Conversely, cysteinyl leukotriene receptor 2 is expressed strongly in pulmonary interstitial macrophages and weakly in smooth muscle cells. Numerous agents have been developed as antiasthmatics.
The role of lipoxygenases in pathophysiology; new insights and future perspectives
A potent LOX-5 inhibitor zileuton introduced in the United States blocks a considerable amount of cysteinyl leukotriene production for a short period of time. This mutation causes an alteration in the electronic charge of the C-terminal catalytic domain from negative to positive, implicating defective changes in enzymatic activity and protein interaction. Mutations in the Sp1 binding site in the ALOX5 promoter has been associated with airway hyperresponsiveness, but not with asthma [98,99]. Some evidence suggests that low 5-LOX expression in tumors found in humans might lead to greater LOX expression followed by cancer formation through impaired apoptotic activity [47,,].
As mentioned previously, immune cells express leukotriene receptor 1 and 2 as well as cysteinyl leukotriene receptor 2; as such, the role of Alox5 could account for the migration of these immune cells. As expected, neutrophilic inflammation is one of the apparent phenotypes in Alox5- deficient mice. These mice have been shown to be resistant to anaphylaxis induced by platelet-activating factor PAF , showing that Alox5 seems to be closely involved in this process [,]. Similarly, Alox5- deficient mice exhibit a suppressed response to chemically induced local inflammation [,].
These mice are also susceptible to Borrelia burgdorferi -induced arthritis .
The role of lipoxygenases in pathophysiology; new insights and future perspectives
In this study, the authors showed that enzymatic activity of 5-LOX is not required for the initiation of infection, but it is required for earlier joint swelling and retarded arthritis recovery, suggesting a potential increase in the accumulation of neutrophils. Such altered cytokine production seems to be explained, at least in part, by impaired neutrophilic inflammation.
In an ovalbumin-induced asthma model, Alox5- deficient mice exhibited a suppressed methacholine-induced response to airway hyperresponsiveness with impaired eosinophilic inflammation in the lung . Thus, the production of lipid products from 5-LOX plays an important role under physiological conditions, and its level is tightly regulated by the balance between LOX and other enzymes, such as COX, as shown in an earlier study.
Recently, the roles of oxidation products derived from eicosapentaenoic acid and docosahexaenoic acid have been studied extensively Fig. As seen in their chemical structures, and have four and five bisallylic carbon atoms, respectively, in their molecules, providing a variety of oxidation products through free radical-mediated mechanisms.
In addition, hydroperoxy-5,8,11,14,eicosapentaenoic acid HPETE , a free radical-mediated oxidation product of , can be further metabolized by 5-LOX to produce a novel class of oxidation product collectively called resolvins Fig. Emerging evidence has shown that resolvins assist in terminating inflammation through specific GPCR ChemR23 at nM concentrations in vitro .
The formation of resolvins seems to be critically regulated by local O 2 concentration, as well as the expression and activity of multiple LOX enzymes, both of which influence the final yield of resolvins from its initial substrate Due to its anti-inflammatory function, whether these oxidized lipids might modulate the functions of microRNAs is under investigation .
Impaired expression of functional 5-LOX in LDL receptor-deficient mice has revealed suppressed atherogenesis, suggesting that 5-LOX plays a causative role in this disease . Consistently, another atherosclerotic model induced by COX-2 disruption attenuated disease formation in Alox5- deficient mice .
Given that LOX is involved in atherosclerosis, these studies provide examples that atherosclerosis can be induced by lipid peroxidation products formed from any isoforms. This finding is entirely consistent with observations indicating that antioxidants generally exhibit protective effects in experimental models.
Using such a disease model, Alox5 deficiency consistently improved disease phenotypes . Colorectal cancer is often caused by mutation of the tumor suppressor Adenomatous polyposis coli APC gene. Mast cells play an important role in the development of colorectal cancer in this animal model, as they induce epithelial proliferation .
In this model, a deficiency in Alox5 led to impairment, implying that LOX5 acts as an important role in colorectal tumorigenesis . FLAP expression is limited in myeloid cells.
Drugs targeting FLAP protein have been actively developed in humans. This compound also reduces the incidence of ischemic myocardial infarction by reducing LTB 4 production . In asthma, two intronic single-nucleotide polymorphisms have been associated with ALOX5AP , suggesting that these mutations can be used for diagnostic markers . Alox5ap- deficient mice exhibited unique phenotypes similarly observed in Alox5- deficient mice, such as an impaired response to PAF-induced anaphylaxis and zymosan-induced peritonitis .
In a collagen-induced arthritis model, Alox5ap- deficient mice displayed impaired arthritis, whereas the accumulation of antibody against collagen remained unchanged, suggesting that 5-LOX positively regulated inflammation without affecting the immune response. In a cerebral artery occlusion model, disruption of the Alox5ap gene caused impaired median infarct size and a better functional score, demonstrating that FLAP protein positively regulates cerebral inflammation . The expression of Alox5ap is independent of the expression of 5-LOX.
