Inflammation is a response of vascularized tissues to infections and damaged damaged tissues that bring specialized cells and molecules of the host defense to eliminate offending agents (e.g. microbes, toxins, necrotic cells/tissues). The mediators of defense include phagocytic leukocytes, antibodies, and complement proteins, which can be recruited from the blood or may be resident to the tissue. Components of the innate immunity include natural killer cells, dendritic cells, epithelial cells, as well as soluble factors (e.g. the complement systems ). A typically inflammation response can be summarized in the following steps: Offending agent is recognized by host cell and molecules. Leukocytes and plasma proteins are recruited. Leukocytes and proteins are activated and destroy offending agent. Reaction is controlled and stopped. Damaged tissue is repaired.
Components of the inflammatory response: Blood vessels and leukocytes. Blood vessels dilate to slow blood flow and become permeable to leukocytes, which then become active and acquire the ability to ingest and destroy microbes, dead cells, or foreign bodies.
Harmful consequences of inflammation: Reaction to innocuous agents or uncontrolled reaction can lead to pathogenic consequences such as rheumatoid arthritis, atherosclerosis, lung fibrosis, type II diabetes, Alzheimer disease, cancer as well as hypersensitivity to insect venom, drugs, foods, or toxins.
Local and systemic inflammation: Localized infection or damage can often trigger systemic reactions (e.g. fever, sepsis or other systemic inflammatory response syndrome).
Mediators of inflammation: Vascular cells, microbes, necrotic cells, and response to hypoxia can trigger elaboration of inflammatory mediators eliciting inflammation.
Acute and chronic inflammation: Acute inflammation lasts at most days and typically consists of edema and emigration of leukocytes (primarily neutrophils); it is typically associated with the innate immune response. Chronic inflammation lasts much longer and consists of greater tissue destruction, presences of lymphocytes, macrophages, proliferative blood vessels, and deposition of connective tissue; it is typically associated with the adaptive immune response.
Termination of inflammation and initiation of tissue repair: Once the offending agent is eliminated, mediators are broken down and dissipated followed by tissue repair through regeneration of surviving cells and deposition of connective tissue (scarring).
Infections: Bacterial, viral, fungal, parasitic, and microbial toxins are among the most common causes of inflammation with varied responses, which are determined largely by the type of pathogen and characteristics of the host (e.g. poor defense).
Tissue necrosis: Necrosis elicits inflammation regardless of the cause (ischemia, trauma, physical/chemical injury).
Immune reactions: Also called hypersensitivity, caused by cytokine release of T lymphocytes as reactions to one’s own tissue, or may inappropriate responses to innocuous substances or non-harmful microbes.
As the first step of inflammation, receptors to offending agents are integral to mounting an inflammation response.
Cellular receptors for microbes: Cells express receptors on their surfaces, in endosomes, and in the cytosol to detected invasion of microbes at any point of interface. The most well defined are those of the innate immune response—toll like receptors (TLRs)—that are expressed on epithelial and dendritic cells, macrophages, and leukocytes; their activation triggers release of adhesion molecules, cells, cytokines, and other mediators.
Sensors of cell damage: Receptors that sense signs of cell damage (e.g. uric acid, ATP levels, low K+, cytosolic DNA) activate the formation of the inflammasome, a mulitmeric, cytosolic enzyme that induces production of IL-1, which recruits leukocytes. Gain-of-function mutations can cause autoinflammatory syndromes treatable with IL-1 antagonists. Pathogenic action of the inflammasome is known to cause gout, metabolic syndrome, atherosclerosis, and Alzheimer disease by attacking urate crystals, lipids, cholesterol crystals, and amyloid deposists in the brain, respectively.
Other cellular receptors: Leukocytes express receptors for the Fc tails of antibodies and compliment proteins, which coat microbes and facilitate opsonization and promote ingestion and destruction of microbes as well as promote inflammation.
Circulating proteins: Circulating mannose-binding lectin recognizes microbial sugars and activates the complement system, which produces an inflammatory response. Other proteins—collectins—bind to microbes.
Acute inflammation has three major components: (1) dilation of small blood vessels leading to increased blood flow, (2) increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the micovasculature, accumulation thereof at the site of injury, and activation thereof to eliminate the offending agent. Phagocytes attempts to eliminate offending agents while also liberating cytokines, lipid messengers, and other mediator along with sentinel cells. Some of the mediators promote efflux of plasma and attract circulating leukocytes.
Vascular changes during acute inflammation maximize movement of plasma proteins and leukocytes out of circulation and into the site of infection or injury though dilation and increased permeability. Escape of this kind called an exudate. More generally, exudation refers to escape of fluid and proteins from the vasculature into interstitial tissue of body cavities. In contrast, transudate refers to escape of fluid with very low protein content (usually due to osmotic pressure). Edema can be cause by either exudate or transudate fluid in interstitial tissue or serous cavities.
