Objectives of Acute Inflammation-2

Objectives of Acute Inflammation-2

• Chemical mediators (overview)
• More detail mechanism of fluid loss
• More detail neutrophil emigration
• Action of neutrophils-phagocytosis
• Local complications and systemic effects
• Sequelae
• Clinical examples

Chemical Mediators of Acute Inflammation

• Proteases: Plasma proteins produced in the liver.
  • Kinins (Bradykinin and Kallikrein)
  • Complement system (C3a, C5a)
  • Coagulation/fibrinolytic system
• Prostaglandins/Leukotrienes: Metabolites of arachidonic acid.
  • Synthesis blocked by Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin
• Cytokines/chemokines: Produced by white blood cells (WBCs).
  • Many varied examples: Interleukins, platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), etc.

Other Inflammatory Mediators

• From platelets: 5-HT, histamine, ADP
• From neutrophils: Lysosomal constituents
• Products released upon neutrophil death
• From endothelium: Prostacyclin, nitric oxide
• Plasminogen activators/inhibitors
• Oxygen-derived free radicals
• Endothelial damage, inactivation of antiproteases, injury to other cells

Vascular Changes

• Vascular dilatation: Histamine, prostaglandins, nitric oxide
• Increase in vascular permeability: Transient (histamine), bradykinin, leukotrienes (C4, D4, E4)
• Emigration of neutrophils: C5a, leukotriene B4, bacterial products

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 from leukocytes)
• Increased transcytosis (channels across endothelial cytoplasm – VEGF)

Mechanisms of Neutrophil Migration

• Neutrophil adhesion and emigration due to binding of complementary adhesion molecules on endothelial and neutrophil surfaces
• Chemical mediators changing 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 cytoskeleton
• Production of pseudopod

Phagocytosis

• Contact, Recognition, Internalization
• Cytoskeletal changes (as with chemotaxis)

Microbial Killing

• Recognition facilitated by opsonins (e.g., C3b receptors on phagocytes recognizing organisms coated with immunoglobulin or complement).
• Phagosomes fuse with lysosomes to produce secondary lysosomes.

Killing Mechanisms

• O2-dependent:
  • Produces superoxide and hydrogen peroxide
  • H2O2-Myeloperoxidase-halide system – produces HOCl
  • Myeloperoxidase-independent killing less efficient
• O2-independent:
  • Lysozyme & hydrolases
  • Bactericidal Permeability Increasing Protein (BPI)
  • Cationic proteins ('defensins')
  • Major Basic Protein (MBP; eosinophils)

Complications of Acute Inflammation

• Local: Rubor, calor, dolor, tumor (redness, heat, pain, swelling)
• Systemic: Effects on the whole body

Local Complications of Acute Inflammation

• Swelling: Blockage of tubes (e.g., bile duct, intestine), exudate, compression (e.g., cardiac tamponade — serositis), loss of fluid (e.g., burns), pain & loss of function (especially if prolonged).

Systemic Effects of Acute Inflammation

• Acute phase response: Decreased appetite, altered sleep patterns, raised heart rate, changes in plasma concentrations of acute-phase proteins.
  • C-reactive protein (CRP)
  • 1-antitrypsin
  • Haptoglobin
  • Fibrinogen
  • Serum amyloid A protein
• Spread of micro-organisms and toxins
• Shock: A clinical syndrome of circulatory failure

Systemic Effects of Acute Inflammation (Continued)

• Fever: Endogenous pyrogens (IL-1 and TNF) produced; influence of prostaglandins (aspirin reduces fever).
• Leukocytosis: IL-1 and TNF accelerate marrow release; macrophages and T lymphocytes produce colony-stimulating factors; bacterial infections — neutrophils; viral infections — lymphocytes

Acute Inflammation: Sequelae

• Complete resolution
• Continued acute inflammation with chronic inflammation; chronic suppuration (abscess).
• Chronic inflammation and fibrous repair, possibly with tissue regeneration
• Death

Resolution

• Mediators have short half-lives and inactivated by degradation, dilution or inhibition.
• Gradually, all acute inflammatory changes reverse, vascular changes stop, neutrophils stop marginating, vessel permeability and calibre return normal.
• Exudate drains via lymphatics; fibrin degraded by plasmin/other proteases; neutrophils die.

Resolution (Continued)

• Damaged tissue may regenerate, but if architecture destroyed, complete resolution not possible.

Clinical Examples: Lobar Pneumonia

• Causative organism: Streptococcus pneumoniae (“pneumococcus”)
• Population at risk: Young adults in confined conditions, alcoholics...
• Clinical course: Worsening fever, prostration, hypoxaemia over a few days, dry cough; fairly sudden improvement (“resolution by crisis”) when antibodies appear.

Skin Blister

• Causes: Heat, sunlight, chemical
• Predominant features: Pain, exudate (collection of fluid that strips off overlying epithelium; more pain, more tissue damage)
• Inflammatory cells relatively few (therefore exudate clear unless bacterial infection develops)

Abscess

• Solid tissues and exudate forces tissues apart
• Liquefactive necrosis in center (can cause high pressure and pain)
• May cause tissue damage and squash adjacent structures

Hepatic Abscess

(Image of a section of a liver with an abscess)

Acute Inflammation in Serous Cavities

• Exudate pours into cavity (ascites, pleural or pericardial effusion)
• Respiratory or cardiac impairment
• Localized fibrin deposition; in pericarditis, pericardium becomes inflamed and increase pressure on the heart.

Pericarditis

(Image showing a microscopic view of pericarditis and a macroscopic view of a heart with pericarditis).

Disorders of Acute Inflammation: Hereditary Angioedema

• Recurrent episodes of severe swelling (limbs, face, intestinal tract, airways)
• Caused by a deficiency of C1 inhibitor
• C1 is a complement protein that cleaves C2 and C4 to form C3
• C1 inhibitor inhibits not only C1 but also Bradykinin
• Uninhibited bradykinin greatly increases vascular permeability, causing edema
• Treatment: C1 inhibitor infusion or fresh frozen plasma.

α1-Antitrypsin Deficiency

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

Chronic Granulomatous Disease

• Recessive, sex-linked
• Immune phagocytes do not function properly
• Granulomas formed to contain bacteria
• Individuals with this disease likely to have recurring infections (lungs, skin, lymph nodes, liver, and intestine).