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Original Research: CRITICAL CARE |

Mechanical Ventilation-Induced Oxidative Stress in the Diaphragm: Role of Heme Oxygenase-1

Darin J. Falk, PhD; Andreas N. Kavazis, PhD; Melissa A. Whidden, PhD; Ashley J. Smuder, MS; Joseph M. McClung, PhD; Matthew B. Hudson, MS; Scott K. Powers, PhD, EdD
Author and Funding Information

From the Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL.

Correspondence to: Scott K. Powers, PhD, EdD, University of Florida, PO Box 118206, Gainesville, FL 32611; e-mail: spowers@hhp.ufl.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

Funding/Support: This work was supported by the National Institutes of Health [Grant R01 HL072789, awarded to Dr Powers].


© 2011 American College of Chest Physicians


Chest. 2011;139(4):816-824. doi:10.1378/chest.09-2787
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Background:  Prolonged mechanical ventilation (MV) results in a rapid onset of diaphragmatic atrophy that is primarily due to increased proteolysis. Although MV-induced protease activation can involve several factors, it is clear that oxidative stress is a required signal for protease activation in the diaphragm during prolonged MV. However, the oxidant-producing pathways in the diaphragm that contribute to MV-induced oxidative stress remain unknown. We have demonstrated that prolonged MV results in increased diaphragmatic expression of a key stress-sensitive enzyme, heme oxygenase (HO)-1. Paradoxically, HO-1 can function as either a pro-oxidant or an antioxidant, and the role that HO-1 plays in MV-induced diaphragmatic oxidative stress is unknown. We tested the hypothesis that HO-1 acts as a pro-oxidant in the diaphragm during prolonged MV.

Methods:  To determine whether HO-1 functions as a pro-oxidant or an antioxidant in the diaphragm during MV, we assigned rats into three experimental groups: (1) a control group, (2) a group that received 18 h of MV and saline solution, and (3) a group that received 18 h of MV and was treated with a selective HO-1 inhibitor. Indices of oxidative stress, protease activation, and fiber atrophy were measured in the diaphragm.

Results:  Inhibition of HO-1 activity did not prevent or exacerbate MV-induced diaphragmatic oxidative stress (as indicated by biomarkers of oxidative damage). Further, inhibition of HO-1 activity did not influence MV-induced protease activation or myofiber atrophy in the diaphragm.

Conclusions:  Our results indicate that HO-1 is neither a pro-oxidant nor an antioxidant in the diaphragm during MV. Furthermore, our findings reveal that HO-1 does not play an important role in MV-induced protease activation and diaphragmatic atrophy.

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