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Background <p>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.</p> Methods <p>Three groups of male Wistar rats were studied: Control (NaCl 0.9%)(<i>n</i> = 14), Heparin (<i>n</i> = 14), and Carrageenan (<i>n</i> = 16). Rats underwent 1&#xa0;h of left pulmonary warm ischemia. The reperfusion period was 3&#xa0;h for one subgroup (H3) and 3&#xa0;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 (<i>p</i> &lt; 0.05).</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年3月25日

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  • Vincent Magnan,
  • Antoine Hérault,
  • Ingrid Fruitier-Arnaudin,
  • Manon Valet,
  • Anaïs Dumesnil,
  • Sylvanie Renet,
  • Paul Mulder,
  • Mickaël Palmier,
  • Didier Plissonnier,
  • Laurence Chevalier,
  • Hugo Groult,
  • Paul Billoir,
  • Nicolas Piton,
  • Jérémy Bellien,
  • Jean-Marc Baste,
  • Jean Selim

摘要

Background

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.

Methods

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).

Results

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.

Conclusion

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.