Acute Inflammation — Vascular Changes, the Leukocyte Adhesion Cascade, Chemical Mediators and Outcomes

Inflammation is the body's response to tissue injury from infection, trauma, toxins or dead tissue. The classic signs are rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function). Redness and heat come from increased blood flow, swelling from fluid that leaks into the tissue, and pain from chemicals that stimulate nerve endings.

Subacute inflammation is the transition between the two and lasts 2 to 6 weeks; inflammation persisting beyond 6 weeks is chronic, marked by T lymphocytes and plasma cells. The acute response is triggered when innate sensors such as toll-like receptors recognise microbial patterns (PAMPs) or signals from damaged cells (DAMPs) — for example TLR4 with its co-receptor CD14 recognises gram-negative lipopolysaccharide.

1. Vasodilation — mediators such as histamine act on vascular smooth muscle. It starts in the arterioles and opens new capillary beds, so more blood flows to the area: redness (erythema) and heat.
2. Increased vascular permeability — mast-cell histamine (and heparin) opens the junctions between endothelial cells. The acute leak occurs mainly at the postcapillary venules, and the escaping fluid has a protein content approaching that of plasma: an exudate, which produces oedema.
3. Increased lymph flow — lymphatics drain the oedema fluid along with leukocytes, debris and microbes, and lymphatic vessels proliferate to handle the load.

Bradykinin adds to the leak: activation of the Hageman factor (factor XII) triggers the kinin system, and bradykinin increases permeability, dilates vessels and causes pain. Leukotrienes C4, D4 and E4 also contribute to oedema formation.

Macrophages and mast cells that sense injury release cytokines such as TNF-α and IL-1, which make the local endothelium express selectins and integrin ligands. Leukocyte extravasation then follows four classic steps — rolling, activation, firm adhesion and transmigration — followed by migration through the extracellular matrix towards the stimulus.

Neutrophils make up 50–70% of circulating leukocytes and are the most numerous cells to arrive at the site. Once there they recognise microbes and debris, phagocytose them and kill them in phagolysosomes, where myeloperoxidase-containing granules fuse and a respiratory burst generates reactive oxygen species. Opsonins such as C3b coat microbes to speed up phagocytosis.

Drugs target this arachidonic acid pathway. NSAIDs inhibit cyclooxygenase: non-selective agents such as naproxen block both the constitutive COX-1 and the inducible COX-2, while the coxibs are COX-2 selective. Because of the risk of severe cardiovascular events, celecoxib is the only coxib still marketed in the United States. Leukotriene pathway drugs and corticosteroids act further upstream or on other branches.

Cytokines released at the site — IL-6 above all, helped by IL-1, TNF-α and interferon-γ — act on the liver to change the production of acute-phase proteins. These cause the general features of illness (fever, malaise, anorexia, weakness) and give the commonest laboratory markers of inflammation.

Leukocyte adhesion deficiency (LAD) is an autosomal recessive defect in which leukocytes cannot leave the blood. Infected tissue contains almost no neutrophils, so patients cannot form pus or abscesses, while the peripheral blood shows marked neutrophilia (counts above 29,000/µL have been described).

LAD is one of the phagocyte disorders in the differential of recurrent bacterial infection, along with chronic granulomatous disease (respiratory burst defect, detected by the NBT test), Chediak–Higashi syndrome and hyper-IgE syndrome. Delayed cord separation plus neutrophilia without pus points to LAD.

• Resolution — the usual outcome once the organisms are killed: inflammation subsides and the tissue regenerates or is repaired.
• Abscess formation — a localised collection of neutrophils and debris (pus); this is exactly what LAD patients cannot form.
• Healing by fibrosis or scarring — when injury is severe or inflammation persists; scar tissue replacing functional cells explains lasting loss of function.
• Progression to chronic inflammation — persistent infection or inadequate resolution perpetuates tissue injury, with fibrosis or scarring.

Resolution is an active process, not just the fading of signals. Lipid mediators switch from prostaglandins and leukotrienes to specialised pro-resolving mediators — lipoxins, resolvins, protectins and maresins — which stop further neutrophil entry and increase macrophage uptake of apoptotic neutrophils, debris and microbes. Aspirin-triggered 15-epi-lipoxin A4 is one example.