Immunity and Inflammation

Immunity and Inflammation

1. Definition, overview, and the pharmacological rationale

• Inflammation is a physiological, protective response to tissue injury and infection; it is not a synonym for infection, though infection is one trigger (G&G 14e Ch.38, p.759).
• The response was described by the Romans ~2000 years ago by its four cardinal signs: rubor (redness), calor (heat), tumor (swelling), and dolor (pain); a fifth, functio laesa (loss of function), was added later (G&G 14e Ch.38, p.759).
  • Rubor and calor arise from vasodilation → increased blood flow to the injured area.
  • Tumor (oedema) arises from increased vascular permeability → leakage of plasma fluid into tissue.
  • Dolor arises from mediators (prostaglandins, bradykinin) sensitising afferent nociceptors.
• The purpose of the acute inflammatory response is threefold: restrict damage to the localised site, recruit immune cells to eliminate the pathogen, and initiate wound repair (G&G 14e Ch.38, p.759).
• The immune and inflammatory responses are the substrate for a large fraction of therapeutics: introduction of pathogens/foreign proteins stimulates immune recognition → inflammatory and allergic responses, and "aspects of these responses are subject to pharmacological modulation" (G&G 14e Ch.38, p.749).
• Central pharmacological principle: almost every soluble mediator or cellular step in this cascade corresponds to a druggable target — histamine (antihistamines), eicosanoids (NSAIDs, coxibs, leukotriene modifiers), cytokines (biologicals), the arachidonic-acid cascade upstream (glucocorticoids), leukocyte trafficking (anti-integrins), and immune checkpoints (checkpoint inhibitors) (synthesised across G&G 14e Ch.38 and KDT 8e Ch.13–14).