Protective Effect of Phosphatidylserine Blockade in Hemorrhagic Shock

Abstract

Introduction: Phosphatidylserine (PS) is a key cell membrane phospholipid normally maintained on the inner cell surface, but externalizes to the outer surface in response to cellular stress. We hypothesized that PS exposure mediates organ dysfunction in hemorrhagic shock.Our aims were to evaluate PS blockade on: 1) pulmonary, 2) renal, and 3) gut function, as well as 4) serum lysophosphatidic acid (LPA), an inflammatory mediator generated by PS externalization, as a possible mechanism mediating organ dysfunction. Materials and Methods:Rats were either: a) monitored for 130 minutes (controls, n=3), b) hemorrhaged then resuscitated (hemorrhage only group, n=3), or c) treated with Diannexin (DA), a PS blocking agent, followed by hemorrhage and resuscitation, (DA + hemorrhage group, n=4). Pulmonary dysfunction was assessed by PaO 2 , renal dysfunction by serum creatinine, and gut dysfunction by mesenteric endothelial permeability (L P ). LPA levels were measured in all groups.Results: Pulmonary: There was no difference in PaO 2 between groups. Renal: After resuscitation, creatinine levels were lower after PS blockade with Diannexin vs hemorrhage only group (p=0.01). Gut: L P was decreased after PS blockade with Diannexin vs hemorrhage only group (p<0.01). Finally, LPA levels were also lower after PS blockade with Diannexin vs the hemorrhage only group, but higher than the control group (p<0.01). Conclusion:PS blockade with Diannexin decreased renal and gut dysfunction associated with hemorrhagic shock and attenuated the magnitude of LPA generation. Our findings suggest

Phosphatidylserine is an overlooked mediator of COVID-19 thromboinflammation

“…Development of such imaging modalities could be used not only to explore the contribution of the endothelium to thrombosis in severe infections, but other conditions where endothelial dysfunction may contribute to pathophysiology, such as acute kidney injury or systemic hypotension. Studies with an engineered annexin V dimer, for example, suggest its potential for improving health, even in the absence of proof of high levels of circulating PS in targeted disease states [ 61 , 62 , 63 ].…”

Long-circulating XTEN864-annexin A5 fusion protein for phosphatidylserine-related therapeutic applications

“…Moreover, diannexin was shown to protect against renal, lung, pancreatic, and hepatic ischemia reperfusion injury (IRI) in mice [47][48][49][50] and might thus reduce rejection responses of organ transplants. It also reduced infarct size within hours following severe myocardial ischemia in rabbits [51] by suppression of inflammatory responses and was helpful in critical conditions such as sepsis and hemorrhagic shock [30,31]. Besides diannexin, the blood half-life of anxA5 has been extended to about 5 h in mice by chemically coupling multiple PEG chains via the amine groups of anxA5 [52].…”

“…In myocardial ischemia–reperfusion injury, anxA5 was shown to suppress the inflammatory response and reduce infarction size [ 29 ]. A dimeric anxA5, administered after the onset of hemorrhagic shock or sepsis, was able to protect the lungs, kidneys, and gut from massive dysfunction [ 30 , 31 ].…”

A serum lipidomics study for the identification of specific biomarkers for endometrial polyps to distinguish them from endometrial cancer or hyperplasia

“…Under the action of physiological processes such as cell activation and apoptosis, PS is externalized to the outer surface of cells, thus driving various pathological processes such as infectious diseases and cancer. 42,43 Studies have shown that low levels of PS are observed in both follicular fluid and endometrial tissue in patients with endometriosis, which may be related to a decrease in apoptotic cells in the endometrium of patients. 44,45 PA(37:4) can affect cell growth, proliferation, migration and invasion by involvement in cell signaling.…”