Hepoxilin A3-specific binding in human neutrophils

Reynaud, Dénis; Demin, Peter; Pace-Asciak, Cecil R.

doi:10.1042/bj3130537

Cited by 24 publications

(27 citation statements)

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“…HepA 3 binding to an unidentified receptor in human PMNs shows clear specificity (17) in a manner similar to findings obtained in our studies (Table 1), further supporting the overall identification of hepA 3 as a stimulator of PMN migration across the epithelial TJ without premature degranulation (5), previously known as PEEC.…”

Section: Examination Of Metabolic Pathwayssupporting

confidence: 78%

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Mrsny

Gewirtz

Siccardi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

156

225

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The mechanism by which neutrophils [polymorphonuclear leukocyte (PMNs)] are stimulated to move across epithelial barriers at mucosal surfaces has been basically unknown in biology. IL-8 has been shown to stimulate PMNs to leave the bloodstream at a local site of mucosal inflammation, but the chemical gradient used by PMNs to move between adjacent epithelial cells and traverse the tight junction at the apical neck of these mucosal barriers has eluded identification. Our studies not only identify this factor, previously termed pathogen-elicited epithelial chemoattractant, as the eicosanoid hepoxilin A 3 (hepA3) but also demonstrate that it is a key factor promoting the final step in PMN recruitment to sites of mucosal inflammation. We show that hepA 3 is synthesized by epithelial cells and secreted from their apical surface in response to conditions that stimulate inflammatory events. Our data further establish that hepA 3 acts to draw PMNs, via the establishment of a gradient across the epithelial tight junction complex. The functional significance of hepA 3 to target PMNs to the lumen of the gut at sites of inflammation was demonstrated by the finding that disruption of the 12-lipoxygenase pathway (required for hepA 3 production) could dramatically reduce PMN-mediated tissue trauma, demonstrating that hepA 3 is a key regulator of mucosal inflammation. Bacterial pathogens continually confront epithelial barriers of the body, such as those of the gastrointestinal, respiratory, and reproductive tracts. Polymorphonuclear leukocyte (PMNs) represent a class of white cells critical to defend the host from such pathogens. Previous studies have identified factors such as IL-8, secreted from the basolateral surface of epithelial barriers that establish chemical gradients essential for PMN activation and recruitment from the bloodstream (1). After this IL-8 gradient, PMNs are drawn to the lateral surfaces of epithelial cells. Migration to the actual site of bacterial infection, however, i.e., within the intestinal lumen, requires the action(s) of an additional chemical gradient established across a final barrier present at the apical neck of epithelia, the tight junction (TJ) complex. Any molecule that could function to establish a gradient across such a barrier would have unique properties: selective secretion from the apical rather than basolateral epithelial cell surface, capacity to permeate the TJ to establish a chemical gradient, and a labile nature that would prevent excessive PMN migration. Identification of such a factor has been an important unanswered question of epithelial pathobiology.Salmonellosis, a frequent cause of diarrhea worldwide, represents one example of epithelial pathobiology where extensive PMN transmigration into the lumen is observed, in this case into small intestine crypts in response to apical infection by Salmonella typhimurium. PMN actions on the epithelium, culminating in the formation of intestinal crypt abscesses and subsequent loss of barrier function, underline the key events in mediat...

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Section: Examination Of Metabolic Pathwayssupporting

confidence: 78%

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Mrsny

Gewirtz

Siccardi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

156

225

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“…The hepoxilins (HXs) may be candidates for the control of lung fibrosis as they are formed through the 12-lipoxygenase pathway of metabolism of arachidonic acid (Pace-Asciak et al, 1983;Pace-Asciak, 1984;Pace-Asciak and Martin, 1984). These compounds have previously been shown to have significant biological actions (Pace-Asciak, 1984;Dho et al, 1990;Laneuville et al, 1992;Pace-Asciak et al, 1995;Reynaud et al, 1996Reynaud et al, , 1999Sutherland et al, 2000). HXs raise free intracellular calcium in human neutrophils ex vivo through the release from stores and vascular tissue in vitro and block the intracellular calcium rise evoked by inflammatory mediators (Laneuville et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Jankov

