Protective effect of Cl-amidine against CLP-induced lethal septic shock in mice

Sci Rep. 2016 Nov 7;6:36696. doi: 10.1038/srep36696.

Abstract

Production of innate and adaptive immune cells from hematopoietic stem cells, and maturation of T lymphocytes are effective immune responses to fight severe microbial infection. In sepsis, this emergency myelopoiesis is damaged, leading to failure of bacterial clearance, and excessive stress-induced steroids cause immature T-lymphocyte apoptosis in thymus. We recently found that Cl-amidine, a peptidylarginine deiminase (PAD) inhibitor, improves survival in a mouse model of cecal ligation and puncture (CLP)-induced septic shock. In the present study we investigated how Cl-amidine promotes survival, focusing on protective effects of Cl-amidine on immune response. We confirmed survival-improving effect of Cl-amidine and are the first to explore the role of Cl-amidine in immune response. CLP caused bone marrow (BM) and thymus atrophy, decreased innate immune cells in BM. CLP increased levels of cytokines (IL-1β, IL-6, and TNF-α) and bacteria load in blood/liver. In primary splenocyte culture, lipopolysaccharide increased TNF-α production. In contrast, Cl-amidine attenuated these CLP and lipopolysaccharide-induced alterations. Moreover, Cl-amidine increased circulating monocytes. Collectively, our results demonstrate Cl-amidine plays protective roles by significantly decreasing BM and thymus atrophy, restoring innate immune cells in BM, increasing blood monocytes and blood/liver bacteria clearance, and attenuating pro-inflammatory cytokine production in a murine model of lethal sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrophy
  • Bone Marrow / pathology
  • Cecum / drug effects
  • Cecum / microbiology
  • Cytokines / metabolism
  • Immunity, Innate
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Lipopolysaccharides
  • Liver / drug effects
  • Liver / microbiology
  • Male
  • Mice, Inbred C57BL
  • Ornithine / administration & dosage
  • Ornithine / analogs & derivatives*
  • Shock, Septic / drug therapy*
  • Shock, Septic / immunology
  • Shock, Septic / pathology
  • Survival Analysis
  • Thymus Gland / pathology

Substances

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