perhaps other inflammatory skin conditions. HxA3 has also been implicating in promoting the neutrophil-based inflammatory response to various bacteria in the intestines and lungs of rodents.; this allows that this hepoxilin may also promote the inflammatory response of humans in other tissues, particularly those with a mucosa surface, besides the skin. In addition, HxA3 and a synthetic analog of HxB3, PBT-3, induce human neutrophils to produce neutrophil extracellular traps, i.e. DNA-rich extracellular fibril matrixes able to kill extracellular pathogens while minimizing tissue; hence these hepoxilins may contribute to innate immunity by being responsible of the direct killing of pathogens. Circulation In addition to 12S-HETE and 12R-HETE (see 12-HETE#Blood pressure), HxA3, TrXA3, and TrXC3 but neither HxB3 nor TrXB3 relax mouse mesentery arteries pre-contracted by thromboxane A2)(TXA2). Mechanistically, these metabolites form in the vascular endothelium, move to the underlining smooth muscle, and reverse the smooth muscle contraction caused by TXA2 by functioning as a Receptor antagonist, i.e. they competitively inhibit the binding of TXA2 to its thromboxane receptor, α isoform. In contrast, 15-lipoxygenase-derived epoxyalcohol and trihydroxy metabolites of arachidonic acid viz., 15-hydroxy-11,12-epoxyeicosatrienoic acid, 13-hydroxy-14,15-epoxy-eicosatrienoic acid (a 14,15-HxA4 isomer), and 11,12,15-trihydroxyeicosatrienoic acid dilate rabbit aorta by an Endothelium-derived hyperpolarizing factor (EDHF) mechanism, i.e. they form in the vessels endothelium, move to underlying smooth muscles, and trigger a response of Hyperpolarization (biology)-induced relaxation by binding to and thereby opening their apamin-sensitive small conductance (SK) Calcium-activated potassium channel#SK channels. The cited metabolites may use one or the other of these two mechanisms in different vascular beds and in different animal species to contribute in regulating regional blood flow and blood pressure. While the role of these metabolites in the human vasculature has not been studied, 12S-HETE, 12R-HETE, HxA3, TrXA3, and TrXC3 do inhibit the binding of TXA2 to the human thromboxane receptor. Pain perception HXA3 and HXB3 appear responsible for hyperalgesia and tactile allodynia (pain caused by a normally non-painful stimulus) response of mice to skin inflammation. In this model, the hepoxilins are released in spinal cord and directly activate TRPV1 and TRPA1 receptors to augment the perception of pain. TRPV1 (the transient receptor potential cation channel subfamily V member 1 (TrpV1), also termed the capsaicin receptor or vanilloid receptor) and TRPA1 (Transient receptor potential cation channel, member A1) are plasma membrane ion channels on cells; these channels are known to be involved in the perception of pain caused by exogenous and endogenous physical