Sex Hormone–Dependent Lipid Mediator Formation in Male and Female Mice During Peritonitis

Abstract

Introduction: Sex differences in inflammation are obvious and contribute to divergences in the incidence and severity of inflammation-related diseases that frequently preponderate in women. Lipid mediators (LMs), mainly produced by lipoxygenase (LOX) and cyclooxygenase (COX) pathways from polyunsaturated fatty acids (PUFAs), regulate all stages of inflammation. Experimental and clinical studies revealed sex divergences for selected LM pathways without covering the entire LM spectrum, and only few studies have addressed the respective role of sex hormones. Here, we performed the comprehensive LM profile analysis with inflammatory peritoneal exudates and plasma from male and female mice in zymosan-induced peritonitis to identify the potential sex differences in LM biosynthesis during the inflammatory response. We also addressed the impact of sex hormones by employing gonadectomy.Methods: Adult male and female CD1 mice received intraperitoneal injection of zymosan to induce peritonitis, a well-established experimental model of acute, self-resolving inflammation. Mice were gonadectomized 5 weeks prior to peritonitis induction. Peritoneal exudates and plasma were taken at 4 (peak of inflammation) and 24 h (onset of resolution) post zymosan and subjected to UPLC–MS-MS–based LM signature profiling; exudates were analyzed for LM biosynthetic proteins by Western blot; and plasma was analyzed for cytokines by ELISA.Results: Pro-inflammatory COX and 5-LOX products predominated in the peritoneum of males at 4 and 24 h post-zymosan, respectively, with slightly higher 12/15-LOX products in males after 24 h. Amounts of COX-2, 5-LOX/FLAP, and 15-LOX-1 were similar in exudates of males and females. In plasma of males, only moderate elevation of these LMs was apparent. At 4 h post-zymosan, gonadectomy strongly elevated 12/15-LOX products in the exudates of males, while in females, free PUFA and LOX products were rather impaired. In plasma, gonadectomy impaired most LMs in both sexes at 4 h with rather up-regulatory effects at 24 h. Finally, elevated 15-LOX-1 protein was evident in exudates of males at 24 h which was impaired by orchiectomy without the striking impact of gonadectomy on other enzymes in both sexes.Conclusions: Our results reveal obvious sex differences and roles of sex hormones in LM biosynthetic networks in acute self-resolving inflammation in mice, with several preponderances in males that appear under the control of androgens.

Factors affecting variability in free oxylipins in mammalian tissues

“…Sex differences in oxylipins in the context of cardiovascular disease has been recently reviewed, highlighting higher levels of prostaglandin E 2 , thromboxane A 2 and epoxy-eicosatrienoic acids and lower levels of prostaglandin I 2 and 20-HETE in females in various rat and mouse tissues [78 ▪ ]. Several other recent studies in rats [19] and mice [74 ▪ ,79] also reveal tissue sex differences, confirming several previous studies [80,81], highlighting that disaggregating data by sex is necessary to reduce variability of oxylipin data.…”

Sex hormone deprivation abolishes sex‐specific differences in murine colon inflammation and related lipid mediator production

“…3,36,37 We reported a sex bias in experimental models of inflammation (i.e., zymosan-induced peritonitis and ovalbumin-induced asthma in mice, and carrageenaninduced pleurisy in rats), where testosterone-suppressed pro-inflammatory LT in innate immune cells, resulting in a lower inflammatory response in males. 29,32,33,37,52,53 Along these lines, we identified a sex bias in PG production in neutrophils during acute inflammation (higher in males) under conditions where LT production was elevated in females at the sites of injury. 33,37 Bioactive LM are well known to play key roles in the physiology and pathogenesis of the colon.…”

Sex differences in specialized pro-resolving lipid mediators and their receptors in abdominal aortic aneurysms

“…Moreover, sex differences in SPM formation span both human and experimental models, but to date have been inconsistent and influenced by disease context, experimental settings, microbiome, inflammatory mediators, species, race, age, comorbidities, and additional factors. 6 , 24 , 28 , 29 The limited sociodemographic clinical data and differences in characteristics between the human subjects should be acknowledged as a limitation for the comparison between control and AAA aortas.…”