Mechanism of Inflammation – Alteration in Vascular Permeability and Blood Flow, Migration of WBC’s, Mediators of Inflammation : Pharmaguideline -->

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Mechanism of Inflammation – Alteration in Vascular Permeability and Blood Flow, Migration of WBC’s, Mediators of Inflammation

Alteration in vascular permeability and blood flow, Migration of WBC’s, Mediators of inflammation

Mechanism of Inflammation

Inflammatory responses are formed by coordinated signals that produce mediators of inflammation both in the resident cells of tissues and in the infiltrating inflammatory cells. The inflammatory process is involved in a variety of chronic diseases including cardiovascular disease, bowel disorders, diabetes, arthritis, and cancer. There are different ways in which an initial stimulus impacts the inflammatory response process, but all have the same mechanism.
  • Cells detect detrimental stimuli with receptors on their surfaces.
  • There is an activation of inflammatory pathways.
  • Markers of inflammation are released.
  • The immune system is activated.

Alteration in vascular permeability and blood flow

By stimulating ECs or binding agonists to their receptors, increased vascular permeability can occur. Their activation leads to the release of many different second messengers, including enzymes such as kinases, GTPases, phosphatases, and others. Many intracellular events are controlled by signaling molecules, including transcription, translation, transcytosis, folding, and degradation, which affects cellular processes regulating endothelial barrier function in such ways as cytoskeletal tension, contractility, and junctional and focal adhesion assembly and disassembly. By recruiting focal adhesions within cells, signaling molecules may become more effective due to their location-specific generation or recruitment.

Focal adhesion kinases, for instance, act at specific sites, meaning that regardless of the target they affect integrin adhesion and cytoskeleton dynamics. Multiple signaling molecules regulate the function of the endothelial barrier. Activated protein kinase C, MLCK, Src family kinases, and RhoA, a small GTPase, are a few of the intracellular signaling molecules responsible for mediating barrier dysfunction (increased permeability). Microdomains within cells, such as focal adhesions, are recruited to increase the effectiveness of signaling molecules. For instance, focal adhesion kinases exert strong cytoskeletal influence on integrin adhesion and cytoskeleton dynamics through their site-specificity.

When ECs are stimulated or agonists are bound to EC receptors, vascular permeability is induced. In response to their activation, these receptors produce enzymes as well as second messengers, such as kinases, phosphatases, GTPases, and others. Numerous intracellular events are controlled by signaling molecules, including transcription, translation, transcytosis, folding, and degradation. These processes ultimately regulate the function of endothelial barriers, including cytoskeletal tension, contractility, and assembly and disassembly of cell junctions. Cellular signaling molecules are enhanced through the formation of microdomains, including focal adhesions, that are specific to each cell. Focal adhesion kinase, for instance, selectively accepts target integrins, exerting a powerful effect on the cytoskeletal dynamics of integrin adhesions.

There are numerous signaling molecules that regulate the function of the endothelial barrier. Barrier dysfunction (increased permeability) is often mediated by a combination of signaling molecules, including elevated intracellular calcium, activated protein kinase C, MLCK, and Src family kinases, as well as RhoA, a small GTPase. Sphingosine-1-phosphate (S1P), protein kinase A, and the small GTPase Rac-1 are believed to play a role in barrier protection (reduced permeability). Cyclic GMP may also regulate endothelial barrier function, but whether it increases vascular permeability or decreases it remains a mystery.

Neurotoxicants commonly cause vascular permeability to increase as a result of damage to the BBB and/or BNB. In this example, the microvasculature is the major target. It is possible, however, to breach the barrier and expose other brain cells to toxic effects as well. The NIEHS reports that lead (Pb) neurotoxicity leads to changes in CNS capillaries, predominantly in the cerebellum and cerebrum, including alterations in vessel diameters (narrowing or constrictions), changes within the vessel wall (endothelial swelling, necrosis), and thrombosis.

Migration of WBC’s

A complex series of adhesion events occurs between leukocytes and endothelium in order to ensure that leukocytes leave the bloodstream only at inflammatory sites. The leukocytes adhere to the vessel walls, then wander along them until they reach the endothelial borders, past the subendothelial basement membrane, and then migrate through the interstitial tissues. The inflammatory response is a two-edged sword. An inflammation may be self-directed, persistent for too long, or occurring at the wrong time. Inflammation regulation therefore plays a vital role in health. When leukocytes move across the endothelium lining blood vessels at the site of inflammation, trans endothelial migration (TEM) occurs as a critical step in the regulation of the inflammatory response. The inflammatory response and the majority of collateral damage occur when the leukocytes leave the blood vessels. TEM is primarily caused by paracellular transmigration of cells across endothelium borders. There has been a recent explosion of interest in TEM studies of endothelial cells, especially their migration across cells (transcellular migration).

Mediators of inflammation

An inflammatory response occurs when the body is confronted by injurious substances and infectious organisms. A primary aspect of understanding inflammation is identifying the cells, blood vessels, proteins, and lipid mediators involved in removing the inflammatory stimulus and promoting healing. An injury or infection in the body causes inflammation when a compound reacts with it. The inflammatory response is triggered, maintained, and resolved by mediators of inflammation. When an inflammatory stimulus is detected, proinflammatory mediators are immediately released. As part of the immune response, cells secrete a number of different mediators, including amines, lipids, reactive oxygen species, platelets-activating factors, cytokines, nitric oxide, and chemokines, while the liver also produces acute phase proteins (such as complement, coagulation, and kallikrein-kinin systems). All the actions associated with inflammation are coordinated by inflammation mediators, including dilatation of blood vessels, vascular permeability, leukocyte migration, pain, and inflammation-induced inflammation.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of pharmaguideline.com, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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