Inflammation

Overview

the five cardinal signs of acute inflammation are:

• dolor = pain
• tumor = swelling
• rubor = redness
• calor = heat
• function laesa = loss of function

Acute inflammation has a rapid onset (seconds or minutes) and last for up to a few days. It is characterized by fluid and plasma protein exudation and the extravasation of leukocytes, predominantly neutrophils.

A cascade of events, discrete but related, occur during acute inflammation.

Major cellular sources of inflamamatory molecules include platelets, neutrophils, monocytes/macrophages, masts cells, endothelial cells, smooth muscle, and fibroblasts.

Most mediators work by binding to and activating target cells, but some have direct enzymatic or oxidative activity. Some operate in cascades, and most have a short half life.

In situations of active phagocytosis, the release of lytic enzymes damages healthy cells. The accumulation of dead cells, digested material, and fluid forms pus.

The cast

Stimuli

Acute inflammation can be triggered by a variety of stimuli:

• infections or microbial toxins
• trauma, blunt or penetrating
• thermal or chemical injury
• tissue necrosis
• foreign bodies (ie splinters, dirt, sutures)
• hypersensitivity reactions

innervation, clotting factors, complement split products all induce inflammation

Acute inflammation depends on involvement of connective tissue, vasculature and leukocytes:

• increased vasodilation and vascular permeability leads to increased blood flow and exit of leukocytes and plasma proteins from the circulation
• emigration, accumulation, and activation of leukocytes at the site of injury

In most acute inflammations, neutrophils predominate during the first 6-24 hours, being replaced by monocytes in 24-48 hours. In certain infections, however, this pattern may differ. Pseudomonas infections cause neutrophil predominance for 2-4 days, viral infections cause lymphocyte accumulation, and eosinophils may be the main cell type to certain hypersensitivity reactions.

While all acute inflammatory reactions involve vascular and leukocyte changes, different morphological patterns are also identifiable.

Local acute inflammation is usually accompanied by the acute-phase response, comprised of several changes in plasma proteins.

Leukocyte activation

Leukocyte activation follows cell surface binding by cytokines such as IFN-γ, by microbial products to Toll-like receptors, or by opsonized pathogens coated in IgG or complement protein C3. Several signaling pathways are then triggered, involving increased Ca2+ signaling and activation of PKC and phospholipase A2.

Functional aspects of leukocyte activation include:

• Arachidonic acid metabolites are produced from phospholipids as a result of phospholipase A2.
• Degranulation, secretion of lysosomal enzymes, and activation of the oxidative burst.
• Cytokine secretion, primarily by macrophages, but also by mast cells and others, amplifies and regulates inflammatory reactions.
• Changes in adhesion molecule expression and avidity allows firm adhesion to endothelium.

Leukocyte extravasation occurs following endothelial activation, followed by chemotaxis and migration.

Neutrophil and macrophage phagocytosis is responsible for much of the killing that occurs.

Vascular Changes

While plasma proteins and circulating cells normally remain inside vessels, during acute inflammation, a number of changes allow them to move to the site of injury. These changes develop at varing rates depending on severity of injury.

Vasodilation is one of the first manifestations of acute inflammation, involving both arterioles and capillary beds. This increases blood flow, accounting for heat and redness. It is induced by several mediators, notably histamine and nitric oxide working on vascular smooth muscle.

Increased permeability next occurs, with protein-rich fluid pouring into extracellular tissues, causing edema. This loss of fluid increases the blood viscosity, resulting in stasis as blood flow is reduced. Stasis occurs within minutes of severe injury or not until 15-30 minutes with mild injury.

Increased permeability can be caused by many factors. The most common mechanism is the formation of endothelial gaps in venules, induced by histamine, bradykinin, IL-1, IFN-γ, TNF, neuropeptide substance P, and others. Endothelial gaps usually last 15-30 minutes, though cytokine-induced effects can last for 24 hours or more. Direct and leukocyte-mediated injury or angiogenesis can also increase vascular permeability. Delayed leakage may occur with injury such as sunburns.

Endothelial activation, or surface expression adhesion molecules such as selectins, is induced by histamine, thrombin, PAF, TNF, IL-1, and chemokines. These cell surface molecules facilitates the adhesion of leukocytes to vessel walls and their subsequent extravasation.

Patterns of Acute Inflammation

While all acute inflammatory reactions involve vascular and leukocyte changes, they can also differ depending on their cause and tissue location.

Serous inflammation is marked by the accumulation of a thin fluid, resulting in edema. Burns, blisters, and pleural effusion are examples of serous inflammation.

Fibrinous inflammation results from more severe injuries and greater vascular permeability, with fibrin formation and deposition occurring. Fibrinous exudate is common in the lining of body cavities, including the meninges, the pericardium, and the pleura, and can result from procoagulant activity of cancer cells in the interstitium. Fibrinous exudate can be cleared by fibrinolysis during resolution, but can also remain and cause angiogenesis and fibroblast deposition, leading to scar formation (organization).

Supperative/purulent inflammation is characterized by the production of large amounts of pus containing neutrophils, cell debris, fluid, and bacteria. Pyogenic bacteria (ie staphylococci) produce supperation. Abcesses are localized collections of purulent inflammation, with a necrotic centre and a wall of neutrophils and often fibrotic tissue.

Ulcers are local defects of and organ or tissue produced by the sloughing off of inflammatory necrotic tissue, occuring only when inflammation occurs on or near a surface. Chronic inflammation results in fibroblast proliferation and fibrosis at the ulcer margins.

Causes of chronic inflammation

• chronic infection
• prolonged exposure to toxins
• autoimmune
• idiopathic

Granulomas

Granulomas are collections of aggrgated macrophages that can take on an epitheliod appearance. Multi-nucleated giant cells and peripheral sheaths of lymphocytes may be present. Granulomas can be caseating or non-caseating.

Causes of granulomas include:

• tuberculosis
• Crohn's disease
• sarcoidosis
• cat-scratch fever
• lymphogranuloma inguinale
• schistosomiasis
• leprosy
• brucellosis
• syphilis
• fungal infections
• beryllosis
• foreign bodies, including irritant lipids

Fibrosis

Serum Proteins

C-reactive protein is a major acute-phase protein released from the liver in response to tissue damage. It binds to cell wall components of bacteria and fungi, activating the complement system and resulting in increased clearance of the pathogen.

Kinins are small peptides present in the plasma in inactive form. Tissue injury activates kinins, which then cause vasodilation and increased permeability. Bradykinin also stimulates pain receptors, increaseing protection of an inflamed area.

Components of the clotting cascade enter injured tissue and are activated to result in deposition of insoluble strands of fibrin, the main component of a blood clot. This walls off the injured area from the rest of the body.