title: Heme Oxygenase-1/Carbon Monoxide-regulated Mitochondrial Dynamic Equilibrium Contributes to the Attenuation of Endotoxin-induced Acute Lung Injury in Rats and in Lipopolysaccharide-activated Macrophages.
abstract: Sepsis-associated acute lung injury remains the major cause of mortality in critically ill patients and is characterized by marked oxidative stress and mitochondrial dysfunction. Mitochondrial dynamics are indispensable for functional integrity. Additionally, heme oxygenase (HO)-1/carbon monoxide conferred cytoprotection against end-organ damage during endotoxic shock. Herein, we tested the hypothesis that HO-1/carbon monoxide played a critical role in maintaining the dynamic process of mitochondrial fusion/fission to mitigate lung injury in Sprague-Dawley rats or RAW 264.7 macrophages exposed to endotoxin.
  
  
  
  The production of reactive oxygen species, the respiratory control ratio (RCR), and the expressions of HO-1 and mitochondrial dynamic markers were determined in macrophages. Concurrently, alterations in the pathology of lung tissue, lipid peroxidation, and the expressions of the crucial dynamic proteins were detected in rats.
  
  
  
  Endotoxin caused a 31% increase in reactive oxygen species and a 41% decrease in RCR levels (n = 5 per group). In parallel, the increased expression of HO-1 was observed in lipopolysaccharide-stimulated macrophages, concomitantly with excessive mitochondrial fission. Furthermore, carbon monoxide-releasing molecule-2 or hemin normalized mitochondrial dynamics, which were abrogated by zinc protoporphyrin IX. Additionally, impaired mitochondrial dynamic balance was shown in Sprague-Dawley rats that received lipopolysaccharide, accompanied by pathologic injury, elevated malondialdehyde contents, decreased manganese superoxide dismutase activities, and lowered RCR levels in rat lung mitochondria. However, the above parameters were augmented by zinc protoporphyrin IX and were in turn reversed by hemin.
  
  
  
  The HO-1/carbon monoxide system modulated the imbalance of the dynamic mitochondrial fusion/fission process evoked by lipopolysaccharide and efficiently ameliorated endotoxin-induced lung injury in vivo and in vitro.
authors: From the Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China (J.Y., J.S., D.W., S.D., Y.Z., M.W., L.G.); Department of Intensive Care Medicine, Fourth Center Clinical College of Tianjin Medical University, Tianjin, China (Q.F.); and Department of Pharmacology, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin, China (D.L.).
authors: Jianbo
authors: J
authors: Yu
authors: Jia
authors: J
authors: Shi
authors: Dan
authors: D
authors: Wang
authors: Shuan
authors: S
authors: Dong
authors: Yuan
authors: Y
authors: Zhang
authors: Man
authors: M
authors: Wang
authors: Lirong
authors: L
authors: Gong
authors: Qiang
authors: Q
authors: Fu
authors: Daquan
authors: D
authors: Liu
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004731:Endotoxins; D051547:Heme Oxygenase-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D063154:Mitochondrial Dynamics; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1