Lec 5 Quiz

Five Cardinal Signs of Inflammation

• Pain: Caused by the release of chemicals that make nerve endings more sensitive.
• Redness: More blood in the capillaries.
• Immobility: Potential loss of function.
• Swelling: Fluid accumulation from blood.
• Heat: Increased blood flow to the affected area.

Causes of Acute Inflammation

• Infections (bacterial, viral, parasitic) and microbial toxins.
• Trauma (blunt and penetrating).
• Physical and chemical agents (burns, frostbite, irradiation, chemicals).
• Tissue necrosis.
• Foreign bodies.
• Immune reactions (hypersensitivity).

Types of Inflammation

• Acute inflammation (without neutrophils).
• Allergic acute inflammation.
• Serous inflammation (body cavities).
• Catarrhal inflammation (mucous membranes).
• Fibrinous inflammation.
• Necrotizing/hemorrhagic inflammation.
• Membranous/pseudomembranous inflammation.
• Suppurative/purulent inflammation.

Mast Cell Messengers

• Granule Release:
  • Histamine: Vasodilation, increased capillary permeability, bronchoconstriction, and chemotaxis.
  • Proteoglycans: Bind granule proteases.
  • Neutral proteases and β-glucosaminidase: Activate complement, split off glucosamine.
  • ECF and NCF: Chemotaxis of eosinophils and neutrophils.
  • Platelet-activating factor: Mediator release.
  • IL-3, IL-6, GM-CSF, TNF: Activate macrophages, initiate acute phase proteins.
• Lipoxygenase Pathway: Leukotrienes C4, D4 (SRS-A), B4 (vasoactive, bronchoconstriction, chemotaxis).
• Cyclooxygenase Pathway: Prostaglandins and thromboxanes (affect bronchial muscle, platelet aggregation, vasodilation).

Extravasation Process:

• Rolling Adhesion: Leukocytes bind transiently to selectin proteins on endothelial cells.
• Tight Binding: Integrins on leukocytes bind to adhesion proteins on endothelial cells (e.g., TNF-a inducing LFA-1 and ICAM-1 expression).
• Diapedesis: Leukocytes slow down and exit blood vessels.
• Migration: Leukocytes move through tissues toward pathogens via chemotaxis.

Extravasation Inhibition (Drug Use)

• Natalizumab: A humanized monoclonal antibody that binds to a4-integrin and prevents adhesion to endothelial cells. Used to treat MS and Crohn’s disease.

Resolution Stage of Acute Inflammation

• Anti-inflammatory mechanisms activate as the injurious agent is gone.
• The inflammatory response subsides and the host returns to normal health.

Stop Signals/Checkpoints of Inflammation

• Lipoxins, resolvins, other prostaglandins
• Monocyte migration and differentiation into macrophages. Macrophages remove dead cells and exit the inflammation site.

Arachidonate to Prostaglandins/Thromboxanes

• Arachidonic acid.
• COX-1 (constitutive): Homeostatic functions (e.g., GI, renal, platelets).
• COX-2 (induced): Inflammation (e.g., cytokine-induced).
• Phospholipid-arachidonate → Phospholipase A2 → Arachidonate → Cyclooxygenase activity of COX → PGG2 → Peroxidase activity → PGH2 → Prostaglandins/Thromboxanes.

Lipoxygenase Pathway for Leukotrienes/Lipoxins

• Arachidonic acid → Lipoxygenase → 12-Hydroperoxyeicosateraenoate (12-HPETE) → Leukotrienes.
• Arachidonic acid → Lipoxygenase → 5-HPETE → Leukotriene A4 → LTC4 → LTD4 → Lipoxins.

Free Radical Creation During Inflammation

• Phagocytes kill pathogens using free radicals.
• Neutrophil phagocytosis → Phagosome fusion → pH rise → Antimicrobial response activated → Bacterium killed→ pH dec → Lysosome fusion → Complete degradation → Neutrophil apoptosis → Macrophage phagocytosis.
• NADPH oxidase complex (cytochrome b558, free Fe2+, hydroxyl radical, superoxide ion).

Dangers of Free Radicals

• Escape into cytoplasm/nucleus.
• Damage to DNA, lipids, and proteins, changing nucleotide residues.

Chronic Inflammation

• Long-term inflammation (weeks/months).
• Active inflammation, tissue destruction, and repair happening simultaneously.
• Often follows acute inflammation, beginning insidiously as a low-grade, smoldering response.
• Causes tissue damage in diseases like RA, atherosclerosis, TB, chronic lung disease.

Acute vs. Chronic Inflammation

Macrophages in Chronic Inflammation

• Tissue Injury: Toxic oxygen metabolites, proteases, neutrophil chemotactic factor, coagulation factors, AA metabolites, nitric oxide.
• Fibrosis: Growth factors (PDGF, FGF, TGFβ), fibrogenic cytokines, angiogenesis factors (FGF), collagen remodeling.

COX-1 and COX-2 in Inflammation

• COX-1: Constitutive enzyme, involved in homeostatic functions.
• COX-2: Induced enzyme, crucial in inflammation.
• Cytokines (TNF-α, IL-1β) induce COX-2.

Granuloma

• Microscopic aggregation of transformed macrophages (epithelium-like cells) surrounded by mononuclear leukocytes (lymphocytes, plasma cells).
• Purpose: Contain and isolate pathogens or foreign agents.

Fibroblast Role in Chronic Inflammation

• Increased proliferation, collagen synthesis, collagenase, and protease production, increasing PGE synthesis.

Chronic Inflammation and Disease (based on TIME article):

• Heart Disease: Chronic inflammation contributes by destabilizing cholesterol plaques and promoting clots. CRP levels correlate with risk.
• Cancer: Inflammation might promote development. Inflammatory cells release free radicals damaging DNA and contributing to uncontrolled cell growth.
• Alzheimer's: Brain inflammation exacerbates cognitive decline. Glial cell release inflammatory cytokines.
• Diabetes: Fat cells release inflammatory cytokines disrupting insulin function.
• Nutrition and Inflammation:
  • Pro-inflammatory Foods: High sugar, saturated fats, processed foods.
  • Anti-inflammatory Foods: Fruits/vegetables (antioxidants), fish (Omega-3s), natural COX-2 inhibitors (turmeric, polyphenols).
• Lifestyle choices (diet, exercise, weight management) to control inflammation and prevent diseases.