Inhibition of peptidylarginine deiminase attenuates inflammation and improves survival in a rat model of hemorrhagic shock

详细信息    查看全文

• 作者：Wei He ; MD^a ; ^b ; Peter Zhou ; BS^b ; ^c ; Zhigang Chang ; MD^b ; ^d ; Baoling Liu ; MD^b ; Xuefeng Liu ; PhD^e ; Yanming Wang ; MD ; PhD^f ; Yongqing Li ; MD ; PhD^b ; Hasan B. Alam ; MD ; FACS^b ; ^{alamh@med.umich.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Peptidylarginine deiminase inhibitor ; Hemorrhagic shock ; Survival ; Inflammation ; Rat
• 刊名：Journal of Surgical Research
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：200
• 期：2
• 页码：610-618
• 全文大小：1090 K

文摘

We have recently shown that inhibition of peptidylarginine deiminase (PAD) improves survival in a rodent model of lethal cecal ligation and puncture. The roles of PAD inhibitors in hemorrhagic shock (HS), however, are largely unknown. The goal of this study was to investigate the effects of YW3-56, a novel PAD inhibitor, on survival after severe HS.

Methods

Mouse macrophages were exposed to hypoxic conditions followed by reoxygenation in the presence or absence of YW3-56. Enzyme-linked immunosorbent assay (ELISA) was performed to measure levels of secreted tumor necrosis factor α and interleukin-6 in the culture medium. Cell viability was determined by methyl thiazolyl tetrazolium assay. In the survival experiment, anesthetized male Wistar–Kyoto rats (n = 10/group) were subjected to 55% blood loss, and treated with or without YW3-56 (10 mg/kg, intraperitoneally). Survival was monitored for 12 h. In the nonsurvival experiment, morphologic changes of the lungs were examined. Levels of circulating cytokine-induced neutrophil chemoattractant 1 (CINC-1) and myeloperoxidase (MPO) in the lungs were measured by ELISA. Expression of lung intercellular adhesion molecules-1 (ICAM-1) was also determined by Western blotting.

Results

Hypoxia/reoxygenation (H/R) insult induced tumor necrosis factor α and interleukin-6 secretion from macrophages, which was significantly attenuated by YW3-56 treatment. YW3-56 treatment also increased cell viability when macrophages were exposed to H/R up to 6/15 h and improved survival rate from 20% to 60% in lethal HS rat model. Compared to the sham groups, pulmonary MPO activity and ICAM-1 expression in the HS group were significantly increased, and acute lung injury was associated with a higher degree of CINC-1 levels in serum. Intraperitoneal delivery of YW3-56 significantly reduced pulmonary MPO and ICAM-1 expression and attenuated acute lung injury.

Conclusions

Our results demonstrate for the first time that administration of YW3-56, a novel PAD inhibitor, can improve survival in a rat model of HS and in a cell culture model of H/R. The survival advantage is associated with an attenuation of local and systemic pro-inflammatory cytokines and the protection against acute lung injury after hemorrhage. Thus, PAD inhibition may represent a novel and promising therapeutic strategy for severe HS.