Dual phenotypic characteristics of P-selectin in a mouse model of hemorrhagic shock and hepatectomy

Jen-Lung Chen; Tzu-Ting Cheng; Chien-Chi Huang; Hsin-Hou Chang; Chen-Fuh Lam

doi:10.1016/j.heliyon.2023.e18627

Dual phenotypic characteristics of P-selectin in a mouse model of hemorrhagic shock and hepatectomy

Heliyon. 2023 Jul 28;9(8):e18627. doi: 10.1016/j.heliyon.2023.e18627. eCollection 2023 Aug.

Authors

Jen-Lung Chen¹, Tzu-Ting Cheng², Chien-Chi Huang³, Hsin-Hou Chang⁴, Chen-Fuh Lam^{2

5}

Affiliations

¹ Division of General Surgery, Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, 824, Taiwan.
² Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung, 824, Taiwan.
³ Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, 824, Taiwan.
⁴ Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, 907, Taiwan.
⁵ Department of Anesthesiology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 622, Taiwan.

Abstract

Background: 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).

Materials and methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Hemorrhagic shock; Inflammation; Liver regeneration; P-selectin; Trauma.