Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury

Abstract

Intestinal ischemia reperfusion (IR)-induced tissue injury represents an acute inflammatory response with significant morbidity and mortality. The mechanism of IR-induced injury is not fully elucidated, but recent studies suggest a critical role for complement activation and for differences between sexes. To test the hypothesis that complement initiation differs by sex in intestinal IR, we performed intestinal IR on male and female WT C57B6L/, C1q-/-, MBL-/-, or properdin (P)-/- mice. Intestinal injury, C3b and C5a production and ex vivo secretions were analyzed. Initial studies demonstrated a difference in complement mRNA and protein in male and female WT mice. In response to IR, male C1q-, MBL- and P-deficient mice sustained less injury than male WT mice. In contrast, only female MBL-/- mice sustained significantly less injury than female wildtype mice. Importantly, wildtype, C1q-/- and P-/- female mice sustained significant less injury than the corresponding male mice. In addition, both C1q and MBL expression and deposition increased in WT male mice, while only elevated MBL expression and deposition occurred in WT female mice. These data suggested that males use both C1q and MBL pathways, while females tend to depend on lectin pathway during intestinal IR. Females produced significantly less serum C5a in MBL-/- and P-/- mice. Our findings suggested that complement activation plays a critical role in intestinal IR in a sex-dependent manner.

Association of Gut Microbiota With Intestinal Ischemia/Reperfusion Injury

“…Intestinal ischemia/reperfusion (II/R) injury is a clinical emergency with high morbidity and mortality due to a dramatic reduction in intestinal blood supply, which is associated with mesenteric artery thrombosis, strangulated ileus, trauma, abdominal aortic aneurysm surgery, intestinal transplantation and other clinical conditions ( Ma et al., 2020 , Wu et al, 2021a ). Intestinal ischemia results in cellular damage and impaired intestinal mucosal barrier function during reperfusion, leading to systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and even death ( Gutiérrez-Sánchez G et al., 2021 ).…”

C1q as a target molecule to treat human disease: What do mouse studies teach us?

“…MBL is also a key player for I/R injury in gastrointestinal ischemia ( 53 – 55 ). In regard to C1q deficiency there was evidence for protection from I/R injury in male but not female mice ( 55 ), an effect which might have been missed in other studies ( 54 ).…”

“…MBL is also a key player for I/R injury in gastrointestinal ischemia ( 53 – 55 ). In regard to C1q deficiency there was evidence for protection from I/R injury in male but not female mice ( 55 ), an effect which might have been missed in other studies ( 54 ). While C1qKO mice were protected against remote pulmonary injury as a sign of reperfusional damage in the severe protocol of 2 h of hindlimb ischemia ( 57 ), this was not the case in the setting of 20 min of gastrointestinal I/R ( 53 ).…”

The role of intestinal microbiota and its metabolites in intestinal and extraintestinal organ injury induced by intestinal ischemia reperfusion injury

“…Perioperative acute intestinal I/R injury is a common emergency and critical condition [2]. It not only causes damage to the intestinal barrier, but can also lead to multiple organ injury outside the intestine, with a very high complication rate and mortality rate [20].…”

“…Intestinal ischemia/reperfusion (I/R) injury is common in the perioperative period, especially in both surgical and trauma patients, and has high morbidity and mortality associated with it [1][2][3]. Intestinal I/R plays an important role in the pathophysiological evolution of severe infection, trauma, shock, intestinal obstruction, mesenteric artery embolism, abdominal aortic aneurysm surgery, cardiopulmonary bypass surgery, liver transplantation, and small intestine transplantation [4,5].…”