Time heals all wounds—but 12-HHT is faster

Abstract

Chronic nonhealing wounds such as diabetic ulcers are a major problem associated with human disease. In this issue, Liu et al. offer new hope for tackling nonhealing wounds by defining a novel role for the leukotriene B4 receptor type 2 (BLT2) and its ligand 12-hydroxyheptadecatrienoic acid (12-HHT) in wound healing. They also show that high-dose aspirin delays wound healing by reducing the levels of 12-HHT.Endogenously produced lipid autacoids are locally acting, small molecule mediators that regulate diverse processes such as inflammation, asthma, colitis, tissue regeneration, and cancer. Unlike prostaglandins and leukotrienes, the biological roles of 12-HHT and its receptor BLT2 have been poorly characterized. 12-HHT, a downstream lipid metabolite of cyclooxygenase 1 (COX1) and COX2, was previously assumed to be an inert by-product of arachidonic acid metabolism until its recent identification as an endogenous high-affinity ligand for BLT2 by this group. It is known that high-dose aspirin, the most commonly used nonsteroidal anti-inflammatory drug (NSAID) targeting the COX pathway, delays wound healing but the mechanism by which this delay occurs has been poorly characterized. Most of aspirin’s pharmacological effect has been attributed to its blockage of thromboxanes and prostaglandin production. However, low-dose aspirin has been found to trigger production of beneficial, anti-inflammatory, and pro-resolution mediators by COX2, the aspirin-triggered resolvins, and lipoxins, thus alleviating inflammation via stimulating endogenous resolution mechanisms. It is possible that high-dose aspirin inhibits a range of anti-inflammatory lipid metabolites, some yet unidentified, which may account for some of its side effects.