Carbon Monoxide Confers Protection in Sepsis by Enhancing Beclin 1-Dependent Autophagy and Phagocytosis
Publication: Antioxidants & Redox Signaling
Volume 20, Issue Number 3
Abstract
Aims: Sepsis, a systemic inflammatory response to infection, represents the leading cause of death in critically ill patients. However, the pathogenesis of sepsis remains incompletely understood. Carbon monoxide (CO), when administered at low physiologic doses, can modulate cell proliferation, apoptosis, and inflammation in pre-clinical tissue injury models, though its mechanism of action in sepsis remains unclear. Results: CO (250 ppm) inhalation increased the survival of C57BL/6J mice injured by cecal ligation and puncture (CLP) through the induction of autophagy, the down-regulation of pro-inflammatory cytokines, and by decreasing the levels of bacteria in blood and vital organs, such as the lung and liver. Mice deficient in the autophagic protein, Beclin 1 (Becn1+/−) were more susceptible to CLP-induced sepsis, and unresponsive to CO therapy, relative to their corresponding wild-type (Becn1+/+) littermate mice. In contrast, mice deficient in autophagic protein microtubule-associated protein-1 light chain 3B (LC3B) (Map1lc3b−/−) and their corresponding wild-type (Map1lc3b+/+) mice showed no differences in survival or response to CO, during CLP-induced sepsis. CO enhanced bacterial phagocytosis in Becn1+/+ but not Becn1+/− mice in vivo and in corresponding cultured macrophages. CO also enhanced Beclin 1-dependent induction of macrophage protein signaling lymphocyte-activation molecule, a regulator of phagocytosis. Innovation: Our findings demonstrate a novel protective effect of CO in sepsis, dependent on autophagy protein Beclin 1, in a murine model of CLP-induced polymicrobial sepsis. Conclusion: CO increases the survival of mice injured by CLP through systemic enhancement of autophagy and phagocytosis. Taken together, we suggest that CO gas may represent a novel therapy for patients with sepsis. Antioxid. Redox Signal. 20, 432–442.
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Information & Authors
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Published In
Antioxidants & Redox Signaling
Volume 20 • Issue Number 3 • January 20, 2014
Pages: 432 - 442
PubMed: 23971531
Copyright
Copyright 2014, Mary Ann Liebert, Inc.
History
Published in print: January 20, 2014
Published online: 15 January 2014
Published ahead of print: 5 October 2013
Published ahead of production: 25 August 2013
Accepted: 23 August 2013
Revision received: 5 August 2013
Received: 14 April 2013
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