Inflammation and Immune Response

Trauma to the cell membrane
Hypoxic injury (examples: myocardial infarction, stroke)
Chemical injury (examples: aspiration of gastric fluid in lungs, peptic ulcer disease, pancreatitis)
Immune injury (examples: autoimmune disease, allergic reactions)
Infection
Thermal injury (i.e., burns)
Ionizing radiation

Mast cell degranulation and release of initial vasoactive mediators (e.g., histamine)
White blood cell margination and migration
Release of cytokines and inflammatory mediators
Activation of the plasma protein systems

Most important activator of local inflammatory response
Location: throughout tissues (especially near blood vessels)
Activators:
- Local cellular injury
- Endotoxin
- Complement proteins
- Immunologic factors: IgE hypersensitivity
Function:
- Degranulation: release of preformed chemicals
  - Histamine: vasodilation, increased capillary permeability, non-vascular smooth muscle contraction
  - Histamine Receptors:
    - H1 receptors: promote inflammation
      - Arterial smooth muscle - vasodilation
      - Endothelial cells – endothelial cell retraction/increased capillary permeability
      - Bronchial smooth muscle – bronchoconstriction
      - WBCs – chemotaxis
      - Mast cells – more degranulation
    - H2 receptors: inhibit inflammation and have other actions
      - Mast cells – inhibits degranulation
      - WBCs – inhibits chemotaxis
      - Parietal and chief cells lining stomach – HCl and gastric enzyme secretion
- Synthesis of mediators: arachadonic acid (AA) metabolites
  - Leukotrienes: actions similar to histamine
  - Prostaglandins (PgE 2): actions similar to histamine and induce pain

Normal range: 0.4-1.0% of total WBC count
Function:
- Similar to mast cells - release histamine and leukotrienes in bloodstream
- Also release heparin

Normal range: 45-73% of total WBC count
Immature neutrophils: bands or stabs (normal range: 3-5% of total WBC count)
Function:
- Arrive during acute phases of inflammation (6-12 hours after degranulation)
- Activated by proinflammatory cytokines (e.g., IL-1 and TNF-alpha)
- Phagocytosis of bacteria and debris – destruction of cells via lysosomal or free radical injury
- Release of inflammatory mediators: more cytokines (interleukins, TNF), platelet activating factor, AA metabolites, etc

Normal range: 1-3% of total WBC count
Function:
- Release chemicals that control inflammation (example: histamine and leukotrienes are inactivated by histaminase and arylsulfatase released by eosinophils)
- Phagocytosis of parasites
- Involved in allergic responses (type I hypersensitivities)
- Phagocytosis of bacteria and yeast (less important role)

Normal range for monocytes: 4-6% of total WBC count
Released into the bloodstream by the bone marrow as a monocyte
Migrate to inflammatory site and transform into a macrophage (triggered by proinflammatory cytokines)
Many tissues have residential macrophages (liver, spleen, lungs, lymph nodes...)
Functions:
- Process antigen (activates the immune response)
- Phagocytosis of bacteria and debris
- Release of inflammatory mediators: interleukins, tumor necrosis factor, free radicals, platelet activating factor, proteases, AA metabolites
- Promote wound healing by activating fibroblasts, stimulating angiogenesis, and releasing growth factors

Function in Inflammation:
- Work with coagulation proteins to stop bleeding
- Release approximately 35 other biochemical mediators
  - Serotonin: vasoconstriction
  - Platelet activating factor (PAF): vasodilation, increased capillary permeability, bronchoconstriction

Function in inflammation:
- Increased capillary permeability
- Express adhesion molecules for WBC guidance to injury area
- Secretion of vasoactive mediators (nitric oxide, PAF, prostaglandins, etc...)
  - Nitric oxide (a.k.a. endothelium-derived relaxation factor (EDRF)): potent vasodilator, also a free radical

10+ proteins = 10% of plasma proteins; pathways converge at C3
Classical pathway activation: Presence of antigen-antibody (Ag-Ab) complexes (IgG or IgM complexes only)
Alternate pathway activation: C3b binds to microbe cell membrane
Lectin pathway activation: Binding of mannose-binding lectin (MBL) to microbe cell membranes
Function of activated complement proteins:
- C2a, C3a, C5a: vasodilation, increased capillary permeability, bronchoconstriction
- C2, C3, C3b, C4, C5: opsonization
- C3a and C5a: chemotaxis
- C5 through C9 (membrane attack complex): bacterial (and other) cell lysis

Sequential activation of a series of clotting factors resulting in the production of fibrin
Extrinsic and Intrinsic pathways
Functions of fibrin:
- Forms a meshwork to stop bleeding
- Limits infection
- Forms framework for scar tissue formation

Functions of Bradykinin:
- Works later and more slowly than histamine
- Vasodilation & increased capillary permeability
- Bronchoconstriction
- Induces pain

Fever: caused by endotoxin, interleukin (IL-1), tumor necrosis factor (TNF), prostaglandins
Leukocytosis: stimulated by granulocyte colony stimulating growth factors (GCSF) from macrophages
- Increased in neutrophils (typically see 70-85% PMNs)
- Increased in bands (typically see 10-20% bands)
Increased circulating plasma proteins – ‘Acute phase reactants’:
- Released by liver in response to fever, IL-1
  - Inflammatory/clotting proteins: Fibrinogen, prothrombin, complement proteins, etc
  - Other liver proteins: Ferritin
  - C-reactive protein (normal < 1 mg/dL; with bacterial infection see > 10 mg/dL)
- Low albumin/pre-albumin
Increased erythrocyte sedimentation rate (ESR):
- When plasma protein levels in the plasma are elevated (e.g., acute phase reactants released during inflammation), RBCs aggregate and precipitate rapidly