(WHS-P4.01) 5-lipoxygenase exerts sex-dependent effects on burn wound healing
Friday, May 17, 2024
10:30 AM – 11:30 AM East Coast USA Time
5-lipoxygenase (5-LO) is the rate-limiting enzyme for the synthesis of bioactive lipid mediators. These mediators are members of the eicosanoids, which are bioactive lipids, derived from polyunsaturated fatty acids that promote and/or regulate inflammation. Previous research suggests that following in vitro stimulation, 5-LO activity is increased in female neutrophils and monocytes of humans and rodents, compared with that of males, indicating a sex bias. To elucidate whether the sex bias in 5-LO activity influences burn wound healing, we generated global Alox5 (Arachidonate 5-lipoxygenase, the gene that encodes for 5-LO) knockout mice (Alox5-/-) in C57BL/6 background. Alox5-/- and littermate Alox5+/+ control mice underwent burn injury, and wound tissues were isolated and examined 3, 7, and 14 days later. Our data show a sex-specific effect of 5-LO activity in burn wound healing. Female Alox5-/- mice exhibited increased re-epithelialization compared to their controls, on day 14 post injury (pi). Furthermore, flow cytometric analysis on day 7pi revealed increased total numbers of wound immune (CD45+) cells, but no differences in their make-up, in female Alox5-/- mice compared to their controls. This suggests that 5-LO activity regulates overall immune cell recruitment in burn wounds of female mice; however, whether these cells are directly involved in the wound healing process is not currently elucidated. On the other hand, Alox5-/- male mice showed decreased re-epithelization on days 7 and 14 pi, compared to their controls. In contrast with female mice, infiltration levels of male Alox5-/- wounds on day 7 pi were not different than those of their controls. This suggests that the observed delay in re-epithelialization may be independent of the inflammatory environment and could instead be mediated via 5-LO-induced effects on local skin cells. Collectively, these results suggest that 5-LO activity affects burn wound healing in a sex-dependent manner. We hypothesize that sex-specific 5-LO-induced changes in the eicosanoid profile play a key role in the differential burn wound healing process. In this study, we will present eicosanoid wound profiles over time and in relation to sex and genotype. Differences in collagen production and transcriptome signatures will also be presented. Our study will help elucidate sex-specific 5-LO evoked mechanisms in burn wound healing.