Li²,

Demin³

et al. 2002

J Pharmacol Exp Ther

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Bleomycin has been suggested to incite plasma extravasation and influx of inflammatory cells leading to pulmonary fibrosis. We hypothesized that stable analogs of the 12-lipoxygenase product, hepoxilin, may attenuate these effects. We initially investigated the effects of the four hepoxilin analogs (PBT-1 to -4) coadministered intradermally with bleomycin and found that PBT-1 and -2 significantly opposed the vascular permeability effects of bleomycin in rat skin. We subsequently tested the hepoxilin analogs for their actions in opposing the intratracheal bleomycin-evoked acute inflammatory phase of lung fibrosis in the mouse, characterized by a marked accumulation of macrophages and an increase in the rate of collagen synthesis and deposition. We found that the bleomycin-evoked effects on macrophage influx were inhibited by all the hepoxilin analogs (PBT-1, -3, and -4 Ͼ PBT-2) administered i.p. for 8 days. Increased total lung collagen was completely abrogated by PBT-1 and -2, whereas PBT-3 and -4 had little effect. A doseresponse study with PBT-1 indicated that the effective dose for inhibition of bleomycin-induced inflammatory and histological changes was below 10 g/day. These studies demonstrate an in vivo action of stable analogs of hepoxilin and support an effect on inflammation and vascular permeability from these novel compounds, especially for PBT-1.Idiopathic pulmonary fibrosis is a devastating disorder that is poorly understood and resistant to treatment (Cooper, 2000). The observation that the antibiotic bleomycin sulfate (BL), a potent cancer chemotherapeutic agent (Adamson, 1984;Nici et al., 1998), may cause interstitial lung fibrosis in humans (Yagoda et al., 1972) led to the development of animal models in which a single dose of BL administered intratracheally induced changes resembling human idiopathic pulmonary fibrosis histopathologically (Kelley et al., 1980). The acute phase of this response is characterized by a marked accumulation of inflammatory cells and an increase in the rate of collagen synthesis and deposition (Cooper et al., 1988;Gurujeyalakshmi and Giri, 1995;Giri and Hollinger, 1996).Previous animal studies have demonstrated that BLevoked lung fibrosis is exacerbated with nordihydroguaiaretic acid, a lipoxygenase inhibitor, suggesting that a lipoxygenase product may be involved in endogenous mechanisms controlling lung fibrosis (Giri and Hollinger, 1996). The hepoxilins (HXs) may be candidates for the control of lung fibrosis as they are formed through the 12-lipoxygenase pathway of metabolism of arachidonic acid (Pace-Asciak et al., 1983;Pace-Asciak, 1984;Pace-Asciak and Martin, 1984). These compounds have previously been shown to have significant biological actions (Pace-Asciak, 1984;Dho et al., 1990;Laneuville et al., 1992;Pace-Asciak et al., 1995;Reynaud et al., 1996Reynaud et al., , 1999Sutherland et al., 2000). HXs raise free intracellular calcium in human neutrophils ex vivo through the release from stores and vascular tissue in vitro and block the intracellular calc...

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“…A hepoxilin receptor has not been identifi ed, but several reports ( 34,(47)(48)(49) support its existence.…”

mentioning

confidence: 99%

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Cronin

Decker

Arand

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org of an epoxide hydrolase (EH) and a lipid phosphatase in each of its subunits ( 2-4 ). The sEH is abundantly expressed throughout the organism ( 5, 6 ) and accepts a broad range of substrates ( 7,8 ), in particular, endogenous epoxides derived from unsaturated fatty acids such as epoxyeicosatrienoic acids (EETs) ( 9 ). The organism utilizes these lipid epoxides as important signaling molecules, which regulate a variety of physiological functions. EETs were identifi ed as endothelium-derived hyperpolarizing factors (EDHFs) ( 10 ) acting on vascular smooth muscle cells leading to hyperpolarization and vasodilation ( 11,12 ). Since then, several experimental hypertensive models confi rmed a role for EETs in blood pressure regulation and end organ protection ( 13,14 ). Further, EETs have anti-infl ammatory and antinociceptive properties ( 15-17 ) and fi nally, seem to promote cell proliferation, migration, and angiogenesis (18)(19)(20).The metabolism of these lipid epoxides by sEH to the corresponding diols is generally considered a deactivation process. For this reason, the sEH is a promising target for the treatment of hypertension, infl ammatory diseases, pain, diabetes, and stroke ( 16,(21)(22)(23)(24)(25). A number of sEH inhibitors (sEHIs) have been developed ( 26, 27 ) for therapeutic applications. Yet the sEH also serves some function in xenobiotic metabolism by accepting certain trans -substituted epoxides, which are very poor substrates for microsomal epoxide hydrolase (mEH) ( 28,29 ).Other epoxide hydrolases with rather narrow substrate selectivity have been identifi ed in mammals. Of those, hepoxilin A 3 epoxide hydrolase (hepoxilin hydrolase, EC Abstract Hepoxilins are lipid signaling molecules derived from arachidonic acid through the 12-lipoxygenase pathway. These trans -epoxy hydroxy eicosanoids play a role in a variety of physiological processes, including infl ammation, neurotransmission, and formation of skin barrier function. Mammalian hepoxilin hydrolase, partly purifi ed from rat liver, has earlier been reported to degrade hepoxilins to trioxilins. Here, we report that hepoxilin hydrolysis in liver is mainly catalyzed by soluble epoxide hydrolase (sEH): i ) purifi ed mammalian sEH hydrolyses hepoxilin A 3 and B 3 with a V max of 0.4-2.5 mol/mg/min; ii ) the highly selective sEH inhibitors N-adamantyl-N'-cyclohexyl urea and 12-(3-adamantan-1-yl-ureido) dodecanoic acid greatly reduced hepoxilin hydrolysis in mouse liver preparations; iii ) hepoxilin hydrolase activity was abolished in liver preparations from sEH ؊ / ؊ mice; and iv ) liver homogenates of sEH ؊ / ؊ mice show elevated basal levels of hepoxilins but lowered levels of trioxilins compared with wild-type animals . We conclude that sEH is identical to previously reported hepoxilin hydrolase. This is of particular physiological relevance because sEH is emerging as a novel drug target due to its major role in the hydrolysis of important lipid signaling molecules such as epoxyeicosatrien...

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Hepoxilin A3-specific binding in human neutrophils

Cited by 24 publications

References 33 publications

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

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Hepoxilin A3-specific binding in human neutrophils

Cited by 24 publications

References 33 publications

Identification of hepoxilin A3in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Identification of hepoxilin A3in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

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Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia