Inflammation


Inflammation is part of the biological defence response of body tissues. Inflammatory immunovascular responses can be triggered by a broad range of stimuli, including physical trauma, "dead, damaged, malfunctioning or stressed tissues", pathogens, irritants, toxins, overuse, autoimmunity, allergens, and foreign bodies. The five cardinal signs are heat, pain, redness, swelling, and loss of function.
Inflammation is a generic response, and therefore is considered a mechanism of innate immunity, not adaptive immunity. It involves immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus and compromise the survival of the organism. However, inflammation can also have negative effects. For instance, too much inflammation, in the form of chronic inflammation, is associated with various diseases, such as hay fever, periodontal disease, atherosclerosis, and osteoarthritis.
Inflammation can be classified as acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli, and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells in the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and involves simultaneous destruction and healing of the tissue.
Inflammation has also been classified as Type 1 and Type 2 based on the type of cytokines and helper T cells involved.

Signs and symptoms

Cardinal signs – acute

Inflammation is characterized by five cardinal signs, :
The first four were described by Celsus.
Pain is due to the release of chemicals such as bradykinin and histamine that stimulate nerve endings. Heat and redness are due to increased blood flow at body core temperature to the inflamed site. Swelling is caused by accumulation of fluid. The fifth sign, loss of function, is believed to have been added later by Galen, Thomas Sydenham or Rudolf Virchow. Examples of loss of function include pain that inhibits mobility, severe swelling that prevents movement, having a worse sense of smell during a cold, or having difficulty breathing when bronchitis is present. Loss of function has multiple causes.

Cardinal signs – chronic

Common signs and symptoms that develop during chronic inflammation are:
  • Body pain, arthralgia, myalgia
  • Chronic fatigue and insomnia
  • Depression, anxiety and mood disorders
  • Gastrointestinal complications such as constipation, diarrhea, and acid reflux
  • Weight gain or loss
  • Frequent infections

    Causes

Acute and chronic

Acute

Acute inflammation is a short-term process, usually appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus. It involves a coordinated and systemic mobilization response of various immune, endocrine and neurological mediators of acute inflammation. In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and then ceases.
Acute inflammation occurs immediately upon injury, lasting only a few days. Cytokines and chemokines promote the migration of neutrophils and macrophages to the site of inflammation. Pathogens, allergens, toxins, burns, and frostbite are some of the typical causes of acute inflammation. Toll-like receptors recognize microbial pathogens. Acute inflammation can be a defensive mechanism to protect tissues against injury. Inflammation lasting 2–6 weeks is designated subacute inflammation.

Acute process

The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors, which recognize two subclasses of molecules: pathogen-associated molecular patterns and damage-associated molecular patterns. PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage.
At the onset of an infection, burn, or other injuries, these cells undergo activation and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness and increased heat. Increased permeability of the blood vessels results in an exudation of plasma proteins and fluid into the tissue, which manifests itself as swelling. Some of the released mediators such as bradykinin increase the sensitivity to pain. The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils and macrophages, to flow out of the blood vessels and into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury. The loss of function is probably the result of a neurological reflex in response to pain.
In addition to cell-derived mediators, several acellular biochemical cascade systems—consisting of preformed plasma proteins—act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis.
Acute inflammation may be regarded as the first line of defense against injury. Acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators are short-lived and are quickly degraded in the tissue. Hence, acute inflammation begins to cease once the stimulus has been removed.

Chronic

Chronic inflammation is inflammation that lasts for months or years. Macrophages, lymphocytes, and plasma cells predominate in chronic inflammation, in contrast to the neutrophils that predominate in acute inflammation. Diabetes, cardiovascular disease, allergies, and chronic obstructive pulmonary disease are examples of diseases mediated by chronic inflammation. Obesity, smoking, stress and insufficient diet are some of the factors that promote chronic inflammation.

Vascular component

Vasodilation and increased permeability

As defined, acute inflammation is an immunovascular response to inflammatory stimuli, which can include infection or trauma. This means acute inflammation can be broadly divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells. The vascular component of acute inflammation involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins, into inflamed tissue.
Upon contact with PAMPs, tissue macrophages and mastocytes release vasoactive amines such as histamine and serotonin, as well as eicosanoids such as prostaglandin E2 and leukotriene B4 to remodel the local vasculature. Macrophages and endothelial cells release nitric oxide. These mediators vasodilate and permeabilize the blood vessels, which results in the net distribution of blood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell. This exuded tissue fluid contains various antimicrobial mediators from the plasma such as complement, lysozyme, antibodies, which can immediately deal damage to microbes, and opsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded platelets, coagulants, plasmin and kinins can clot the wounded area using vitamin K-dependent mechanisms and provide haemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a fibrin lattice – as would construction scaffolding at a construction site – for the purpose of aiding phagocytic debridement and wound repair later on. Some of the exuded tissue fluid is also funneled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system.
Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.

Plasma cascade systems

  • The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC.
  • The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
  • The coagulation system or clotting cascade, which forms a protective protein mesh over sites of injury.
  • The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.