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Abstract
The endothelial glycocalyx (eGC) is considered a key regulator of several mechanisms that prevent vascular injury and disease. Degradation of this macromolecular layer may be associated with post-transplant graft dysfunction. In this study, we aimed to demonstrate the benefits of eGC protection via heparanase inhibition on graft quality. We established rat models of lung grafts with damaged or preserved eGC using ischemic insult and transplanted the grafts into recipients. Lung grafts were also subjected to normothermic ex vivo lung perfusion for detailed assessment under isolated conditions. Physiologic parameters and eGC-associated cellular events were assessed in grafts before and after reperfusion. Structurally degraded eGC and highly activated heparanase were confirmed in lungs with ischemic insult. After transplant, lungs with damaged eGC exhibited impaired graft function, inflammation, edema, and inflammatory cell migration. Increased eGC shedding was evident in the lungs after reperfusion both in vivo and ex vivo. These reperfusion-related deficiencies were significantly attenuated in lungs with preserved eGC following heparanase inhibition. Our studies demonstrated that eGC plays a key role in maintaining lung graft quality and function. Heparanase inhibition may serve as a potential therapeutic to preserve eGC integrity, leading to improved post-transplant outcomes.
Highlights
The endothelial glycocalyx is considered a key regulator of several mechanisms that prevent vascular injury and disease
After cardiopulmonary arrest was induced in donor rats with an anesthesia overdose, the donor was kept at room temperature for an hour to induce ischemic insult in the lungs
Heparanase activity was significantly elevated in lungs with no treatment and was inhibited by both heparin and N-acetyl heparin (NAH) (Fig. 1b) No differences in heparanase protein expression in the lung tissues were noted among the groups (Supplemental Fig. S1)
Summary
The endothelial glycocalyx (eGC) is considered a key regulator of several mechanisms that prevent vascular injury and disease Degradation of this macromolecular layer may be associated with posttransplant graft dysfunction. The endothelial glycocalyx (eGC) is a complex matrix of membrane-bound proteoglycans, glycoproteins, glycosaminoglycans (GAGs), and adherent plasma proteins that lines the internal surfaces of blood vessels[1,2,3] This protective layer shields the entire endothelial luminal surface, reduces the shear stress of blood flow, and regulates platelet adhesion, inflammatory cell migration, and water penetration[4]. We hypothesized that increased eGC degradation may critically impact graft quality and attenuate post-transplant graft functional outcomes. To address this hypothesis, we established rat lung models with damaged or preserved eGC and tested lung graft function after single-lung transplant or ex vivo lung perfusion (EVLP)
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