Vasodilation in induced by histamine (and other agents) on vascular smooth muscle, which first causes the arterioles to open new capillary beds leading to increased blood flow. This causes erythema or heat and redness. Along with increased permeability (i.e. an out pour of fluid and proteins) the blood flow slows and is termed statis, which manifests as localized redness. The endothelium then expression integrins and selectins, which allow leukocytes, principally neutrophils, to adhere and migrate through the vascular wall.
Increased vascular permeability is caused by a verity of different mechanisms. Histamine causes contraction of endothelial cells leading to increased intercellular space. It is usually short lived (15-30 minutes) and is therefore called the immediate transient response. Some forms of mild injury such radiation (i.e. sunburn) or bacterial toxins can cause delayed prolonged leakage 2 to 12 hours after exposure and can last hours or days.
Endothelial damage leading to necrosis and detachment is another obvious cause of leakage. Injury from burns, bacteria, and activity from neutrophils may worsen damage leading to immediate leakage that typically lasts hours until damaged vessels are thrombosed or repaired.
Increases in transcytosis through endothelial cells may be stimulated by VEGF but contribution of this means to vascular leakage is not well studied and remains uncertain. Vascular leakage of any kind can lead to life threatening loss of fluid in burn victims.
During inflammation, lymph flow in increased and lymph vessels proliferate in order to accommodate the increase in interstitial fluid, leukocytes, and cellular debris through secondary inflammation of the lymphatics, lymphangitis, as well as the draining lymph nodes lymphadenitis. During an inflammation the lymph nodes may become enlarged due to hyperplasia of the lymphoid follicles, lymphocytes, and macrophages. The presence of red streaks near a wound follow the course of lymphatic channels and is indicative of lymphangitis along with painful enlargement of the draining lymph nodes (i.e. lymphadenitis).
Leukocyte recruitment form the vessel lumen to to tissue is a multistep process mediated by adhesion molecules and chemoattractant cytokines: chemokines.
As a result of stasis and decrease in wall shear stress, leukocytes assume a more peripheral position along the endothelial surface i.e. margination, occur. Leukocytes will transiently adhere to the endothelium and appear to be rolling along the vessel wall before eventually slowing and firmly adhering. Expression of the adhesion molecules responsible for this action is enhanced by cytokines that are secreted by sentinel cells in the infected or damaged tissue.
The rolling action is mediated by three types of selectin named for the cells that expresses them: L-selectin (leukocytes), E-selectin (endothelium), and P-selectin (platelets and endothelium). The ligands for selectin are made of sialylated oligosaccharieds bound to mucine-like glycoprotein backbones. Resident tissue macrophages, mast cells, and endothelial cells at the site of infection or injury secrete tumor necrosis factor (TNF), IL-1, and chemokines, which up regulate expression of selectins and their ligands. Within 1 to 2 hours, endothelial cells begin to express E-selectin and the L-selectin ligands. Leukocytes express L-selectin and the ligands for E- and P-selectin.
The weak rolling action allows for leukocytes to bind firmly using a family of heterodimeric surface proteins: integrins. TNF and IL-1 induce expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which are the respective ligands of β1 integrin VLA-4 and β2 integrins LFA-1/Mac-1. Chemokines that bind to rolling leukocytes convert expression of low affinity integrins to high affinity VLA-4 and LFA-1, facilitating adhesion of leukocytes.
Transmigration or diapedesis occurs mainly through postcapillary venules toward the chemical concentration gradient produced by injured cells, namely of CD31 and PECAM-1 (platelet endothelial cell adhesion molecule). After moving through endothelial cells, leukocytes mostly likely pass the basement membrane by secreting collegenases.
Movement of leukocytes toward the site of injury is a process called chemotaxis that is driven by exogenous and endogenous agents such as bacterial products or cytokines, complement system components, and arachidonic acid metabolites (leukotriene B4: LTB4). These signals all bind to transmembrane G protein-coupled receptors that transduce signals to activate actin and myosin mediated movement. Neutrophils predominate inflammatory infiltration and are replaced my monocytes within 1 to 2 days because they are more common in the blood stream and undergo apoptosis with in 24 to 48 hours while monocytes live longer and may also proliferate within the tissue(s).
Recognition of infection or necrosis (i.e. leukocyte activation) is driven primarily by increased cytosolic Ca2+ and activation of protein kinase C (PKC) and phospholipase A2, which—most importantly—activate phagocytosis and intracellular killing.
The phagocytotic response involves recognition and attachment, engulfment, and killing or degradation.
Macrophages expression mannose receptors, or lectin, that bind to terminal mannose or fucose residues of glycoproteins and glycolipids commonly expressed on microbial cell walls (mammalian glycoprotein/lipids contain terminal sialic acid or N-acetylgalctosamine). Scavenger receptors bind to a variety of microbes including modified LDL particles. Integrins, namely Mac-1 may also bind to microbes. All phagocytotic binding is enhanced by opsoninization of microbes such as: IgG antibodies and C3b breakdown products of complement.
