Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock.

Abstract

Objective: Sepsis causes millions of deaths on a global scale annually. Activation of peptidylarginine deiminase (PAD) enzymes in sepsis causes citrullination of histones, which results in neutrophil extracellular trap formation and sepsis progression. This study evaluates pan-PAD inhibitor, Cl-amidine, in a model of lipopolysaccharide (LPS)-induced endotoxic shock in rabbits. We hypothesized that Cl-amidine would improve survival and attenuate kidney injury. Methods: In the survival model, rabbits were injected injected intravenously with 1 mg/kg of LPS, and then randomly assigned either to receive dimethyl sulfoxide (DMSO; 1 mcL/g) or Cl-amidine (10 mg/kg diluted in 1 mcL/g DMSO). They were then monitored for 14 days to evaluate survival. In the non-survival experiment, the same insult and treatment were administered, however; the animals were euthanized 12 hours after LPS injection for kidney harvest. Acute kidney injury (AKI) scoring was performed by a histopathologist who was blinded to the group assignment. Serial blood samples were also collected and compared. Results: Rabbits that received Cl-amidine had a higher survival (72%) compared with the rabbits that received DMSO (14%; p < 0.05). Cl-amidine-treated rabbits had lower (p < 0.05) histopathologic AKI scores, as well as plasma creatinine and blood urea nitrogen (BUN) levels 12 hours after insult. Conclusions: Pan-PAD inhibitor Cl-amidine improves survival and attenuates kidney injury in LPS-induced endotoxic shock in rabbits.

• Authors: Ali Z Siddiqui, Umar F Bhatti, Qiufang Deng, Ben E Biesterveld, Yuzi Tian, Zhenyu Wu, Julia Dahl, Baoling Liu, Jie Xu, Yui Koike, Jun Song, Jifeng Zhang, Yongqing Li, Hasan B Alam, Aaron M Williams
• Journal: Surgical infections (Surg Infect (Larchmt)) Vol. 22 Issue 4 Pg. 421-426 (May 2021) ISSN: 1557-8674 [Electronic] United States
• PMID: 32833601 (Publication Type: Journal Article)

Chemical References

• Lipopolysaccharides
• N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
• Ornithine

Topics

• Animals
• Rabbits
• Extracellular Traps
• Kidney
• Lipopolysaccharides (toxicity)
• Ornithine (analogs & derivatives)
• Shock, Septic (drug therapy)