Anti-heparanase shields against endothelial dysfunction in a rat model of warm pulmonary ischemia–reperfusion

Primary graft dysfunction (PGD) occurs within the first three days after lung transplantation (LT), primarily due to ischemia–reperfusion (I/R) injury. Heparanase is an enzyme involved in I/R mechanisms. We investigated the effects of heparanase inhibition using derivative from λ-Carrageenan referred to as “Carrageenan”, and Heparin on endothelial dysfunction, inflammation, and glycocalyx integrity in a warm I/R rat model. Three groups of male Wistar rats were studied: Control (NaCl 0.9%)(n = 14), Heparin (n = 14), and Carrageenan (n = 16). Rats underwent 1 h of left pulmonary warm ischemia. The reperfusion period was 3 h for one subgroup (H3) and 3 days for another (D3). Pulmonary artery endothelium-dependent and independent relaxation to acetylcholine and sodium nitroprusside respectively were analyzed using a wire myograph, with a Sham group (without I/R) for comparison. Pulmonary inflammation markers were assessed by RT-qPCR and immunohistochemistry, while glycocalyx degradation and systemic inflammation markers were evaluated using enzyme-linked immunosorbent assays (ELISA). Data were expressed as mean ± SD for all analyses, except vascular function (mean ± SEM). Normality was assessed using Kolmogorov–Smirnov and Shapiro–Wilk tests. Kinetic data were analyzed using one-way repeated-measures ANOVA or, when non-normal, the Friedman test. Other data were analyzed using one-way ANOVA or the Kruskal–Wallis test for non-normal distributions. Tukey or Dunn’s post hoc tests were applied, respectively, to identify significant differences between groups (p < 0.05). Endothelial dysfunction was observed in the Control and Heparin groups, with reduced pulmonary vasorelaxation to acetylcholine compared to the Sham group, without change in endothelium-independent relaxation. In contrast, Carrageenan preserved endothelium-dependent relaxation. Moreover, Carrageenan reduced macrophage and lymphocyte infiltration, as well as lung inflammation (IL-6 and TNF-α) compared to the Control group at H3. Carrageenan also showed pulmonary anti-inflammatory effects at D3. However, Carrageenan did not reduce circulating levels of markers of glycocalyx degradation or systemic inflammation. Carrageenan protects against pulmonary endothelial dysfunction and exerts strong pulmonary anti-inflammatory effects. It may serve as a protective agent against I/R injury in LT, potentially limiting the risk of primary graft dysfunction.