Once a particle is bound pseudopods (extensions of cytoplasm) flow around it and the plasma membrane pinches off to form a phagosome (vesicle) that then merges with a lysosomal granule. The phagosome may release its contents into the cytoplasm. This process hinges on highly coordinated changes in membrane remodeling and cytoskeletal changes that depend on actin filament polymerization.
Elimination of microbes and necrotic tissue is preformed in the lysosome—to prevent damage to the host cells—of neutrophils and macrophages with use of reactive oxygen species (ROS) and nitric oxide along with lysosomal enzymes.
ROS are produced by the multisubunit enzyme complex that forms during phagocytosis: NADPH oxidase, which oxidizes NADPH and reduces oxygen to produce superoxide anions, O$^{\bar{\bullet}}_{2}$. The superoxide anion is converted into hydrogen peroxide—which can also be converted into a hydroxyl radicals—leading to oxidation of proteins and lipids or myeloperxidase (MPO) will use H2O2 and Cl− to create hypochlorite (OCl2−) to halogenate microbes. There are several mechanisms for host cells that protect against harmful self-oxidation: superoxide dismutase, catalase, glutathione peroxidase, ceruloplamin and transferrin.
NO is soluble gas that is made from arginine with inducible nitric oxide synthase (iNOS) when neutrophils and macrophages are activated by cytokines (e.g. INF-β) or microbial products. NO reacts with O$^{\bar{\bullet}}_{2}$ to generate peroxynitrite (ONOO−), which attacks, lipids, proteins, nucleic acids or microbes and host cells.
In unrelated functions, NO relaxes smooth muscle and is a vasodilator. Additionally endothelial and neuronal NOS (eNOS, nNOS) use NO to maintain vascular tone and as a neurotransmitter.
Different types of granules that contain acid proteases to degrade bacteria and debris aided by membrane bound proton pumps or neutral protease that degrade extracellular components (e.g. collagen, basement membrane, fibrin, elastin and cartilage), which results in tissue destruction. Neutral protease action can also yield anaphylatoxins. Azurophil granules contain myeloperoxidase, lysozyme defensins, acid hydrolases, and neutral proteases (elatase, cathepsin G, nonspecific collagenases, proteinase 3). Specific granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase.
Antiproteases are typically found in serum and tissue fluids to protect host tissue and cells from the harmful effects of lysosomal enzymes. One notable examples is α1-anitrypsin, which inhibits neutrophil elastase. Deficiency in α1-anitrypsin can lead to emphysema, lung disease, or liver disease.
In response to infectious pathogens and inflammatory mediators (e.g. cytokines such as chemokines and interferons, complement proteins, and ROS), neutrophils generate an extracellular fibrillar network to trap invaders. Neutrophils sacrifice their nuclei to crate a viscous trap made of nuclear chromatin that binds and concentrates granule proteins. These traps have been detected in blood during sepsis and its speculated that they may be the source of DNA that is used to create nuclear antigens seen in autoimmune diseases such as lupus.
Once activated, the effector mechanisms of leukocytes do not necessarily distinguish between offender and host. Neutrophils and macrophages also release ROS, NO, and lysosomal enzymes in extracellular space, which can damage endothelial cells and other normal unaffected cells making the leukocytes the offending agent of injury. Such release is a normal mechanism and can be observed during frustrated phagocytosis: phagocytes cannot engulf materials—complex attached to flat immovable surfaces i.e. the basement membrane—and instead release lysosomal enzymes into interstitial space. Digestion of some materials can also cause damage to the phagoloysosome membrane such as urate crystals.
Injuries of this type are characteristic of infections that are difficult to eradicate such as tuberculosis and the prolonged inflammation response leads to collateral damage. It is also, by definition, seen in autoimmune diseases. Finally it occurs in reaction to often innocuous environmental substances such as asthma.
Leukocytes, especially macrophages, secrete cytokines that promote or limit inflammation; growth factors that stimulate proliferation of endothelium, fibroblasts to synthesis collagen; and simulate enzymes to remodel connective tissue. There also also T lymphocytes that produce IL-17 (TH17 cells) that secrete chemokins to recruit leukocytes.
A large part termination of the inflammatory response is due simply due to rapid and burst-like nature of inflammatory mediators; without continued stimulation neutrophils undergo apoptosis with a few hours after leaving the blood stream. Additionally, release of TGF-β, IL-10, and switching arachidonic acid intermediate leukotrienes to lipoxins elicits termination of the inflammatory response.
The most important mediators of inflammation include vasoactive amines, lipid products (i.e. prostaglandins and leukotrienes), cytokines, and products of complement activation, which may have overlapping function(s). They are produced and secreted by cells or created from plasma proteins. Sentinel cells: i.e. macrophages, dendritic cells, and mast cells contain mediators in granules or synthesize them de novo (e.g. prostaglandins, leukotrienes, and cytokines) while plasma derived mediators are created mainly in the liver and present as inactive precursors. While these mediators can stimulate the release or production of other mediators, they are generally short lived.
Histamine and serotonin are stored in and released by leukocyte granules. Histamine is stored and released primarily by mast cells in connective tissue near blood vessels.