Critical Care Medicine  |   December 2016
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
Author Notes
  • 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.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • J.Y., J.S., and D.W. contributed equally to this article.
    J.Y., J.S., and D.W. contributed equally to this article.×
  • Submitted for publication November 15, 2015. Accepted for publication August 3, 2016.
    Submitted for publication November 15, 2015. Accepted for publication August 3, 2016.×
  • Address correspondence to Dr. Yu: Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, 122 Sanwei Road, Tianjin 300100, China. yujianbo11@126.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Central and Peripheral Nervous Systems / Critical Care / Respiratory System
Critical Care Medicine   |   December 2016
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
Anesthesiology 12 2016, Vol.125, 1190-1201. doi:10.1097/ALN.0000000000001333
Anesthesiology 12 2016, Vol.125, 1190-1201. doi:10.1097/ALN.0000000000001333
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.