title: Blocking NAD(+)/CD38/cADPR/Ca(2+) pathway in sepsis prevents organ damage.
abstract: BACKGROUND
  Although the nicotinamide adenine dinucleotide (NAD(+))/CD38/cyclic ADP ribose (cADPR)/Ca(2+) signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD(+)/CD38/cADPR/Ca(2+) signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage.
  
  
  METHODS
  Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD(+), cADPR, CD38, and intracellular Ca(2+) levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin-eosin-stained and assayed for malondialdehyde and superoxide dismutase activities.
  
  
  RESULTS
  NAD(+), cADPR, CD38, and intracellular Ca(2+) levels increased in the hearts, livers, and kidneys of septic rats as early as 6-24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca(2+) mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats.
  
  
  CONCLUSIONS
  The NAD(+)/CD38/cADPR/Ca(2+) signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage.
authors.affiliation: Department of Critical Care Medicine, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Qian-Yi
authors.initials: QY
authors.lastname: Peng
authors.affiliation: Department of Critical Care Medicine, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Ai
authors.affiliation: Department of Critical Care Medicine, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Critical Care Medicine, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Ma
authors.affiliation: Department of Critical Care Medicine, Xiang-Ya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: ayhicu1978@126.com.
authors.forename: Yu-Hang
authors.initials: YH
authors.lastname: Ai
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D009243:NAD / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C493642:8-bromo-cyclic-ADP-ribose; D008562:Membrane Glycoproteins; D009243:NAD; D036563:Cyclic ADP-Ribose; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D036541:ADP-ribosyl Cyclase; C498156:Cd38 protein, rat; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium
keywords: CD38; Calcium ions; Cyclic ADP-ribose; Nicotinamide adenine dinucleotide; Sepsis