1. بسم الله الرحمن الرحيم Inflammation Professor Dr. Wahda M.T. Al-Naeimy Pathology Department Faculty of Medicine University of Mosul

2. Definition of INFLAMMATION §Inflammation is the response of living tissues to cell injury. § Its purpose is to localize & eliminate the causative agent, to limit tissue injury & then to restore the tissue to normality or as close to normality as possible. §It is often beneficial, but sometime harmful. §The nomenclature used to describe inflammation in different tissues employs the tissue name and the suffix “-itis” e.g., l Appendicitis,Dermatitis,Cholecystitis, hepatitis,lung, brain …..ect.

3. Cardinal signs of (acute) inflammation §Rubor = redness due to V.D. §Tumor = swelling due to exudate. §Calor = heat due to V.D. §Dolor = pain due to secretion of PG,BK & nerve compression & irritation. (described by Celsus 1 st. Century AD) §Functio laesa = loss of function due to pain & swelling i.e. reflux immobilization due to pain. (added by R. Virchow) Cellulits = acute skin infection commonly caused by Streptococcus pyogenes or Staphylococcus aureus

5. Causes of Inflammation: 1.Infections:e.g., bacterial, viral, parasitic fungal ….. 2.Physical agents: e.g., heat, cold, radiation……. 3.Chemical agents: e.g., acid, alkaline, drugs…….. 4.Hypersensitivity: e.g., rheumatic fever……….. 5.Tissue necrosis: e.g., Ischemic necrosis.

6. Components involved in inflammation §1- Blood vessels. §2- Plasma & plasma proteins. §3- Cells l Circulating cells include :Neutrophiles, Monocytes, L, E, B, & plasma cells. l Connective tissue cell include : mast cells, fibroblasts, Macrophage & Lymphocytes. §4- Extra-celluar matrix l Collagen, elastic tissue, adhesive glycoproteins, protoglycans & basement membrane.

7. Main Functions of Inflammatory response §1.Dilute,destroy and wall off injurious agents. §2.Start process of healing. Types of inflammation §1.Acute inflammation. §2.Chronic inflammation. §3. Acute on chronic inflammation.

8. Acute inflammation §Short duration: hours - days –weeks. §Exudative fluid (protein rich fluid + inflammatory cells + debris). §Main inflammatory cells l Neutrophile & Macrophage. Chronic inflammation §Long duration: months – years. §Fibrosis ( productive ). §Main inflammatory cells l L, M, plasma cells + fibroblasts & endothelial cells.

10. Exudate §Due to increase vascular permeability induced by chemical mediators and due to the direct damage of the vessels, excessive fluid passes to the extra-cellular spaces result in edema. §It is consist of: l 1.Fluid rich in plasma proteins. l 2.Fibrin. l 3.Cells: Neutrophils, Macrophages, eosinophils, few lymphocytes & red blood cells. l 4.Debris.

12. What are the function of EXUDATE? l 1.It dilutes toxins. l 2.It contains fibrin which localize infection. l 3.It carries oxygen, nutrients to the inflammatory cells. l 4.It carries Drugs, antibodies against bacteria.  It may have harmful effects e.g. causing life- threatening hypersensitivity reactions, or relentless and progressive organ damage from chronic inflammation and subsequent fibrosis ( e.g. rheumatoid arthritis, atherosclerosis).

14. What’s the effects of Acute Inflammation BENIFITIAL effect §Dilution of toxins §Entry of antibodies §Drug transport §Fibrin formation §Delivery of nutrient & O2 §Stimulation of immune system HARMFUL effect §Digestion of normal tissue §Swelling & pain §Inappropriate inflammatory response.

15. Acute inflammation It is the response of living vascularised tissue to injury. This response is: 1.Uniform, 2.Last for short time. 3.Characterised by exudation of fluid (Edema) and cells (Neutrophile). §Neutrophiles are predominant inflammatory cells in early stages (6 - 24 hours). §Monocytes ( macrophages) predominate inflammatory cells in later stages (24 - 48 hours).

16. Processes of acute inflammatory response I- Vascular changes l Alteration in vascular caliber resulting in local increase in blood flow. l Structural changes resulting in increase vascular permeability. II- Leukocyte cellular events l Margination, pavementation & rolling. l Adhesion & transmigration. l Chemotaxis & activation. l Phagocytosis & degranulation. l Release of leukocyte products.

17. I- Vascular changes §1) Change in caliber l Initially arteriolar vasoconstriction. l Then arteriolar vasodilatation. §2) Increase permeability l Hallmark of acute inflammation. l Result in marked outflow of fluid into interstitial tissue ( exudate). l Ending in increase blood viscosity & slowing of the circulation (stasis).

19. Active hyperemia Increased blood flow at the site of inflammation is due to the vasodilatation and due to opening of new capillaries. It last for minutes to hours depending on the severity of injury. It is the cause of redness (erythema) and hotness.

