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  1. 1. Acute and Chronic Inflammation CHEGE.B.M Lecturer/Medical Physiologist
  2. 2. Learning objectives • Definition • Introduction • Cellular events • Vascular events • Patterns including suppurative • Outcomes
  3. 3. Acute Inflammation
  4. 4. Definition • Inflammation is a response of vascularized tissues to infections and tissue damage that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents • Rapid host response that serves to deliver leucocytes and plasma proteins such as antibodies to sites of infection or tissue injury.
  5. 5. Inflammation is a war • Coordinated response to eliminate the cause and consequence of injury or infection (noxious agent) • Involves immune (cellular events) and vascular systems (Vascular events)
  6. 6. Inflammatory process • Inflammation • Purpose is 3 d’s:  Destroy  Dilute  Dam-off • Desired result is healing  Regeneration (hyperplasia)  Fibrosis (scarring) • Collateral damage may occur
  7. 7. CARDINAL SIGNS OF INFLAMMATION Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Functio laesa (loss of function)
  8. 8. Inflammatory stimuli Infective agents like bacteria, viruses and their toxins, fungi, parasites Immunological agents like cell-mediated and antigen-antibody reactions Physical agents like heat, cold, radiation, mechanical trauma Chemical agents like organic and inorganic poisons Inert materials such as foreign bodies
  9. 9. The typical inflammatory reaction develops through a series of sequential steps: • The offending agent, which is located in extravascular tissues, is recognized by host cells and molecules. • Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located. • The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance. • The reaction is controlled and terminated. • The damaged tissue is repaired.
  10. 10. Types of Inflammation Inflammation may be of two types,  Acute inflammation  Chronic inflammation
  11. 11. Acute Inflammation • The initial, rapid response to infections and tissue damage is called acute inflammation. • It typically develops within minutes or hours and is of short duration, lasting for several hours or a few days. • Acute inflammation is a stereotyped response (unlearned behavioral reaction of an organism to some environmental stimulus)to recent or ongoing injury Chronic Inflammation • If the initial response fails to clear the stimulus, the reaction progresses to a protracted type of inflammation that is called chronic inflammation. • Chronic inflammation may follow acute inflammation or arise de novo (From beginning). • It is of longer duration and is associated with more tissue destruction, the presence of lymphocytes and macrophages, the proliferation of blood vessels, and fibrosis.
  12. 12. ACUTE INFLAMMATION Acute inflammation has three major components: (1) dilation of small vessels, leading to an increase in blood flow, (2) increased permeability of the microvasculature, enabling plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
  13. 13. Reactions of Blood Vessels in Acute inflammation (Acute Vascular Changes) • The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury. • Definitions • An exudate? • Transudate? • Edema?
  14. 14. Acute vascular changes • Transient arteriolar constriction (seconds) • Nerve reflex, endothelin • Like the immediate first step of hemostasis • Vasodilation of arterioles (until resolution) • Histamine, bradykinin mediate rapid response • Sustained by prostaglandins and NO • Hyperemia, erythema • Transudation increases blood viscosity, slows flow • Stasis and congestion in venules allows cells to contact endothelium • Vascular leakage (minutes to hours to days) • Histamine, bradykinin mediate rapid response • Sustained by C3a, C5a, PAF, leukotrienes • Exudation results in local edema
  15. 15. Increased vascular permeability • Contraction of vascular endothelium—rounding of cells and widening of intercellular spaces  Immediate, transient response (15-30 min) • Stimulated by histamine, bradykinin, substance P • venules of 20 – 60 um diameter respond  Delayed prolonged leakage (radiation burns) • begins after 2 – 12 h delay, lasts hours – days • stimulated by cytokines and apoptotsis of injured skin cells • venules and capillaries respond  Immediate, sustained response (days) • caused by direct damage to vasular endothelium • venules, capillaries, arterioles respond • ended by hemostasis, thrombosis, regeneration  Neutrophil-induced damage (days) • caused when neutrophils adhere and emigrate
  16. 16. Leukocyte extravasation • Margination, rolling • Decreased flow rate and volume push WBCs toward vascular walls • Intermittent binding of selectins with glycoproteins causes rolling • Adhesion, pavementing • mediated by integrins on leukocytes, activated by cytokines • integrin ligands VCAM-1, ICAM-1 on endothelial cells induced by TNF and IL-1 • Transmigration or diapedesis • chemokines stimulate adherent leukocytes to migrate through interendothelial spaces
  17. 17. • The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines. • This process can be divided into phases, consisting first of adhesion of leukocytes to endothelium at the site of inflammation, then transmigration of the leukocytes through the vessel wall, and movement of the cells toward the offending agent.
