Tschirhart Brent J, Lu Xiangru, Gomes Janice, Chandrabalan Arundhasa, Bell Gillian, Hess David A, Xing Guangxin, Ling Hong, Burger Dylan, Feng Qingping
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
Pharmaceuticals (Basel). 2023 Jun 3;16(6):837. doi: 10.3390/ph16060837.
Sepsis is caused by a dysregulated immune response to infection and is a leading cause of mortality globally. To date, no specific therapeutics are available to treat the underlying septic response. We and others have shown that recombinant human annexin A5 (Anx5) treatment inhibits pro-inflammatory cytokine production and improves survival in rodent sepsis models. During sepsis, activated platelets release microvesicles (MVs) with externalization of phosphatidylserine to which Anx5 binds with high affinity. We hypothesized that recombinant human Anx5 blocks the pro-inflammatory response induced by activated platelets and MVs in vascular endothelial cells under septic conditions via phosphatidylserine binding. Our data show that treatment with wildtype Anx5 reduced the expression of inflammatory cytokines and adhesion molecules induced by lipopolysaccharide (LPS)-activated platelets or MVs in endothelial cells ( < 0.01), which was not observed with Anx5 mutant deficient in phosphatidylserine binding. In addition, wildtype Anx5 treatment, but not Anx5 mutant, improved trans-endothelial electrical resistance ( < 0.05) and reduced monocyte ( < 0.001) and platelet ( < 0.001) adhesion to vascular endothelial cells in septic conditions. In conclusion, recombinant human Anx5 inhibits endothelial inflammation induced by activated platelets and MVs in septic conditions via phosphatidylserine binding, which may contribute to its anti-inflammatory effects in the treatment of sepsis.
脓毒症是由对感染的免疫反应失调引起的，是全球范围内死亡的主要原因。迄今为止，尚无特异性疗法可治疗潜在的脓毒症反应。我们和其他人已经表明，重组人膜联蛋白A5（Anx5）治疗可抑制促炎细胞因子的产生，并提高啮齿动物脓毒症模型的存活率。在脓毒症期间，活化的血小板释放带有磷脂酰丝氨酸外化的微泡（MVs），Anx5与磷脂酰丝氨酸具有高亲和力结合。我们假设重组人Anx5通过磷脂酰丝氨酸结合阻断脓毒症条件下血管内皮细胞中活化血小板和MVs诱导的促炎反应。我们的数据表明，用野生型Anx5处理可降低脂多糖（LPS）活化的血小板或MVs在内皮细胞中诱导的炎性细胞因子和粘附分子的表达（<0.01），而在缺乏磷脂酰丝氨酸结合的Anx5突变体中未观察到这种情况。此外，野生型Anx5处理而非Anx5突变体可改善跨内皮电阻（<0.05），并降低脓毒症条件下单核细胞（<0.001）和血小板（<0.001）对血管内皮细胞的粘附。总之，重组人Anx5通过磷脂酰丝氨酸结合抑制脓毒症条件下活化血小板和MVs诱导的内皮炎症，这可能有助于其在脓毒症治疗中的抗炎作用。
