Inflammation mediators leukotrienes

Boswellinic acids Leukotrienes appear to play a special role as inflammation mediators in the pathogenesis of PBC they also correlate closely with the increase in cholestasis-indicating enzymes. Boswellinic acids are selective non-redox inhibitors of 5-lipoxygen-ase and therefore inhibit leukotriene biosynthesis. So far, they have not been used in PBC treatment. Based on existing pharmacological data, their application should now be considered. 

Fluocinolone is a low- to medium-potency topical corticosteroid with antiinflammatory, antipruritic, and vasoconstrictive properties, thought to act by induction of phospholipase A2 inhibitory proteins (lipocortins). Lipo-cortins appear to control biosynthesis of potent mediators of inflammation (prostaglandins, leukotrienes) by inhibiting... 

Horie and coworkers synthesized a series of flavones that showed promising inhibitory activity against archidonate 5-lipooxygenase. This enzyme is responsible for the initiation of bioactive leukotrienes that are chemical mediators of anaphylaxis and inflammation. Under standard K-R conditions o-hydroxyarylketone 66 and anhydride 67 in presence of the corresponding anhydride 68 delivered flavones 69 in yields of 42-65%. Subsequent hydrogenation of 69 afforded the flavone inhibitors 70. 

These cells respond to a number of different chemoattractants which have specific and distinct receptors on the membrane surface (for recent reviews see Refs. 3 and 4). Such chemoattractants include N-formylpeptides, which are bacterial peptides, and mediators of inflammation such as leukotriene B4, C5a, and platelet activating factor. 

With regard to epinephrines potential adverse cardiac effects, it is important to remember that in anaphylaxis, the heart is a target organ. Mast cells located between myocardial fibers, in perivascular tissue, and in the arterial intima are activated through IgE and other mechanisms to release chemical mediators of inflammation, including histamine, leukotriene C4, and prostaglandin D2. Coronary artery spasm, myocardial injury, and cardiac dysrhythmias have been documented in some patients before epinephrine has been injected for treatment of anaphylaxis, as well as in patients with anaphylaxis who have not been treated with epinephrine [11, 12]. 

Inflammation is a non-specific reaction which can be induced by a variety of agents apart fiom microorganisms. Lymphokines and derivatives of arachidonic acid, including prostaglandins, leukotrienes and thromboxanes are probable mediators of the inflammatory response. The release of vasoactive amines such as histamine and serotonin (5-hydroxytryptamine) firm activated or damaged cells also contribute to inflammation. 

Eosinophils may be increased in some patients, particularly during exacerbations. Activated inflammatory cells release a variety of mediators, most notably leukotriene B4, interleukin-8, and tumor necrosis factor-a (TNF-a). Various proteinases, such as elastase, cathepsin G, and proteinase-3, are secreted by activated neutrophils. These mediators and proteinases are capable of sustaining inflammation and damaging lung structures. 

At the cellular level, eosinophils, mast cells, alveolar macrophages, lymphocytes and neutrophils recruited to the airways of asthmatics produce a variety of inflammatory mediators, such as histamine, kinins, neuropeptides, and leukotrienes, which lead to airway smooth muscle constriction and obstruction of airflow, and the perpetuation of airway inflammation [20, 21]. An understanding of the inflammatory processes and the molecular pathways of these mediators has led to the development and widespread use of several pharmacologic agents that mitigate airway inflammation and bronchoconstriction. 

Neutrophils are also a source of mediators (PAFs, prostaglandins, thromboxanes, and leukotrienes) that contribute to BHR and airway inflammation. 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

Figure 4.1. Model of neurogenic inflammation. Stimulation at the skin initiates orthodromic impulses in sensory nerve receptors which elicit antidromic impulses in branching collaterals. The release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and somatostatin (SOM) from nerve terminals ensues and they in turn stimulate the release of histamine (H) and the generation of leukotrienes (LT) from nearby mast cells. These mediators then produce vasodilatation and an increase in vascular permeability. In addition, they act on the nerve terminal to produce further...

The effects of LCPUFAs in inflammation have been reviewed by Calder (2006). Briefly, if is h) ofhesized fhaf fhe effecfs of LCPUFA n-3 fatty acids on immune function are mediated by their ability to compete with the metabolism of fhe n-6 fatty AA. AA can be metabolized into the pro-inflammatory prostaglandin-E2 (PGE2) or leukotriene-B4 (LTB4). 

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