Pathophysiology of the hepoxilins

There is increasing evidence from various scientific groups that hepoxilins represent novel inflammatory mediators. In vitro studies have shown that the hepoxilins cause mobilization of intracellular calcium in human neutrophils, cause plasma leakage, and potently stimulate chemotaxis of human neutrophils. In vivo, the hepoxilin pathway is activated in conditions of inflammation, e.g. after pathogen infection, in inflamed conditions (psoriasis, arthritis), and hepoxilins promote inflammatory hyperalgesia and allodynia. Although much work has demonstrated an effect of hepoxilins on neutrophils, the hepoxilin pathway has been demonstrated in a variety of tissues, including the lung, brain, pituitary, pancreatic islets, skin, etc. A genetic defect linked to a deficiency in hepoxilin formation has been described and believed to be responsible for the scaly skin observed in ichthyosis. Despite their biological and chemical instability, the involvement of the hepoxilin pathway in pathology has been demonstrated in vitro and in vivo through either isolation of the hepoxilins themselves (or their metabolites) or implied through the use of stable hepoxilin analogs. These analogs have additionally shown efficacy in animal models of lung fibrosis, cancer, thrombosis and diabetes. Research on these compounds has merely scratched the surface, but results published to date have suggested that the hepoxilin pathway is a distinct and novel pathway leading to inflammation and hepoxilin antagonists may provide the means of controlling early aspects of the acute inflammatory phase. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.