Inflammation, Inflammatory Disorders, and Wound Healing PDF

Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, 1 and Wound Healing INTRODUCTION I. INFLAMMATION A. Allo...

Www.Medicalstudyzone.com Inflammation, Inflammatory Disorders, 1 and Wound Healing INTRODUCTION I. INFLAMMATION A. Allows inflammatory cells, plasma proteins (e.g., complement), and fluid to exit blood vessels and enter the interstitial space B. Divided into acute and chronic inflammation ACUTE INFLAMMATION I. BASIC PRINCIPLES A. Characterized by the presence of edema and neutrophils in tissue (Fig. 2.lA) B. Arises in response to infection (to eliminate pathogen) or tissue necrosis (to clear necrotic debris) C. Immediate response with limited specificity (innate immunity) IL MEDIATORS OF ACUTE INFLAMMATION A. Toll-like receptors (TLRs) 1. Present on cells of the innate immune system (e.g., macrophages and dendritic cells) 2. Activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes i. CD14 (a co-receptor for TLR4) on macrophages recognizes lipopoly- saccharide (a PAMP) on the outer membrane of gram-negative bacteria. 3. TLR activation results in upregulation of NF-κB, a nuclear transcription factor that activates immune response genes leading toproduction of multiple immune mediators. 4. TLRs are also present on cells of adaptive immunity (e.g., lymphocytes) and, hence, play an important role in mediating chronic inflammation. B. Arachidonic acid (AA) metabolites 1. AA is released from the phospholipid cell membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase. i. Cyclooxygenase produces prostaglandins (PG). a. PGI 2, PGD 2, and PGE2 mediate vasodilation and increased vascular permeability. b. PGE2 also mediates pain and fever. ii. 5-lipoxygenase produces leukotrienes (LT). a. LTB 4 attracts and activates neutrophils. b. LTC 4, LTD 4, and LTE 4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vascular permeability. C. Mast cells 1. Widely distributed throughout connective tissue 2. Activated by (1) tissue trauma, (2) complement proteins C3a and C5a, or (3) cross-linking of cell-surface IgE by antigen pathoma.com 11  Www.Medicalstudyzone.com 12 FUNDAMENTALS OF PATHOLOGY Immediate response involves release of preformed histamine granules, which i. mediate vasodilation of arterioles and increased vascular permeability. ii. Delayed response involves production of arachidonic acid metabolites, particularly leukotrienes. D. Complement 1. Proinflammatory serum proteins that "complement" inflammation 2. Circulate as inactive precursors; activation occurs via i. Classical pathway - C1 binds IgG or IgM that is bound to antigen. ii. Alternative pathway - Microbial products directly activate complement. iii. Mannose-binding lectin (MBL) pathway - MBL binds to mannose on microorganisms and activates complement. 3. All pathways result in production of C3 convertase (mediates C3 →C3a and C3b), which, in turn, produces C5 convertase (mediates C5 → C5a and C5b). C5b complexes with C6-C9 to form the membrane attack complex (MAC). i. C3a and C5a (anaphylatoxins) - trigger mast cell degranulation, resulting in histamine-mediated vasodilation and increased vascular permeability ii. C5a - chemotactic for neutrophils iii. C3b - opsonin for phagocytosis iv. MAC - lyses microbes by creating a hole in the cell membrane E. Hageman factor (Factor XII) 1. Inactive proinflammatory protein produced in liver 2. Activated upon exposure to subendothelial or tissue collagen; in turn, activates i. Coagulation and fibrinolytic systems ii. Complement iii. Kinin system - Kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which mediates vasodilation and increased vascular permeability (similar to histamine), as well as pain. III. CARDINAL SIGNS OF INFLAMMATION A. Redness (rubor) and warmth (calor) 1. Due to vasodilation, which results in increased blood flow 2. Occurs via relaxation of arteriolar smooth muscle; key mediators are histamine, prostaglandins, and bradykinin. B. Swelling (tumor) 1. Due to leakage of fluid from postcapillary venules into the interstitial space (exudate) 2. Key mediators are (1) histamine, which causes endothelial cell contraction and (2) tissue damage, resulting in endothelial cell disruption. C. Pain (dolor) 1. Bradykinin and PGE2 sensitize sensory nerve endings. 4' , * 1 L > mwwf fV - y; v j& ' '* , v r , » »4 t. /4 i. : ,4 ~( W / ^ *« 4 » 4 * f *. « ikfmmj * - % 7 '. % # , '.ifc i * 1% iS * * -^ 4* #* * '. y v - # # t Fig. 2.1 Inflammation. A, Acute inflammation with neutrophils. B, Chronic inflammation with lymphocytes and plasma cells.