These examples strongly suggested that FLAP protein is required for atherogenesis in these mouse models. Consistently, Alox5ap- deficient mice exhibited attenuated disease formation in an experimental model generated by Cox deficient mice . These results supported the phenotype of Alox5- deficient mice, showing that both 5-LOX and FLAP mutually and collaboratively play critical roles in the leukotriene pathway in neurological disorders.
There are many studies reporting synthesis and characterization of lipoxygenase inhibitors reviewed in [,]. Generally, substances sharing similarity to either lipids or phenolic antioxidants have lower inhibitory activity for LOX enzyme. Furthermore, due to the presence of multiple isoforms, the development of selective inhibitor seems to be challenging. Therefore, there is a limited number of successful drugs that can be used for therapeutic purposes. One clinically applicable example includes zileuton that acts as anti-asthmatic agent by inhibiting 5-LOX.
Apart from direct regulation of enzymes, there are some studies targeting FLAP for modulating 5-LOX under pathophysiological conditions in clinical trials. Plasma concentration of GSK reaches maximal at two hours after oral administration. The physiological roles of LOX enzymes have been studied extensively, due to the close link between them and various diseases.
Apparently, the best characterized example includes the relation between 5-LOX and asthma, because cysteinyl leukotriene receptor 1, a GPCR activated by leukotrienes produced by 5-LOX, is widely expressed on bronchiolar smooth muscle cells. In humans, some mutations in ALOX12 are found in tumor cells, suggesting this isoform might have anti-tumor effect. An increased expression of LOX enzymes in response to Th2 cytokines has been well established; how their expression is controlled and its consequences need to be investigated in the future.
ipdwew0030atl2.public.registeredsite.com/sitemap33.xml We thank Professor Emeritus Etsuo Niki of the University of Tokyo for suggesting the importance of the study of resolvins mentioned in this article. National Center for Biotechnology Information , U. Journal List Redox Biol v.
Redox Biol. Published online Aug 7. Author information Article notes Copyright and License information Disclaimer. Ryuichi Mashima: pj. This article has been cited by other articles in PMC. Abstract Lipoxygenases LOXs are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic acid. Keywords: Lipoxygenase, Phenotype, Signal transduction, Resolvins. Introduction Lipoxygenases LOXs catalyze the oxygenation of polyunsaturated fatty acids such as arachidonic acid and linoleic acid [1,2]. Table 1 Properties of LOX enzymes.
Open in a separate window. Table 2 Human diseases that potentially links to lipoxygenase genes. Table 3 Phenotypes of LOX-deficient mice. Alox15 Atherosclerosis is an inflammatory disease characterized by an accumulation of lipid-loaded macrophages in blood vessels. Alox15b There are a limited number of studies involving Alox15b. Alox12 Consistent with the expression of ALOX12 in the platelets of humans, mice lacking Alox12 have shown increased platelet sensitivity and mortality due to thrombosis in response to the administration of adenosine diphosphate, whereas aggregation and secretion in response to most agonizts seemed normal .
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ALOX12B Genetic failure of the above process leads to ARCI, a heterogeneous skin disease characterized by rough and scaly skin, with a prevalence of one in , newborns throughout the world [81—86]. Alox12b Disruption of the Alox12b gene in the murine model provides an effective means of studying human ichthyosis. Epidermal lipoxygenase 3 eLOX-3 As mentioned previously, the conversion of linoleoyl ceramide in CLE into CE plays a crucial role in the proper maintenance of epidermal barrier formation.
Aloxe3 A previous study showed that Aloxe3- deficient mice also exhibit a similarly severe ichthyosis phenotype with the loss of covalently bound ceramides and impaired CLE development . Alox5 7. Inflammation As mentioned previously, immune cells express leukotriene receptor 1 and 2 as well as cysteinyl leukotriene receptor 2; as such, the role of Alox5 could account for the migration of these immune cells. Tumor Colorectal cancer is often caused by mutation of the tumor suppressor Adenomatous polyposis coli APC gene.
Alox5ap Alox5ap- deficient mice exhibited unique phenotypes similarly observed in Alox5- deficient mice, such as an impaired response to PAF-induced anaphylaxis and zymosan-induced peritonitis . Clinical Trials There are many studies reporting synthesis and characterization of lipoxygenase inhibitors reviewed in [,]. Conclusions The physiological roles of LOX enzymes have been studied extensively, due to the close link between them and various diseases.
Acknowledgment We thank Professor Emeritus Etsuo Niki of the University of Tokyo for suggesting the importance of the study of resolvins mentioned in this article. References 1. Brash A.