  18. 18. Leukocyte Adhesion to Endothelium • Normally, Leukocytes are pushed out toward the wall of the vessel, but the flow prevents the cells from attaching to the endothelium • As the blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases),and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called margination.
  19. 19. • By moving close to the vessel wall, leukocytes are able to detect and react to changes in the endothelium. If the endothelial cells are activated by cytokines and other mediators produced locally, they express adhesion molecules to which the leukocytes attach loosely. • These cells bind and detach and thus begin to tumble ‘somersaults’ on the endothelial surface, a process called rolling. • The cells finally come to rest at some point where they adhere firmly (resembling pebbles over which a stream runs without disturbing them).
  20. 20. • The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines. • The two major families of molecules involved in leukocyte adhesion and migration are the selectins and integrins. • These molecules are expressed on leukocytes and endothelial cells, as are their ligands. • Selectins mediate the initial weak interactions between leukocytes and endothelium. • Firm adhesion of leukocytes to endothelium is mediated by a family of leukocyte surface
  21. 21. Leukocyte Migration Through Endothelium • After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions • This extravasation of leukocytes, called transmigration, occurs mainly in postcapillary venules, the site at which there is maximal retraction of endothelial cells  Further movement of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate leukocytes to travel along a chemical gradient
  22. 22. • After traversing the endothelium, leukocytes pierce the basement membrane, probably by secreting collagenases, and they enter the extravascular tissue. • Typically, the vessel wall is not injured during leukocyte transmigration
  23. 23. Chemotaxis of Leukocytes • After exiting the circulation, leukocytes move in the tissues toward the site of injury by a process called chemotaxis. • Chemotaxis :is defined as locomotion along a chemical gradient. • Both exogenous and endogenous substances can act as chemoattractants, including the following: • Bacterial products, particularly peptides with Nformylmethionine termini • Cytokines, especially those of the chemokine family • Components of the complement system, particularly C5a • Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4) NB: These chemoattractants are produced by microbes and by host cells in response to infections and tissue damage and during immunologic reactions.
  24. 24. Which types of leukocytes respond • Neutrophils are generally the first types of leukocytes to respond in acute (non-viral) inflammation or to necrosis • Lymphocytes are usually the first cells to respond to viral infections or autoimmune diseases  lymphocytes and plasma cells also participate in most chronic inflammation, regardless of the inciting cause • Macrophages begin to appear a few days after the onset of inflammation from almost any cause, and increase in numbers over time  activated macrophages may develop abundant cytoplasm, called epithelioid macrophage  macrophages merge to create giant cells with multiple nuclei • Eosinophilic inflammation is highly suggestive of a response to helminths, arthropods, or allergens
  25. 25. Acute inflammation • Immediate, early response  Vasodilation  Vascular permeability  Emigration of leukocytes into tissues • Reactions of leukocytes in inflammation  Recognition of microbes and dead tissues  Removal of the offending agents  Macrophage activation  Leukocyte-mediated tissue injury
  26. 26. Actions of activated neutrophils • Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation • The Leukocytes must be activated to perform their functions. • Phagocytosis has three steps  recognition and attachment of the particle to be ingested  engulfment, with subsequent formation of a phagocytic vacuole  killing or degradation of the ingested material • Initiation of repair  stimulate the proliferation of endothelial cells and fibroblasts  stimulate synthesis of collagen and enzymes that remodel connective tissues
  27. 27. • Several types of inflammation vary in their morphology and clinical correlates. • Why?  The severity of the reaction  specific cause  the particular tissue  site involved Morphologic Patterns of Acute Inflammation
  28. 28. Morphologic Patterns of Acute Inflammation • serous inflammation • fibrinous inflammation • suppurative or purulent inflammation • ulcers
  29. 29. Patterns of Acute Inflammation • SEROUS INFLAMMATION:  Serous inflammation is marked by the outpouring of a thin fluid  e.g. the skin blister resulting from a burn or viral infection represents a large accumulation of serous fluid
  30. 30. • FIBRINOUS INFLAMMATION  more severe injuries and more greater vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited Morphologic Patterns of Acute Inflammation
  31. 31.  A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium and pleura  Bread and butter apperance Morphologic Patterns of Acute Inflammation FIBRINOUS INFLAMMATION
  32. 32. • FIBRINOUS INFLAMMATION  Fibrinous exudates may be removed by fibrinolysis  But when the fibrin is not removed, it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring Morphologic Patterns of Acute Inflammation
  33. 33. SUPPURATIVE OR PURULENT INFLAMMATION  characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic cells, and edema fluid  Certain bacteria (e.g., staphylococci) produce this localized suppuration and are therefore referred to as pyogenic (pus- producing) bacteria Morphologic Patterns of Acute Inflammation,
  34. 34. Suppurative inflammation. A, A subcutaneous bacterial abscess with collections of pus. B, The abscess contains neutrophils, edema fluid, and cellular debris.
