Abstract
Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells—a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role.
Highlights
Inflammation is a conserved mechanism that serves as a defense against injurious stimuli, including invasion of pathogens, tissue injury, and intracellular damage signals [1].Cells release a variety of factors, including histamines, prostaglandins, and bradykinin.These signals promote an acute inflammatory response, including changes to vascular permeability, with localized infiltration and accumulation of immune cells from the circulation, accompanied by the release of inflammatory mediators such as cytokines, chemokines, and eicosanoids
The LOX enzymes catalyze the oxidative metabolism of multiple polyunsaturated fatty acids (PUFAs) substrates, including arachidonic acid (AA), dihomo-γ-linoleic acid (DLA), linolenic acid (LA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) to generate a multitude of bioactive products involved in pro- and anti-inflammatory cellularof docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) to activities
This study revealed that depletion of 12-LOX lead to significantly reduced vascular permeability upon LPS treatment along with improved gas exchange and increased survival compared to the control littermates [121]
Summary
Inflammation is a conserved mechanism that serves as a defense against injurious stimuli, including invasion of pathogens, tissue injury, and intracellular damage signals [1]. Cells release a variety of factors, including histamines, prostaglandins, and bradykinin These signals promote an acute inflammatory response, including changes to vascular permeability, with localized infiltration and accumulation of immune cells from the circulation, accompanied by the release of inflammatory mediators such as cytokines, chemokines, and eicosanoids. This cascade of inflammation is followed by tissue remodeling and a repair process to restore tissue health. This inflammatory response is completed upon the eradication of the pathogens or after tissue repair. Chronic inflammation is known to be an underlying cause of several diseases, such as metabolic syndrome, type 1 and type 2 diabetes (T1D and T2D), non-alcoholic fatty liver disease (NAFLD), hypertension, cardiovascular disease (CVD), chronic kidney disease, neurodegenerative, and autoimmune diseases [2]
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