title: Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats.
abstract: BACKGROUND
  Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI.
  
  
  METHODS
  Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-μ, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured.
  
  
  RESULTS
  NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-μ and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats.
  
  
  CONCLUSIONS
  The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.
authors.affiliation: Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Qian-Yi
authors.initials: QY
authors.lastname: Peng
authors.affiliation: Department of Anesthesia, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Ai
authors.affiliation: Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Yu-Hang
authors.initials: YH
authors.lastname: Ai
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications*; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C493642:8-bromo-cyclic-ADP-ribose; D014409:Tumor Necrosis Factor-alpha; D036563:Cyclic ADP-Ribose; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium