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Published ahead of print on February 25, 2005, doi:10.1164/rccm.200407-887OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 10, May 2005, 1116-1124

A more recent version of this article appeared on May 15, 2005
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Submitted on July 9, 2004
Accepted on February 15, 2005

Oxidative Stress and Respiratory Muscle Dysfunction in Severe Chronic Obstructive Pulmonary Disease

Esther Barreiro1*, Beatriz de la Puente1, Joan Minguella1, Josep M Corominas1, Sergi Serrano1, Sabah NA Hussain2, and Joaquim Gea1

1 Departments of Respiratory Medicine, Surgery and Pathology, Muscle Research and Respiratory System Unit, Universitat Pompeu Fabra and Universitat Autonoma, IMIM-Hospital del Mar, Barcelona, Spain, 2 Critical Care and Respiratory Divisions, McGill University, Royal Victoria Hospital and Meakins-Christie Laboratories, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: ebarreiro{at}imim.es.

Rationale: Oxidative stress is involved in the skeletal muscle dysfunction observed in patients with severe chronic obstructive pulmonary disease. We hypothesized that the diaphragms of such patients might generate greater levels of oxidants than those neutralized by antioxidants. Objectives: To assess the levels of both oxidative and nitrosative stress and different antioxidants in the diaphragms of those patients, and to analyze potential relationships with lung and respiratory muscle dysfunctions. Methods and Measurements: We conducted a case-control study in which reactive carbonyl groups, hydroxynonenal-protein adducts, antioxidant enzyme levels, nitric oxide synthases, and 3-nitrotyrosine formation were detected using immunoblotting and immunhistochemistry in diaphragm specimens (thoracotomy) obtained from six severe and six moderate chronic obstructive pulmonary disease patients, and seven control subjects. Main Results: Diaphragms of severe chronic obstructive pulmonary disease patients showed both higher protein carbonyl groups and hydroxynonenal-protein adducts than controls. When only considering chronic obstructive pulmonary disease patients, negative correlations were found between carbonyl groups and airway obstruction, and between hydroxynonenal-protein adducts and respiratory muscle strength. While diaphragmatic neuronal nitric oxide synthase did not differ among the three groups and no inducible nitric oxide synthase was detected in any muscle, muscle endothelial nitric oxide synthase was lower in severe chronic obstructive pulmonary disease patients than in controls. Muscle nitrotyrosine levels were similar in both severe patients and controls. Conclusions: This study shows that oxidative stress rather than nitric oxide is likely to be involved in the respiratory muscle dysfunction in severe chronic obstructive pulmonary disease.
Key words: COPD, diaphragm strength, oxidative stress




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