21. §Definitions: l Edema: excess fluid in interstitial tissue or body cavities. May be either an exudate or transudate Exudate: an inflammatory extravascular fluid that has a high protein concentration ( 35-50 gm/l), cellular debris, and a specific gravity above 1.020. Transudate: an extravascular fluid with low protein content and a specific gravity of less than 1.015. essentially an ultrafiltrate of blood plasma resulting from eleveted hydrostatic pressure or diminished osmotic forces in the plasma.

22. Vascular changes and fluid leakage during acute inflammation lead to Edema in a process called Exudation Transudate result of hydrostatic or osmotic imbalance ultrafiltrate of plasma Low protein content specific gravity < 1.015 Exudate result of inflammation vascular permeability high protein content specific gravity >1.020

23. Leukocyte cellular events in acute inflammation 1) Margination (pavement) & rolling l With slowing of the circulation, leukocytes accumulate along vascular endothelial surface (Margination or Pavement). l Then they tumble on the endothelial surface, transiently sticking on the way (rolling) using selectins adhesion molecules. 2) Adhesion & transmigration l More firm & stable sticking of leukocytes to endothelial surface (adhesion) using integrins adhesion molecule l Then leukocytes pass between endothelial cells along the intercellular junction (transmigration) using PCAM-1

27. -Pus (purulent exudate): an inflammatory exudate rich in leukocytes (mostly neutrophils), cellular debris, and in many cases microbes.

28. 3) Chemotaxis & activation l Chemotaxis:controled movement of WBCs toward a chemical gradient known as chemotaxins. l Chemotaxins:The substance which induce (stimulate) chemotaxis e.g. bacteria, chemical mediators………. l Types of chemotaxins: Exogenous: bacterial products Endogenous: –C5a (complement factor) –LTB4 (lipo-oxygenase pathway) –IL-8 (Cytokines) –PAF (platelate activating factor)

30. 4) Phagocytosis & degranulation §By neutrophiles & macrophages. §Three steps 1-Recognition & attachment l facilitated by coating of microorganisms by serum proteins called OPSONINS. Mainly IgG & C3b that bind to Fc & C receptors on the WBC. 2-Engulfment l through formation of pseudopodia, phagosome, phagolysosome. 3-Killing or degradation l through formation of free radicals (Superoxides, hydrogen peroxide (H2O2) & hydrochloride (HOCL) ).

31. 5) Release of leukocyte products §These include: l Lysosomal enzymes (protease). l Oxygen-derived active metabolites (free radicals). l Products of Arachidonic acid metabolism (lipo- oxygenase & cyclo-oxygenase products).

32. What’s the Functions of leukocytes? Leukocytes extra-vasation have critical function in inflammation it: §1.Ingest offending agents. §2. Kill bacteria. §3.Digest necrotic materials. §4.Release lysosomal enzymes. §5.Release free radicals. §6. Release chemical mediators.

34. Diapedesis Passage of RBCs through the defect created by the WBCs. It is a passive process.

35. Summary Changes of Acute Inflammation Transient vasoconstriction  Prolonged vasodilatation  Increased blood flow (Active hyperemia)  increased vascular permeability-  Stasis of blood  Swelling of endothelial cells  margination or pavementation of WBC  Exudation of WBC (emigration) and passage of RBC (Diapedesis) & exudation of fluid.

36. Chemical Mediators §A substances which play a role in genesis and modulation of inflammatory reaction. §They are responsible for: l 1. Vasodilatation. l 2.Increased permeability of the blood vessels. l 3.Emigration of WBC ( Chemotactic agent).

37. Types of chemical mediators 1.Those formed in plasma. 2.Those formed in tissue cells.

38. Mediators of acute inflammation Plasma factors synthesized mainly in liver Plasma proteins Factor XII = coagulation system (Hageman factor) activation Kinin system Coagulation system Complement activation C3a C5a C3b C5b-C9 anaphylatoxins opsonin MAC

39. Chemical Mediators of Inflammation A/ Vasoactive Amines 1) Histamine: secreted from mast cells, basophiles & platelets. 2) Serotonin: secreted from platelets, enterochromaffin cells. Effects: arteriolar vasodilatation & increase vascular permeability.

40. B/ Arachidonic Acid (AA) Metabolites §AA present in the cell membrane phospholipids. §Release from phospholipids through the action of phospholipase enzyme by mechanical, chemical & physical stimuli. §AA metabolism proceeds along one of two pathways l Cyclo-oxygenase pathway--- Prostoglandins (PG) l Lipo-oxygenase pathway------Leukotriens (LT)

41. Arachidonic Acid Metabolites Cyclo-oxygenase pathway §Thromboxane A2 l Vasoconstriction l Platelet aggregation §Protacyclin (PGI2) l Vasodilatation l Inhibits Platelet aggregation §PGD2, PGE2 & PGF2 l VD & edema §PGE2: l Fever l Pain Lipo-oxygenase pathway §5-HETE: l Chemotaxis §LTB4: l Chemotaxis l Aggregation of neutrophils §LTC4, LTD4, LTE4 l Vasoconstriction l Bronchospasm l Increase vascular permeability

42. C/ Platelet-Activating Factor (PAF) §Synthesized from membrane phospholipids through the action of phospholipase A2 in basophiles, endothelial cells & neutrophiles. §Effect: l Platelet aggregation. l V.D. & increase vascular permeability. l Chemotaxis. l Smooth muscle contraction.

