Possible contribution of the neprilysin/ACE pathway to sepsis in mice

Life Sci. 2020 Oct 1;258:118177. doi: 10.1016/j.lfs.2020.118177. Epub 2020 Jul 30.

Abstract

Aim: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis.

Main methods: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed.

Key findings: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group.

Significance: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.

Keywords: ACE; Mice; Neprilysin; Omapatrilat; Sepsis.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lung / enzymology
  • Lung / pathology
  • Male
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Neprilysin / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress
  • Peptidyl-Dipeptidase A / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sepsis / enzymology*
  • Sepsis / pathology
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Biomarkers
  • Interleukin-6
  • NF-kappa B
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Peptidyl-Dipeptidase A
  • Neprilysin