contribute to this disease as well as to pain perception and atherosclerosis (see 9-Hydroxyoctadecadienoic acid##Biological and clinical relevancy of 9-HODEs). The two HODEs can be further metabolized to their ketones, 13-oxo-9Z,11E-octadecenoic acid and 9-oxo-10E, 12Z-octadecenoic acid; these ketones have been implicated as biomarkers for and possible contributors to the inflammatory component of atherosclerosis, Alzheimer's disease, Steatohepatitis, and other pathological conditions. Dihomo-γ-linolenic acid Human neutrophils, presumably using their ALOX 15, metabolize Dihomo-γ-linolenic acid (8Z,11Z,14Z-eicosatrienoic acid) to 15S-hydroperoxy-8Z,11Z,13E-eicosatrienoic acid and 15S-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15S-HETrE). 15S-HETrE possesses anti-inflammatory activity. Gene manipulation studies Mice made deficient in their 12/15-lipoxygenase gene (Alox15) exhibit a prolonged inflammatory response along with various other aspects of a pathologically enhanced inflammatory response in experimental models of cornea injury, airway inflammation, and peritonitis. These mice also show an accelerated rate of progression of atherosclerosis whereas mice made to overexpress 12/15-lipoxygenase exhibit a delayed rate of atherosclerosis development. Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of periodontitis. Finally, Control mice, but not 12/15-lipoxygense deficient mice responded to eicospentaenoic acid administration by decreasing the number of lesions in a model of endometriosis. These studies indicate that the suppression of inflammation is a major function of 12/15-lipoxygenase and the Specialized proresolving mediators it produces in rodents; although rodent 12/15-lipoxygenase differs from human ALOX15 in the profile of the PUFA metabolites that it produces as well as various other parameters (e.g. tissue distribution), these genetic studies allow that human ALOX15 and the specialized proresolving mediators it produces may play a similar major anti-inflammatory function in humans. Clinical significance Inflammatory diseases À huge and growing number of studies in animal models suggest that 15-LOX-1 and its lipoxin, resolvin, and protectin metabolites (see Specialized proresolving mediators) to inhibit, limit, and resolve diverse inflammatory diseases including periodontitis, peritonitis, sepsis, and other pathogen-induced inflammatory responses; in eczema, arthritis, asthma, cystic fibrosis, atherosclerosis, and adipose tissue inflammation; in the insulin resistance that occurs in obesity that is associated with diabetes and the metabolic syndrome; and in Alzheimer's disease. While these studies have not yet been shown to translate to human diseases, first and second generation synthetic resolvins and lipoxins, which unlike their natural analogs, are relatively resistant to metabolic inactivation, have been made and tested as inflammation inhibitors in animal models. These synthetic analogs may prove to be clinically useful for treating the cited human inflammatory diseases. By metabolizing the ω-3 polyunsaturated fatty acids,