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Chemokines - Key Mediators of Inflammation
Chemokines are a superfamily of small polypeptides, most of which contain 90-130 amino acid residues. They selectively, and often specifically, control the adhesion, chemotaxis, and activation of many types of leukocyte populations and subpopulations. Some chemokines are primarily involved in inflammatory processes, others are constitutively expressed and play important homeostatic or developmental roles. “Housekeeping” chemokines are produced in lymphoid organs and tissues or in non-lymphoid sites such as skin, where they direct normal trafficking of lymphocytes, such as determining the correct positioning of leukocytes newly generated by hematopoiesis and arriving from bone marrow. When a receptor binds an appropriate chemokine, it activates heterotrimeric large G proteins, initiating a signal transduction process that generate such potent second messengers. Cell can respond to a chemokine only if it possesses a receptor that recognizes it. Consequently, differences in the expression of chemokine receptors by leukocytes coupled with the production of distinctive profiles of chemokines by destination tissues and sites provide rich opportunities for the differential regulation of activities of different leukocyte populations.
Other Mediators of Inflammation
The kinin system is an enzymatic cascade that begins when a plasma clotting factor, called Hageman factor, is activated following tissue injury. The activated Hageman factor then activates pre kallikrein to form kallikrein, which cleaves kininogen to produce bradykinin. Another enzymatic cascade that is triggered by damage to blood vessels yields large quantities of thrombin. Thrombin acts on soluble fibrinogen in tissue fluid or plasma to produce insoluble strands of fibrin and fibrinopeptides. The end product of this pathway is the enzyme plasmin, which is formed by the conversion of plasminogen. Activation of the complement system by both classical and alternative pathways results in the formation of a number of complement split products that serve as important mediators of inflammation. Prostaglandins have diverse physiological effects, including increased vascular permeability, increased vascular dilation, and induction of neutrophil chemotaxis. The thromboxanes cause platelet aggregation and constriction of blood vessels. Metabolism of arachidonic acid by the cyclooxygenase pathway produces prostaglandins and thromboxanes. A number of cytokines play a significant role in the development of an acute or chronic inflammatory response.
The Inflammatory Process – I
Inflammation is a physiologic response to a variety of stimuli such as infections and tissue injury. Neutrophil infiltration into the tissue peaks within the first 6 h of an inflammatory response, with production of neutrophils in the bone marrow increasing to meet this need. The hallmarks of a localized acute inflammatory response, first described almost 2000 years ago, are swelling, redness, heat, pain, and loss of function. A local acute inflammatory response can occur without the overt involvement of the immune system. Often, however, cytokines released at the site of inflammation facilitate both the adherence of immune-system cells to vascular endothelial cells and their migration through the vessel wall into the tissue spaces. The local inflammatory response is accompanied by a systemic response known as the acute-phase response. This response is marked by the induction of fever, increased synthesis of hormones such as ACTH and hydrocortisone, increased production of white blood cells (leukocytosis), and production of a large number of acute-phase proteins in the liver.
The Inflammatory Process – II
Chronic inflammation also occurs in a number of autoimmune diseases in which self-antigens continually activate T cells. A type of scar tissue develops at sites of chronic inflammation by a process called fibrosis, a wound-healing reaction that can interfere with normal tissue function. Chronic inflammation may also lead to formation of a granuloma, a tumor-like mass consisting of a central area of activated macrophages surrounded by activated lymphocytes. Recent studies suggest that regions of plump endothelial cells resembling HEVs appear along the vasculature in tertiary extra lymphoid sites of chronic infection. These HEV-like regions, which appear to be sites of lymphocyte extravasation into the inflamed tissue, express several mucins. These HEV-like regions have been observed in a number of chronic inflammatory diseases in humans, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, Graves’ disease, Hashimoto’s thyroiditis, and diabetes mellitus. These observations suggest that an effective approach for treating chronic inflammatory diseases may be to try to control the development of these HEV like regions.
Leukocyte extravasation is an integral part of the inflammatory response. One way to reduce leukocyte extravasation is to block the activity of various adhesion molecules with antibodies. A combination of two anti-adhesins had to be used because failure to block both LFA-1 and ICAM-1 results in rejection. The corticosteroids, which are cholesterol derivative, are used in anti-inflammatory therapy. Corticosteroid treatment causes a decrease in the number of circulating lymphocytes as the result either of steroid induced lysis of lymphocytes or of alterations in lymphocyte-circulation patterns. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used medication for treating pain and inflammation. The major mechanism by which these drugs exert anti-inflammatory effects is by inhibiting the cyclooxygenase pathway that produces prostaglandins and thromboxanes from arachidonic acid. Although NSAIDs such as aspirin, Tylenol, ibuprofen, Naproxen, and others are routinely prescribed for the treatment of ailments as diverse as arthritis, sprains, tissue injury, and back pain, the duration of their use is limited by gastrointestinal side effects that include unease and abdominal pain and in more serious cases bleeding or perforation of the stomach or upper GI tract. Investigation of the mechanism of NSAIDs has provided a basis for the beneficial and deleterious effects of many NSAIDS.