Injury – leads to exposed collagen, platelet-activating factor release, and tissue factor release from endothelium

  Platelets bind collagen – release growth factors (platelet-derived growth factor [PDGF]); leads to PMN and macrophage recruitment

  Macrophages – dominant role in wound healing; release important growth factors (PDGF) and cytokines (IL-1 and TNF-α)

GROWTH AND ACTIVATING FACTORS

  PDGF

•  Chemotactic and activates inflammatory cells (PMNs and macrophages)

•  Chemotactic and activates fibroblasts → collagen and ECM proteins

•  Angiogenesis

•  Epithelialization

•  Chemotactic for smooth muscle cells

•  Has been shown to accelerate wound healing

  EGF (epidermal growth factor)

•  Chemotactic and activates fibroblasts

•  Angiogenesis

•  Epithelialization

  FGF (fibroblastic growth factor)

•  Chemotactic and activates fibroblasts → collagen and ECM proteins

•  Angiogenesis

•  Epithelialization

  PAF (platelet-activating factor) – is not stored, generated by phospholipase in endothelium; is a phospholipid

•  Chemotactic for inflammatory cells; ↑ adhesion molecules

  Chemotactic factors

•  For inflammatory cells – PDGF, IL-8, LTB-4, C5a and C3a, PAF

•  For fibroblasts – PDGF, EGF, FGF

  Angiogenesis factors – PDGF, EGF, FGF, IL-8, hypoxia

  Epithelialization factors – PDGF, EGF, FGF

  PMNs – last 1–2 days in tissues (7 days in blood)

  Platelets – last 7–10 days

  Lymphocytes – involved in chronic inflammation (T cells) and antibody production (B cells)

  TXA₂ and PGI₂ – see Chapter 2 (Hematology)

TYPE I HYPERSENSITIVITY REACTIONS

  Eosinophils

•  Have IgE receptors that bind to allergen

•  Release major basic protein, which stimulates basophils and mast cells to release histamine

•  Eosinophils are increased in parasitic infections

  Basophils

•  Main source of histamine in blood; not found in tissue

  Mast cells – primary cell in type I hypersensitivity reactions

•  Main source of histamine in tissues

  Histamine – vasodilation, tissue edema, postcapillary leakage

•  Primary effector in type I hypersensitivity reactions (allergic reactions)

  Bradykinin – peripheral vasodilation, increased permeability, pain, pulmonary vasoconstriction

•  Angiotensin-converting enzyme (ACE) – inactivates bradykinin; located in lung

NITRIC OXIDE (NO)

  Has arginine precursor (substrate for nitric oxide synthase)

  NO activates guanylate cyclase and increases cGMP, resulting in vascular smooth muscle dilation

  Is also called endothelium-derived relaxing factor

  Endothelin – causes vascular smooth muscle constriction (opposite effect of nitric oxide)

IMPORTANT CYTOKINES

  Main initial cytokine response to injury and infection is release of TNF-α and IL-1

  Tumor necrosis factor-alpha (TNF-α)

•  Macrophages – largest producers of TNF

•  Increases adhesion molecules

•  Overall, a procoagulant

•  Causes cachexia in patients with cancer

•  Activates neutrophils and macrophages → more cytokine production, cell recruitment

•  High concentrations of TNF-α can cause circulatory collapse and multisystem organ failure

  IL-1

•  Main source also macrophages; effects similar to TNF-α and synergizes TNF-α

•  Responsible for fever (PGE₂ mediated in hypothalamus)

•  Raises thermal set point, causing fever

•  NSAIDs decrease fever by reducing PGE₂ synthesis

•  Alveolar macrophages – cause fever with atelectasis by releasing IL-1

  IL-6 – increases hepatic acute phase proteins (C-reactive protein, amyloid A)

INTERFERONS

  Released by lymphocytes in response to viral infection or other stimulants

  Activate macrophages, natural killer cells, and cytotoxic T cells

  Inhibit viral replication

HEPATIC ACUTE PHASE RESPONSE PROTEINS

  IL-6 – most potent stimulus

  Increased – C-reactive protein (an opsonin, activates complement), amyloid A and P, fibrinogen, haptoglobin, ceruloplasmin, alpha-1 antitrypsin, and C3 (complement)

  Decreased – albumin, pre-albumin, and transferrin

CELL ADHESION MOLECULES

  Selectins – L-selectins, located on leukocytes, bind to E- (endothelial) and P- (platelets) selectins; rolling adhesion

  Beta-2 integrins (CD 11/18 molecules) – on leukocytes; bind ICAMs, etc., anchoring adhesion

  ICAM, VCAM, PECAM, ELAM – on endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets. These are also involved in transendothelial migration

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