 89

90. THE EXTRACELLULAR MATRIX ECM is the network that surrounds cells Two forms: interstitial matrix and basement membrane Does lots of things! Sequesters water and minerals Gives cells a scaffold to adhere to Stores growth factors 12/29/2022 90

91. The Extracellular Matrix 12/29/2022 91

92. Bottom line: ECM regulates proliferation, movement, and differentiation of the cells living in it. If you screw up your ECM, you can’t regenerate! You’ll form a scar instead. 12/29/2022 92

93. REGENERATION Occurs all the time in labile tissues Cells are constantly being lost and replaced If demand increases, supply increases easily Occurs in limited form in stable tissues Remove one kidney: the other one undergoes hypertrophy and hyperplasia Remove half of the liver: it will grow back Only occurs if residual tissue is intact! 12/29/2022 93

94. Liver before resection Liver 1 week after resection right lobe to be resected left lobe now enlarged 12/29/2022 94

95. SCARRING If injury is severe, regeneration can’t happen So, fibrosis (a scar) replaces the injured tissue Four components to this process: new vessel formation (angiogenesis) fibroblast proliferation synthesis of collagen (scar formation) remodeling of scar 12/29/2022 95

96. By 24 hours: Endothelial cells start proliferating Fibroblasts emigrate By 3-5 days: granulation tissue present Weeks later: dense fibrosis (scar) scar is remodeled over time 12/29/2022 96

97. Summary: make granulation tissue turn it into a chunk of collagen 12/29/2022 97

98. SKIN WOUND HEALING First intention Second intention 12/29/2022 98

99. first intention healing second intention healing 12/29/2022 99

100. Healing by First Intention Occurs in small wounds that close easily Epithelial regeneration predominates over fibrosis Healing is fast, with minimal scarring/infection Examples: Well-approximated surgical incisions 12/29/2022 100

101. By 24 hours By 3-7 days Weeks later Healing by First Intention: Timeline 12/29/2022 101

102. By 24 hours clot forms neutrophils come in epithelium begins to regenerate Healing by First Intention: Timeline 12/29/2022 102

103. By 24 hours By 3-7 days macrophages come in granulation tissue is formed new blood vessels fibroblasts collagen begins to bridge incision epithelium increases in thickness Healing by First Intention: Timeline 12/29/2022 103

104. By 24 hours By 3-7 days Weeks later granulation tissue gone collagen is remodeled epidermis full, mature (but without dermal appendages!) eventually, scar forms Healing by First Intention: Timeline 12/29/2022 104

105. 12/29/2022 105

106. 6 hours 24 hours 2 days 1 week 12/29/2022 106

107. Occurs in larger wounds that have gaps between wound margins Fibrosis predominates over epithelial regeneration Healing is slower, with more inflammation and granulation tissue formation, and more scarring Involves wound contraction aided by myofibroblasts(modified fibroblasts): Within 6 weeks, for example, large skin defects may be reduced to 5% to 10% of their original size, largely by contraction. Examples: Infarction,Large burns and ulcers Healing by Second Intention 12/29/2022 107

108. More inflammation More granulation tissue Wound contraction Differences from healing by first intention: 12/29/2022 108

109. 12/29/2022 109

110. 12/29/2022 110

111. 12/29/2022 111

112. At suture removal: 10% Rapid increase over next 4 weeks At third month: 70-80% Wound Strength 12/29/2022 112

113. Factors that influence healing Nutrition - vitamin C Metabolic status – diabetes hinders Circulatory status Hormones – steroids/glucocorticoids inhibit Infection Mechanical stress Foreign bodies Size, locations and type of the wound 113 12/29/2022

114. Complications in cutaneous wound healing 1. Deficient scar formation wound dehiscence & incisional hernias ulceration 2. Excessive scar formation Keloid(exuberant amount of collagen giving raised scar) Hypertrophic scar 3. Excessive contraction 114 12/29/2022

115. 12/29/2022 115

116. 12/29/2022 116

117. 117 12/29/2022