TY - JOUR
T1 - Attenuation of neutrophil-mediated liver injury in mice by drug-free E-selectin binding polymer
AU - Milošević, Nenad
AU - Rütter, Marie
AU - Ventura, Yvonne
AU - Kezerle, Yarden
AU - Feinshtein, Valeria
AU - David, Ayelet
N1 - Funding Information:
This project was supported by funds from Israel Science Foundation (ISF grant # 603/16) and US- Israel Binational Science Foundation (BSF grant # 2017200), and the Israeli Ministry of Health (MOS). AD owes gratitude to Dr. Jean de Gunzburg for his generous donation for research on Nanomedicines for Cancer and Inflammation Therapy. We thank Prof. Eli C. Lewis, from the Department of Clinical Biochemistry and Pharmacology at the Ben-Gurion University, for his constructive criticism on the manuscript.
Funding Information:
This project was supported by funds from Israel Science Foundation (ISF grant # 603/16 ) and US- Israel Binational Science Foundation (BSF grant # 2017200 ), and the Israeli Ministry of Health (MOS). AD owes gratitude to Dr. Jean de Gunzburg for his generous donation for research on Nanomedicines for Cancer and Inflammation Therapy. We thank Prof. Eli C. Lewis, from the Department of Clinical Biochemistry and Pharmacology at the Ben-Gurion University, for his constructive criticism on the manuscript. Appendix A
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2020/3/10
Y1 - 2020/3/10
N2 - 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.
AB - 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.
KW - Alcoholic liver disease
KW - Drug-free polymer therapeutics
KW - Inflammation
KW - Liver injury
KW - NIAAA model
UR - http://www.scopus.com/inward/record.url?scp=85077791096&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2019.12.018
DO - 10.1016/j.jconrel.2019.12.018
M3 - Article
C2 - 31838202
AN - SCOPUS:85077791096
VL - 319
SP - 475
EP - 486
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -
