Stereoselective actions of hepoxilins A3 and B3 and their cyclopropane analogs (HxΔA3 and HxΔB3) on bradykinin and PAF-evoked potentiation of vascular leakage in rat skin

Wang, Mei Mei; Demin, Peter; Pace-Asciak, Cecil R.

doi:10.1016/s0306-3623(99)00032-4

Cited by 5 publications

(4 citation statements)

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“…Support for the potential role of hepoxilins in the pathogenesis of in¯ammatory skin diseases includes their potent action on plasma permeability when injected subcutaneously (Laneuville et al, 1991;Wang et al, 1996Wang et al, , 1999a and the detection of a considerable amount in psoriatic lesions in free form (Anto Ân et al, 1998) and also esteri®ed. Hepoxilins could play an autocrine role as intracellular messengers and a paracrine role modulating leukocyte activation (reviewed in Pace-Asciak et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Normal human epidermis synthesized only one of the two possible 10-hydroxy epimers of HxB 3 whose formation is probably catalyzed by 12-LO Anto Ân and Vila, 2000). Hepoxilins exert action on plasma permeability on skin (Laneuville et al, 1991;Wang et al, 1996Wang et al, , 1999a1999b), and induce a speci®c-receptor-dependent Ca 2+ mobilization from endogenous sources (Dho et al, 1990;Laneuville et al, 1993) and the release of AA and diacylglycerol (Nigam et al, 1993). Interestingly, only the epimer 10(R)-HxB 3 , which is probably the epimer synthesized by normal epidermis Anto Ân and Vila, 2000), stereospeci®cally enhances the vascular permeability evoked by intradermal injection of the platelet-activating factor (Wang et al, 1996;1999a;1999b).…”

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confidence: 99%

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Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions

Antón

Camacho

Puig

et al. 2002

Journal of Investigative Dermatology

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In previous studies we observed that normal human epidermis forms 12-oxo-eicosatetraenoic acid (12-oxo-ETE) and hepoxilin B3 (HxB3) as major eicosanoids, both being elevated in psoriasis. We also observed that normal epidermis, in a reaction probably catalyzed by 12-lipoxygenase, only synthesize one of the two possible 10-hydroxy epimers of HxB3. We have now extended these previous studies investigating further transformation of HxB3 into trioxilin B3 (TrXB3) and esterification of both into phospholipids. Phospholipids were extracted from normal epidermis and from psoriatic scales. A combination of high performance liquid chromatography and gas chromatography-mass spectrometry analysis demonstrated the occurrence of HxB3 and TrXB3 in the phospholipids of psoriatic lesions. Alkaline- and phospholipase-A2-mediated hydrolysis of the phospholipids yielded similar quantities of both HxB3 and TrXB3 indicating their preference for the sn-2 position of glycerophospholipids. The thin layer chromatography analysis of the phospholipid classes after incubation of epidermal cells with [14C]-labeled HxB3, TrXB3, 12-hydroxy-eicosatetraenoic acid (12-HETE), 12-oxo-ETE, or 15-HETE showed that 12-HETE was the most esterified (12-HETE >15-HETE > TrXB3 > 12-oxo-ETE > HxB3). HxB3 and TrXB3 were mainly esterified in phosphatidyl-choline and phosphatidyl-ethanolamine. HxB3 was also enzymatically converted into TrXB3 in vitro. HxB3 epoxide hydrolase-like activity was not observed when boiled tissue was incubated with [14C]-HxB3, this activity being located in the cytosol fraction (100,000 x g supernatant) of fresh tissue. These findings suggest that in vivo some part of HxB3 is transformed into TrXB3 and both compounds are partially incorporated into the phospholipids.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions

