Attenuation of endothelial phosphatidylserine exposure decreases ischemia-reperfusion induced changes in microvascular permeability

Strumwasser, Aaron; Bhargava, Aditi; Victorino, Gregory P.

doi:10.1097/ta.0000000000001891

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…In our study, PS blockade was performed prior to the onset hemorrhagic shock. This timing has potential for therapeutic benefit by means of prophylactically blocking PS prior to an additional systemic insult or "second hit," such as damage control laparotomy 19 . Prior studies, including a phase II trial, have shown benefits of Diannexin when administered after an ischemic insult 19,23 .…”

Section: Discussionmentioning

confidence: 99%

“…This timing has potential for therapeutic benefit by means of prophylactically blocking PS prior to an additional systemic insult or "second hit," such as damage control laparotomy 19 . Prior studies, including a phase II trial, have shown benefits of Diannexin when administered after an ischemic insult 19,23 . Additionally, in murine models of ischemia reperfusion with Diannexin, reduction in renal tubule damage was apparent up to 8 days after ischemic insult, suggesting the benefits of PS blockade are durable 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Doses of up to 1000μg/kg have been shown to be safe in animal studies 18 . Diannexin was administered prior to hemorrhage based on our prior studies evaluating L p in the setting of ischemia reperfusion 19 . Following Diannexin infusion, hemorrhage was carried out in an identical manner to the hemorrhage only group.…”

Section: Hemorrhage Protocolmentioning

confidence: 99%

“…Diannexin binds to externalized PS during the early stages of apoptosis, when cellular injury may still be reversible, blocking its downstream effects 11,15 . Phosphatidylserine blockade with Diannexin has minimized the detrimental effects of ischemia reperfusion injury in rat models of renal, pancreatic islet cell, lung, and liver transplant as well as in muscle flaps 11,14,[17][18][19][20][21] . The underlying pathophysiology of hemorrhagic shock, followed by resuscitation is similar to the insult seen with ischemia reperfusion injury after transplant.…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Phosphatidylserine Blockade in Hemorrhagic Shock

Cohan

Beattie

Brigode

et al. 2020

Journal of Surgical Research

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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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hemorrhage Protocolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective Effect of Phosphatidylserine Blockade in Hemorrhagic Shock

Cohan

Beattie

Brigode

et al. 2020

Journal of Surgical Research

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“…The reperfusion group ( n = 11) similarly underwent 60-min occlusion of the superior mesenteric artery and ligation of the marginal arteries. The occlusion was then released by declamping of the mesenteric artery, and reperfusion of the intestine was observed for 60 min without closing the abdomen[ 17 , 18 ]. The hydrogen group ( n = 9) was connected to the respiratory circuit using a gas supply hood that covered the face and head of the rats, in which spontaneous respiration was maintained without using mechanical ventilation[ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Hydrogen gas and preservation of intestinal stem cells in mesenteric ischemia and reperfusion

Yamamoto¹,

Suzuki²,

Homma³

et al. 2022

World J Gastrointest Surg

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BACKGROUND Patients with mesenteric ischemia frequently suffer from bowel necrosis even after revascularization. Hydrogen gas has showed promising effects for ischemia-reperfusion injury by reducing reactive oxygen species in various animal and clinical studies. We examined intestinal tissue injury by ischemia and reperfusion under continuous initiation of 3% hydrogen gas. AIM To clarify the treatment effects and target cells of hydrogen gas for mesenteric ischemia. METHODS Three rat groups underwent 60-min mesenteric artery occlusion (ischemia), 60-min reperfusion following 60-min occlusion (reperfusion), or ischemia-reperfusion with the same duration under continuous 3% hydrogen gas inhalation (hydrogen). The distal ileum was harvested. Immunofluorescence staining with caspase-3 and leucine-rich repeat-containing G-protein-coupled 5 (LGR5), a specific marker of intestinal stem cell, was conducted to evaluate the injury location and cell types protected by hydrogen. mRNA expressions of LGR5, olfactomedin 4 (OLFM4), hairy and enhancer of split 1, Jagged 2, and Neurogenic locus notch homolog protein 1 were measured by quantitative polymerase chain reaction. Tissue oxidative stress was analyzed with immunostaining for 8-hydroxy-2'-deoxyguanosine (8-OHdG). Systemic oxidative stress was evaluated by plasma 8-OHdG. RESULTS Ischemia damaged the epithelial layer at the tip of the villi, whereas reperfusion induced extensive apoptosis of the cells at the crypt base, which were identified as intestinal stem cells with double immunofluorescence stain. Hydrogen mitigated such apoptosis at the crypt base, and the LGR5 expression of the tissues was higher in the hydrogen group than in the reperfusion group. OLFM4 was also relatively higher in the hydrogen group, whereas other measured RNAs were comparable between the groups. 8-OHdG concentration was high in the reperfusion group, which was reduced by hydrogen, particularly at the crypt base. Serum 8-OHdG concentrations were relatively higher in both reperfusion and hydrogen groups without significance. CONCLUSION This study demonstrated that hydrogen gas inhalation preserves intestinal stem cells and mitigates oxidative stress caused by mesenteric ischemia and reperfusion.

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