Complement regulators and mechanisms vary by sex in intestinal ischemia reperfusion injury

Abstract

Abstract Complement activation plays a pivotal role in intestinal ischemia reperfusion (I/R)-induced injury, leads to significant morbidity and mortality. The injury includes significant inflammation including complement activation. Although established primarily using a male models, intestinal I/R-related diseases occur in both sexes. However, multiple animal models of ischemia and complement activation demonstrate sexual. Thus, we hypothesized that complement regulation may differ by sex during intestinal I/R altering the timing, quantity or required molecules. Both sexes of C57Bl/6 mice were subjected to Sham treatment or 30 min intestinal ischemia followed by 15 min, 30 min, 60 min, and 120 min reperfusion. We demonstrate that compared to male mice, females sustain attenuated intestinal I/R-induced tissue damage. In response to I/R, males produce PGE2 regulated by COX-2, while females produce LTB4 by A5-LOX. Complement initiation pathways differed with males tending to use classical pathway while females tend to use MBL pathway. Together these data suggest that local control of complement activation and regulation, eicosanoid production and neutrophil infiltration in response to intestinal I/R varies between sexes suggesting that distinct therapeutic intervention may be needed in clinical ischemic diseases.