Department of Thoracic Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University.
Department of Thoracic Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University.
Transl Res. 2024 Sep;271:93-104. doi: 10.1016/j.trsl.2024.05.010. Epub 2024 May 24.
Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.
肝肺综合征（HPS）是肝脏疾病晚期的一种严重肺部并发症。HPS 患者发生肺水肿是危及生命的。肺血管通透性增加是导致肺水肿的重要机制，而内皮糖萼（EG）是维持血管通透性稳定的屏障。然而，在 HPS 中，肺血管 EG 是否发生变化及其调节机制尚不清楚。脾源性单核细胞参与了 HPS 的发病机制。然而，它们是否调节 HPS 患者或大鼠的肺血管通透性，以及其机制是什么尚不清楚。本研究纳入了健康志愿者和接受或未接受脾切除术的 HPS 患者。我们发现，HPS 患者的呼吸在脾切除术后明显改善，而 EG 降解和肺水肿加重。此外，HPS 患者表达更高水平的肿瘤坏死因子-α（OSM）和成纤维细胞生长因子（FGF）。随后，构建了单核细胞与人脐静脉内皮细胞（HUVEC）的共培养系统。结果发现，单核细胞在 HUVEC 中分泌 OSM 并激活 FGF/FGFR1 信号通路。然后，通过胆总管结扎（CBDL）构建 HPS 大鼠模型进行体内验证。在 CBDL 前 30 分钟，通过尾静脉向 HPS 大鼠静脉注射 OSM 重组蛋白和/或 TNF-α。结果表明，HPS 大鼠脾切除术后呼吸改善，而肺血管 EG 降解和血管通透性增加，肺水肿加重。此外，HPS 大鼠中 OSM 和 FGF 的表达上调，而脾切除术后表达下调。静脉注射外源性 OSM 可消除脾切除术对 FGF 的影响，并改善 EG 降解。由此可见，在 HPS 期间，脾源性单核细胞通过激活 FGF/FGFR1 通路分泌 OSM，促进肺血管 EG 重塑，从而维持稳定的血管通透性，减少肺水肿。本研究为 HPS 的治疗提供了一个有前景的治疗靶点。