  35. 35. Purulent inflammation
  36. 36.  Abscesses : localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, an organ, or a confined space SUPPURATIVE OR PURULENT INFLAMMATION
  37. 37. Brain Abscess
  38. 38. Liver abscess
  39. 39. Localized liquefactive necrosis liver abscess Removal of the dead tissue leaves behind a scar
  40. 40. Morphologic Patterns of Acute Inflammation – ULCERS  An ulcer is a local defect of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflammatory necrotic tissue
  41. 41. ULCERS encountered in: 1) inflammatory necrosis of the mucosa of the mouth, stomach, intestines, or genitourinary tract 2) subcutaneous inflammation of the lower extremities in older persons who have circulatory disturbances Morphologic Patterns of Acute Inflammation
  42. 42. Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface Epithelial Defect Fibrinopurulent exudates Granulation tissue Fibrosis Necrotic base
  43. 43. Termination of acute response • Inflammation declines spontaneously  Mediators of inflammation are produced in rapid bursts only while the stimulus persists  Mediators have short half-lives and are degraded after their release.  Neutrophils also have short half-lives in tissues and die by apoptosis within a few hours after leaving the blood • Active termination mechanisms include  Switch from pro-inflammatory leukotrienes to anti-inflammatory lipoxins  Release of anti-inflammatory cytokines, including transforming growth factor-β (TGF-β) and IL-10, from macrophages  production of anti-inflammatory lipid mediators, called resolvins and protectins, derived from polyunsaturated fatty acids  neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages
  44. 44. Arachidonic Acid Pathway
  45. 45. Arachidonic Acid Pathway
  46. 46. • Acute inflammation may have one of the four outcomes:  Complete resolution  Healing by connective tissue replacement (fibrosis)  Progression of the tissue response to chronic inflammation  Abcess formation Outcomes of Acute Inflammation
  47. 47. Complete resolution When? 1) the injury is limited or short-lived 2) there has been little tissue destruction 3) the damaged parenchymal cells can regenerate Outcomes of Acute Inflammation
  48. 48. Complete resolution Mechanism:  Neutralization and removal of chemical mediators  Normalization of vascular permeability  halting of leukocyte emigration  Clearance of edema (lymphatic drainage) , inflammatory cells and necrotic debris (macrophages). Outcomes of Acute Inflammation
  49. 49. Events in the resolution of inflammation
  50. 50. • Healing by connective tissue replacement (fibrosis): • This occurs after substantial tissue destruction  the inflammatory injury involves tissues that are incapable of regeneration  there is abundant fibrin exudation.  The destroyed tissue is reabsorbed and eventually replaced by fibrosis. Outcomes of Acute Inflammation
  51. 51. • Progression of the tissue response to chronic inflammation:  occurs when the acute inflammatory response cannot be resolved  WHY? Due to: 1. the persistence of the injurious agent 2. some interference with the normal process of healing Outcomes of Acute Inflammation
  52. 52. End of acute inflammation More is Lost by Indecision than Wrong Decision