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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