肝损伤
渗透(HVAC)
趋化因子
外渗
免疫学
细胞粘附分子
脐静脉
白细胞贩卖
医学
炎症
选择素
电子选择素
CD11c公司
药理学
L选择素
细胞粘附
化学
体外
细胞
生物化学
物理
表型
基因
热力学
作者
Nenad Milošević,Marie Rütter,Yvonne Ventura,Yarden Kezerle,Valeria Feinshtein,Ayelet David
标识
DOI:10.1016/j.jconrel.2019.12.018
摘要
Inflammation with neutrophils infiltration is a prominent feature of alcohol-related liver disease (ARLD) and contributes to the severity of liver injury. Although an array of potential treatments has been studied, the standard treatment regimen is controversial and can induce severe side effects and infection-related complications. E-selectin, a cytokine inducible cell adhesion molecule, mediates the initial interaction of leucocytes with endothelial cells, and facilitates their further adhesion and extravasation into inflamed tissues. Given the important role of E-selectin in leukocytes trafficking, we hypothesized that a synthetic polymer presenting multiple copies of E-selectin binding peptide in a polyvalent manner (P-Esbp) may block the “roads” that facilitate neutrophil infiltration, inhibit the recruitment of neutrophils to the inflamed sites and reduce the extent of liver injury. We now demonstrate in vitro that P-Esbp reduced the recruitment of neutrophils (collected from blood of donors) on activated human umbilical vein endothelial cells (HUVEC) under flow conditions. Pre-treatment of mice with P-Esbp prior to alcohol binge attenuated alcohol-induced serum transaminase (ALT, AST) elevation, reduced pro-inflammatory cytokines (TNFα and IL-1ẞ) and chemokines (MIP-2/CXCL2 and MCP-1/CCL2) in National Institute on Alcohol Abuse and Alcoholism (NIAAA) model. Also, the up-regulation of neutrophil marker Ly6G and the number of MPO positive cells in the injured tissue was significantly reduced by the treatment, indicating diminished neutrophil infiltration. Moreover, as a result of P-Esbp treatment, E-selectin expression in the liver (mRNA and protein level) was downregulated, suggesting a potential to decrease ongoing local inflammatory response. Overall, our findings highlight the anti-inflammatory properties of the “drug-free” P-Esbp and its therapeutic potential to attenuate an excessive inflammation where infiltrating neutrophils can damage tissues and organs.
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