Tutorial 01: Inflammation and Healing

Inflammation is the response of vascularised tissue to injury, infection, or irritation. Its purpose is to eliminate the injurious agent, remove damaged tissue, and initiate repair. The word derives from the Latin "inflammatio" (to set on fire), and the cardinal signs — redness (rubor), swelling (tumour), heat (calor), pain (dolor), and loss of function (functio laesa) — reflect the underlying vascular and cellular events.

Before inflammation can occur, cells may undergo adaptive responses to sublethal stress. Hyperplasia is an increase in cell number; hypertrophy is an increase in cell size; atrophy is a decrease in cell size or number; metaplasia is the transformation of one differentiated cell type to another (e.g., squamous metaplasia of bronchial epithelium in smokers, or Barrett's oesophagus where squamous epithelium is replaced by columnar intestinal epithelium). Metaplasia is reversible but predisposes to dysplasia and malignancy.

Cell types differ in their regenerative capacity. Labile cells divide continuously (epithelial cells of skin, gut, bone marrow); stable cells (hepatocytes, renal tubular cells) are quiescent but re-enter the cell cycle when stimulated; permanent cells (neurons, cardiac myocytes, skeletal muscle) cannot regenerate after injury — healing must occur by fibrosis.

Necrosis is pathological cell death characterised morphologically by: pyknosis (nuclear condensation), karyorrhexis (nuclear fragmentation), and karyolysis (nuclear dissolution). These changes reflect activation of autolytic enzymes and DNases. Different patterns: coagulative necrosis (proteins denatured, outline preserved — ischaemia in most organs), liquefactive necrosis (enzymatic digestion destroys architecture — brain, abscesses), caseous necrosis (cheese-like, structureless — TB granulomas), fat necrosis (pancreatic lipase digestion of adipose tissue), and gangrenous necrosis (ischaemia + bacterial infection of limbs).

Acute inflammation involves three vascular events: (1) transient vasoconstriction (seconds), (2) vasodilation — mediated by histamine and prostaglandins — increasing blood flow (redness and heat), (3) increased vascular permeability — mediated by histamine, bradykinin, leukotrienes — allowing protein-rich fluid to leak into tissues (oedema and swelling). Leukocyte emigration follows: margination (neutrophils move to vessel wall periphery), rolling (selectin-mediated low-affinity binding to endothelium), firm adhesion (integrin upregulation — LFA-1 binding ICAM-1), diapedesis (transmigration through endothelial junctions), and chemotaxis (directed migration toward the site of injury following IL-8, C5a, LTB4, and bacterial products).

Patterns of acute inflammation: serous (watery protein-poor fluid — blister fluid), fibrinous (high protein, fibrin exudate — pericarditis "bread-and-butter"), purulent/suppurative (pus = neutrophils + necrotic debris — abscess), and haemorrhagic (vessel damage).

Systemic effects of acute inflammation (acute phase response): fever (IL-1, IL-6, TNF-α → hypothalamic PGE₂ synthesis → raised set-point), leukocytosis (bone marrow demargination and accelerated production — neutrophilia in bacterial infection, lymphocytosis in viral, eosinophilia in allergy/parasites), and elevated acute phase proteins (CRP, fibrinogen, serum amyloid A).

Chronic inflammation is characterised by simultaneous inflammation and attempted repair. The cellular infiltrate consists of macrophages, lymphocytes, and plasma cells. Macrophages are the central cell: they phagocytose debris, secrete pro-inflammatory cytokines (IL-1, TNF, IL-12), and activate lymphocytes. Granulomatous inflammation is a specialised form in which macrophages transform into epithelioid cells and fuse into giant cells around indigestible material (TB, fungal infections, foreign bodies, sarcoidosis).

Healing by fibrosis (repair): macrophages clear debris and secrete growth factors (TGF-β, VEGF, PDGF) → angiogenesis (new capillary sprouts) + fibroblast proliferation form granulation tissue (delicate, pink, highly vascular) → fibroblasts synthesise collagen → scar formation. Primary intention healing (clean surgical wound): minimal tissue loss, quick re-epithelialisation, thin scar. Secondary intention healing (open wound): more granulation tissue, more contraction, larger scar. Bone heals through: haematoma → soft callus (woven bone, fibrocartilage) → hard callus (lamellar bone) → remodelling.