Antón

Camacho

Puig

et al. 2002

Journal of Investigative Dermatology

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“…Given that linoleic acid is used in vivo for biosynthesis of AA and that HNE is generated by peroxidation of 12/15-LOX products of n-6 PUFA, we hypothesized that spinal 12-LOX metabolites of AA, particularly hepoxilins, also contribute to inflammatory hyperalgesia through stimulation of nociceptive afferents. Although hepoxilins increase intracellular Ca 2+ in neutrophils (19,20) and neurons (21) and enhance vascular permeability in rat skin (22,23), its receptors remain undefined. Our findings demonstrate that peripheral inflammation increases spinal HXA 3 , which produces hyperesthesia via activation of TRPV1 and TRPA1 and spinal SP release.…”

mentioning

confidence: 99%

Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Gregus¹,

Doolen

Dumlao

et al. 2012

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

106

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Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA 3 and HXB 3 ). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB 3 at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dosedependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA 3 , or HXB 3 evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA 3 produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA 3 correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA 3 triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA 3 -evoked allodynia. These data indicate that spinal HXA 3 is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.eicosanoid | pain | central sensitization T issue injury and inflammation are associated with hyperalgesia mediated by facilitated spinal nociceptive processing that can be modulated by lipids derived from arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA), including eicosanoids synthesized via three enzymatic pathways: (i) cyclooxygenase (COX)-prostaglandins (PG); (ii) 5-, 12-, and 12/15-lipoxygenases (LOX)-leukotrienes, hydroxyeicosatetraenoic acids (HETEs), hepoxilins (HXA 3 and HXB 3 ), lipoxins, resolvins, and protectins; and (iii) cytochrome P450-epoxyeicosatrienoic acids and HETEs (1). Substantial evidence indicates that peripheral injury or direct activation of spinal dorsal horn receptors [Neurokinin 1 (NK1), AMPA, and NMDA] increases eicosanoid formation and that spinal delivery of COX inhibitors reduces the associated hyperalgesia (2, 3). Recently, we reported that paw carrageenan increases spinal production of both COX and 12-LOX metabolites of AA, including 12(S)-HETE in cerebrospinal fluid (CSF) and hepoxilins in the lumbar spinal cord (4).Several groups point to a peripheral role for 5-and 12-LOX in nociception, as shown by antihyperalgesic actions of LOX inhibitors administered via systemic routes (5-9). It has been suggested that spinal 12-LOX may play a r...

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“…Since the hepoxilins are 12-lipoxygenase products, we hypothesized that they may be candidates for the control of lung fibrosis. Hepoxilin formation is stimulated by inflammatory mediators in the skin [18,19] and in psoriasis [20] suggesting that they may be involved in anti-inflammatory mechanisms. We therefore carried out a study to investigate whether the stable hepoxilin analogs, PBTs, exhibit anti-inflammatory actions in vivo, first on BL-evoked changes in skin vascular permeability, then on BL-evoked changes in lung fibrosis [21].…”

Section: Lung Fibrosis In Vivomentioning

confidence: 99%

Hepoxilin Analogs, Potential New Therapeutics in Disease

Pace-Asciak

Li²,

Qiao³

et al. 2006

CPD

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We have chemically synthesized several stable analogs of the naturally occurring hepoxilins, 12-LO products derived from arachidonic acid, which we found to have promising actions in a variety of test systems of disease. The analogs, PBTs, afford chemical and biological stability to the hepoxilin molecule. This article reviews some of our latest observations with the PBTs in the areas of inflammation (inhibition of the bleomycin-evoked lung fibrosis in mice in vivo), platelet aggregation (antagonism of the thromboxane receptor in human platelets in vitro) and thrombosis (inhibitors in vivo), and cancer (apoptosis of the human leukemia cell line, K562 in vitro and in vivo). The demonstration that the PBTs are active in vivo suggests that they can serve as a platform for their further development as novel therapeutics in disease.

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Stereoselective actions of hepoxilins A3 and B3 and their cyclopropane analogs (HxΔA3 and HxΔB3) on bradykinin and PAF-evoked potentiation of vascular leakage in rat skin

Cited by 5 publications

References 24 publications

Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions

Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions

Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Hepoxilin Analogs, Potential New Therapeutics in Disease

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Stereoselective actions of hepoxilins A3 and B3 and their cyclopropane analogs (HxΔA3 and HxΔB3) on bradykinin and PAF-evoked potentiation of vascular leakage in rat skin

Cited by 5 publications

References 24 publications

Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions

Hepoxilin B3 and its Enzymatically Formed Derivative Trioxilin B3 are Incorporated into Phospholipids in Psoriatic Lesions

Spinal 12-lipoxygenase-derived hepoxilin A3contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Hepoxilin Analogs, Potential New Therapeutics in Disease

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Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors