Protective effect of Cl-amidine against CLP-induced lethal septic shock in mice.
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.
Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, 48019, USA.
Ting
T
Zhao
Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, 48019, USA.
Baihong
B
Pan
Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, 48019, USA.
Hasan B
HB
Alam
Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, 48019, USA.
Baoling
B
Liu
Rodent Histopathology Core - DF/HCC - Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
Roderick T
RT
Bronson
Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, 48019, USA.
Qiufang
Q
Deng
Department of Neurosurgery, Baylor Scott and White Health, Temple, Texas, 76508, USA.
Erxi
E
Wu
Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, 48019, USA.
Yongqing
Y
Li
D000818:Animals; D001284:Atrophy; D001853:Bone Marrow / Q000473:pathology; D002432:Cecum / Q000187:drug effects / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D007113:Immunity, Innate; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D013950:Thymus Gland / Q000473:pathology
D016207:Cytokines; D008070:Lipopolysaccharides; C558727:N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide; D009952:Ornithine