43. D) Cytokines §Polypeptides produced by activated lymphocytes & macrophages. §It involved in cellular immunity & inflammatory responses. l IL-1 & TNF Acute phase reaction including fever & Neutrophilia. Promote endothelial secretion of PG & NO. Induce fibroblastic proliferation & collagen synthesis. l IT-6 Acute phase reactions. l IT-8 Chemotactant & neutrophiles activating agent.

44. E) Nitric Oxide (NO) §Soluble free radical gas synthesized by endothelial cells, macrophages & specific neurons in the brain. §Effects of the Nitric Oxide: l Vascular smooth muscle relaxation causing vasodilatation. l Decreased platelet aggregation & adhesion. l Microbicidal agent.

45. F) Lysosomal Constituents §Potentially act as inflammatory mediators when released from neutrophiles & macrophages. §Effect: l Destruction of ECM. l Direct cleavage of C3 & C5.

46. G) Oxygen Free Radicals §Superoxide (O2 - ), OH -, H2O2 & NO §Effects: l Endothelial cell damage causing increase vascular permeability. l Activation of proteinases. l Injury to surrounding cells.

47. H/ Plasma Proteases 1) Complement System §Present as inactive form in the plasma l Vascular effect (anaphylatoxins): C3a, C5a & C4a causing V.D. & increase vascular permeability. l Leukocyte adhesion, chemotaxis & activation by C5a l Phagocytosis by C3b & C3b1 act as opsonin.

48. 2) Kinin System §Activated by activation of Hageman factor (XII) l Bradykinin: increase vascular permeability, V.D., pain & smooth muscle contraction. l Kallikrein: has chemotactic activity.

49. 3) Clotting System §A cascade activated by Hageman factor (XII) resulting in conversion of fibrinogen to fibrin. l Fibrinopeptides: increase vascular permeability & chemotaxis.

50. 4) Fibrinolytic System: l Plasmin: lyses fibrin clots, degrades fibrin to fibrin degradation products. l Fibrin degradation products: Increase vascular permeability.

51. Microscopic appearance of acute inflammation §Congestion of blood vessels. §Exudation of fluid. §Exudation of inflammatory cells mainly neutrophiles.

54. Microscopic types of acute inflammation 1. Cattarhal l Acute inflammation + mucus hypersecretion of mucus membrane (common cold). 2. Serous l Low protein content, low cellular fluid (pleural effusion). 3. Suppurative (Purulent) l Pus: creamy yellow or blood stained fluid consist of N, M.O., & tissue debris (acute appendicitis). l Abscess:localized collection of pus material (cavity containing pus). l Empyema: Collection of pus in the hallow organ. 4. Fibrinous l Accumulation of thick exudate rich in fibrin, which may resolve by fibrinolysis or organize into thick fibrous tissue. Fibrinous inflammation –bread &butter appearance to the inflamed serous membrane.

55. Morphologic patterns of acute inflammation Serous inflammation: Tissue fluid accumulation indicating a modest increase in vascular permeability Pleura, pericardium, peritoneum: effusion,Blister in burns

57. §Fibrinous inflammation: §More marked increase in vascular permeability, with exudates containing large amounts of fibrinogen §Involvement of serosal surfaces ( pericardium or pleura) : fibrinous pericarditis or pleuritis

59. §Suppurative or purulent inflammation: §Production of purulent exudates consisting of leukocytes and necrotic cells.

60. What’s the fates (outcomes) of acute inflammation? Depending on the nature of lesion, site & response of the host. The followings are the outcome of acute inflammation: 1-Complete resolution: restoration of site of acute inflammation to normal. It involve: l removal of the exudate, fibrin & debris. l reversal of the microvascular changes. l regeneration of lost cells.

61. Complete resolution

62. Fates (outcomes) of acute inflammation (cont.) 2-Healing & organization : replacement of dead tissue by granulation tissue which mature in to fibrous tissue. It is seen in chronic inflammation, In excessive tissue damage & excessive fibrin deposition. 3-Suppuration It may be diffuse in tissue, localized in tissue (abscess), on the surface of a wound, or in serous cavity. 4-Progression to chronic inflammation: Acute inflammation progress in to chronic inflammation when there is persistent infection, when there is foreign body…………….

63. Ulcer: §Local erosions ( Loss of continuity ) of epithelial surfaces produced by sloughing of inflamed necrotic tissue.

64. Role of lymphatic system in inflammation §The local inflammatory reaction may fail in containing the injurious agent §Secondary lines of defense l Lymphatic system; causing lymphangitis (lymphatic vessels inflammation) lymphadenitis (lymph nodes inflammation) l Monocytic-phagocytic system; involve phagocytic cells of spleen, liver & Bone marrow.