Table_1_Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury.docx

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.

肠系膜缺血再灌注（IR）诱导的组织损伤表现为一种具有显著发病率和死亡率的急性炎症反应。IR诱导损伤的机制尚未完全阐明，但近期研究表明，补体激活以及性别差异在其中起着关键作用。为验证补体在肠IR中启动可能存在性别差异的假设，我们对雄性和雌性野生型C57B6L/、C1q-/-、MBL-/-或 Properdin（P）-/-小鼠进行了肠IR处理。分析了肠损伤、C3b和C5a的产生以及体外分泌情况。初步研究显示，雄性和雌性野生型小鼠的补体mRNA和蛋白存在差异。在IR的刺激下，C1q-/-、MBL-和P-/-缺陷型雄性小鼠的损伤程度低于野生型雄性小鼠。相反，只有MBL-/-缺陷型雌性小鼠的损伤程度显著低于野生型雌性小鼠。值得注意的是，野生型、C1q-/-和P-/-雌性小鼠的损伤程度显著低于相应的雄性小鼠。此外，WT雄性小鼠的C1q和MBL表达及沉积增加，而仅WT雌性小鼠的MBL表达及沉积升高。这些数据表明，雄性小鼠在肠IR中同时使用C1q和MBL途径，而雌性小鼠则倾向于在肠IR过程中依赖凝集素途径。在MBL-/-和P-/-小鼠中，雌性小鼠产生的血清C5a显著少于雄性小鼠。我们的研究结果表明，补体激活在肠IR中以性别依赖的方式发挥着关键作用。