Acute Inflammation Chapter 2

Acute Inflammation-2

• Objectives include: Chemical mediators (overview), mechanisms of fluid loss and neutrophil emigration, neutrophil action (phagocytosis), local and systemic effects of inflammation, sequelae, and clinical examples.

• Chemical Mediators:

  • Cellular Sources: Histamine, serotonin, lysosomal enzymes from mast cells, basophils, platelets; prostaglandins, leukotrienes, platelet-activating factors, activated oxygen species, nitric oxide, cytokines produced by various cells (leukocytes, platelets, endothelial cells, macrophages, lymphocytes).
  • Plasma Sources: Factor XII activation (kinin system - bradykinin), Complement system (C3a, C5a), coagulation/fibrinolytic systems, metabolites of arachidonic acid (prostaglandins, leukotrienes), blocked by NSAIDs (e.g., aspirin), cytokines/chemokines from WBCs (interleukins, PAF, TNF-alpha, PDGF, TGF beta)

• Other Inflammatory Mediators:

  • Platelets: 5-HT, histamine, ADP.
  • Neutrophils: lysosomal constituents, products released on cell death.
  • Endothelium: prostacyclin, nitric oxide.
  • Plasminogen activators/inhibitors.
  • Oxygen-derived free radicals.
  • Inactivation of antiproteases, injury to other cells.

Vascular Changes

• Vascular dilatation: Histamine, prostaglandins, nitric oxide are involved.
• Increased vascular permeability: Transient, histamine, bradykinin, leukotrienes (C4, D4, E4).
• Neutrophil emigration: C5a, leukotriene B4, and bacterial products are important mediators.

Mechanisms of Vascular Leakage

• Endothelial contraction --> gaps (histamine, leukotrienes)
• Cytoskeletal reorganization --> gaps (cytokines IL-1 and TNF)
• Direct injury (toxic burns, chemicals)
• Leukocyte-dependent injury (toxic oxygen species and enzymes)
• Increased transcytosis (channels across endothelial cytoplasm - VEGF)

Mechanisms of Neutrophil Migration

• Neutrophil adhesion and emigration: binding of complementary adhesion molecules on endothelial and neutrophil surfaces.
• Chemical mediators change surface expression or avidity of adhesion molecules: Selectins, Immunoglobulins, Integrins.

How do Neutrophils Escape from Vessels?

• Relaxation of inter-endothelial cell junctions.
• Digestion of vascular basement membrane.
• Movement: Diapedesis and emigration; chemotaxis.

Chemotaxis

• Movement along concentration gradients of chemo-attractants.
• Receptor-ligand binding.
• Rearrangement of the cytoskeleton.
• Production of pseudopods.

Phagocytosis

• Contact, Recognition, Internalization, Cytoskeletal changes.

Microbial Killing

• Recognition facilitated by opsonins (e.g., C3b receptors on phagocytes).
• Phagocytes recognize organisms coated with immunoglobulin or complement.
• Phagosomes fuse with lysosomes to form secondary lysosomes with killing mechanisms.

Killing Mechanisms

• O2-dependent: production of superoxide and hydrogen peroxide, H2O2- myeloperoxidase dependent systems- producing HOCl, myeloperoxidase independent killing is less effective
• O2-independent: lysozyme and hydrolases, bactericidal permeability increasing protein (BPI), cationic proteins (defensins), major basic protein (MBP) in eosinophils.

Complications of Acute Inflammation

• Local: rubor, calor, dolor, tumor (swelling, blockage of tubes, exudate, loss of fluid, pain, functional loss)
• Systemic: acute phase response (decreased appetite, altered sleep, raised heart rate, changes in plasma protein concentrations like CRP, 1 antitrypsin, haptoglobin, fibrinogen, serum amyloid A protein), spread of microorganisms and toxins ->shock

Resolution

• Mediators of acute inflammation have short half-lives and may be inactivated by degradation, dilution or inhibition.
• Gradual reversal of changes: vascular changes stop; neutrophil margination stops, permeability & vessel caliber return normal; exudate drains via lymphatics, fibrin degraded, neutrophils die. Damaged tissue regenerates if tissue architecture wasn't destroyed.

Clinical Examples (Lobar Pneumonia)

• Causative organism: Streptococcus pneumoniae.
• Risk factors: young adults in confined spaces, alcoholics.
• Clinical course: worsening fever, prostration, hypoxemia, dry cough, fairly sudden improvement when antibodies appear.

Clinical Examples (Skin Blisters)

• Causes: heat, sunlight, chemicals

• Predominant features: pain, exudate (clear collection of fluid from the epithelium).

• Inflammatory cells are relatively few, so exudate is clear unless bacterial infection develops.

Clinical Examples (Abscesses)

• Solid tissue
• Inflammatory exudate separates tissue
• Liquefactive necrosis in center
• High pressure causes pain
• Potential tissue damage and compression of adjacent structures

Clinical Examples (Hepatic Abscess)

• Image presented.

Clinical Examples (Acute Inflammation in Serous Cavities)

• Exudate pours into cavities (ascites, pleural or pericardial effusion)
• Respiratory or cardiac impairment
• Localized fibrin deposition

Clinical Examples (Pericarditis)

• Image presented.

Clinical Examples (Hereditary Angioedema)

• Recurrent episodes of swelling (limbs, face, intestinal tract, airways).
• Deficiency in C1 inhibitor. C1 cleaves C2 and C4 to form C3. C1 inhibitor also inhibits Bradykinin. Uninhibited bradykinin increases endothelial permeability causing edema.
• Treated with C1 inhibitor infusions or fresh frozen plasma.

Clinical Examples (α₁-Antitrypsin Deficiency)

• α₁-antitrypsin inhibits elastase.
• Without inhibition, elastase breaks down lung/liver tissue, causing emphysema and liver sclerosis.

Clinical Examples (Chronic Granulomatous Disease)

• Recessive sex-linked trait, Immune phagocytes not working properly.
• Granulomas form as an attempt to contain bacteria.
• Individuals often have infections in the lungs, skin, lymph nodes, liver, and intestines.