Chen Jen-Lung, Cheng Tzu-Ting, Huang Chien-Chi, Chang Hsin-Hou, Lam Chen-Fuh
Division of General Surgery, Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, 824, Taiwan.
Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung, 824, Taiwan.
Heliyon. 2023 Jul 28;9(8):e18627. doi: 10.1016/j.heliyon.2023.e18627. eCollection 2023 Aug.
Membrane-bound P-selectin induces endothelial adhesion of leucocytes and amplifies organ inflammations during major trauma, while soluble P-selectin (sP-sel) mediates survival rescue properties. This study characterized the differential effects of P-selectin in a "2-hit" model of hemorrhagic shock (HS) and partial hepatectomy (PH).
HS was induced by withdrawing blood (0.3 mL) directly from the mouse femoral arteries. 70% or 50% of liver volumes were resected after inducing HS. Time of survival in P-selectin deficient (Selp -/-) mice treated with and without intraperitoneal injections of recombinant P-sel IgG-Fc fusion proteins (rP-sel-Fc, 1.5 mg/kg) were recorded for up to 72h after injury. In addition, liver regeneration at 72h after HS and 50% PH was assessed in wild-type and Selp -/- mice.
Compared to wild-types, Selp -/- mice had significantly higher mortality rates post HS and 70% PH, as none of these animals survived up to 48h postoperatively. The survival curve was restored in Selp -/- mice pre-treated with rP-sel-Fc. In the HS followed by 50% PH experimental arm, liver remnant growth ratios were significantly higher in Selp -/- mice (15.7 ± 3.1 vs 11.7 ± 4.9, P = 0.040). The elevated serum concentrations of alanine aminotransferase post-PH were significantly reduced in Selp -/- mice. Hepatocyte proliferation indices (CYP7a1 and PCNA) expression were enhanced and myeloperoxidase activity in the regenerated remnant liver was reduced in the Selp -/- mice.
In critical conditions induced by HS and PH, P-selectin mediates two distinct phenotypic characteristics. Soluble-form circulating P-selectin improves survival in the acute stage of HS and extensive loss of liver parenchyma; membrane-bound P-selectin induces regional pro-inflammatory reactions in the remnant liver after the acute stage of two insults, thereby inhibiting hepatic regeneration. The results of this pre-clinical study may provide molecular mechanistic insight and clinical therapeutic applications of P-selectin in the acute and regenerative phases of traumatic hepatic injury.
膜结合型P选择素可诱导白细胞与内皮细胞黏附，并在严重创伤期间加剧器官炎症，而可溶性P选择素（sP-sel）则具有介导生存救援的特性。本研究在失血性休克（HS）和部分肝切除术（PH）的“二次打击”模型中，对P选择素的不同作用进行了表征。
通过直接从小鼠股动脉采血（0.3 mL）诱导HS。诱导HS后，切除70%或50%的肝脏体积。记录腹腔注射重组P-sel IgG-Fc融合蛋白（rP-sel-Fc，1.5 mg/kg）和未注射的P选择素缺陷（Selp-/-）小鼠损伤后长达72小时的存活时间。此外，评估野生型和Selp-/-小鼠在HS和50% PH后72小时的肝脏再生情况。
与野生型相比，Selp-/-小鼠在HS和70% PH后的死亡率显著更高，因为这些动物在术后48小时内均无存活。用rP-sel-Fc预处理的Selp-/-小鼠的生存曲线得以恢复。在HS后行50% PH的实验组中，Selp-/-小鼠的肝残余生长率显著更高（15.7±3.1对11.7±4.9，P = 0.040）。Selp-/-小鼠PH后升高的血清丙氨酸转氨酶浓度显著降低。Selp-/-小鼠肝细胞增殖指数（CYP7a1和PCNA）表达增强，再生残余肝脏中的髓过氧化物酶活性降低。
在由HS和PH诱导的危急情况下，P选择素介导两种不同的表型特征。可溶性循环P选择素可提高HS急性期和肝实质大量丧失后的生存率；膜结合型P选择素在两次损伤急性期后在残余肝脏中诱导局部促炎反应，从而抑制肝脏再生。这项临床前研究的结果可能为P选择素在创伤性肝损伤的急性期和再生期提供分子机制见解及临床治疗应用。
