Inflammation is closely tied to repair, which is a combination of tissue regeneration and filling of the area with fibrous tissue (scarring).
Acute inflammation is a rapid response to threats aimed at delivering cellular and protein defenses to the site of injury.
the five cardinal signs of acute inflammation are:
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.
Acute inflammation can be triggered by a variety of stimuli:
innervation, clotting factors, complement split products all induce inflammation
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.
Activated neutrophils express increased levels of Fc receptor and complement receptor, providing them with more effective phagocytosis of opsonized particles.
Neutrophil activation also stimulates metabolic pathways associated with the respiratory burst.
Once in the tissues, neutrophils migrate through chemotaxis, due to either endogenous or exogenous factors. Complement split products (C3a, C5a, C5b67), chemokines, fibrinopeptides, prostaglandins, and leukotrienes are all chemotactic for neutrophils, as are bacterial products such as N-formyl methionyl peptides.
Acute Phase Response
IL-6 and other cytokines stimulate the liver to produce CRP and fibrinogen (measured with ESR)
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:
Neutrophil and macrophage phagocytosis is responsible for much of the killing that occurs.
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.
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.
Chronic inflammation is of longer duration than acute inflammation (weeks or months) and is considered to be active inflammation, tissue destruction, and attempts at repair occurring simultaneously. As such, its morphology differs from acute inflammation.
Macrophages predominate during chronic inflammation. They accumulate through homing, proliferation, and immobilization. Macrophages serve to eliminate microbes and initiate the process of repair, but are also responsible for much of the tissue ingury seen during chronic inflammation.
Mast cells, lymphocytes, plasma cells, and eosinophils are also present. Cytokines from activated macrophages, notably Il-1 and TNF, promote leukocyte recruitment.
Macrophages display antigens to T cells and produce costimulators and cytokines (esp Il-12) to stimulate T cell responses. Activated T cells, in turn, produce cytokines such as IFN-γ that further activate macrophages. In some strong chronic inflammatory conditions, such as rheumatoid arthritis, accumulated cells may resemble lymphoid organs.
Tissue damge occurs, and there may be evidence of tissue remodeling in the form of angiogenesis and fibrosis.
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:
The acute phase response is the systemic manifestation of acute inflammation. It is mediated by cytokines stimulated by bacterial products such as LPS and by other inflammatory stimuli.
The acute phase response consists of several physiologic and clinical changes:
glucocorticoids, GH, aldosterone, ADH, decreased divalent cations in plasma, acute-phase proteins
The systemic inflammatory response syndrome (SIRS), or the acute phase response, can accompany local inflammation. It consists of several clincial and pathological events:
Fever is produced in response to pyrogens that act to stimulate prostaglandin synthesis in the hypothalamus. Bacterial products such as LPS are exogenous pyrogens, that induce expression of endogenous pyrogens such as IL-1 and TNF that then act to increase AA conversion into prostaglandins. Prostaglandins, especially PGE2, resets the temperature set point at a higher level. Fever may help ward off microbial infections through expression of leukocyte heat shock proteins.
Acute-phase proteins are plasma proteins synthesized in the liver that increase several hundred-fold in response to inflammatory cytokines such as IL-6, IL-1, and TNF. Important acute-phase proteins include C-reactive protein, fibrinogen, and serum amyloid A protein. Acute phase proteins opsonize microbes and fix complement. These proteins are responsible for increased erythrocyte sedimentation rate (ESR) and also appear to increase risk for myocardial infarction.
Cytokines such as IL-1 and TNF can accelerated release of leukocytes from the bone marrow, with counts normally climbing to 15,000 -20,000 cells/μl, but can reach up to 100,000 cells/μl (leukemoid reactions). A left shift occurs as immature neutrophils (bands) are released.
Viral infections cause an increase in lymphocyte numbers.
Other manifestations of systemic inflammation include
Sepsis can result in release of enormous quantities of IL-1 and TNF, potentially causing disseminated intravascular coagulation (DIC). Spetic shock is the combination of DIC, hypoglycemia, and cardiovascular failure.
Adult respiratory distress syndrome (ARDS) can be caused by neutrophil-mediated lung injury that results in fluid escape into the airspace. Kindey and bowel can be injured due to low perfusion. Sepsis is often fatal.
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.
Anti-inflammatory drugs can be effective