Published ahead of print on August 26, 2005, doi:10.1164/rccm.200503-403OC Am. J. Respir. Crit. Care Med., Volume 172, Number 10, November 2005, 1267-1275 A more recent version of this article appeared on November 15, 2005
Submitted on March 14, 2005 Diaphragm Unloading via Controlled Mechanical Ventilation Alters the Gene Expression ProfileKeith C DeRuisseau1*,1 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA, 2 Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, USA, 3 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Faculty of Medicine, Sports Medicine Department, Ankara University, Ankara, Turkey * To whom correspondence should be addressed. E-mail: keithd{at}hhp.ufl.edu.
Rationale: Prolonged controlled mechanical ventilation results in diaphragmatic inactivity and promotes oxidative injury, atrophy, and contractile dysfunction in this important inspiratory muscle. However, the impact of controlled mechanical ventilation on global mRNA alterations in the diaphragm remains unknown. Objectives: In these experiments we used an Affymetrix oligonucleotide array to identify the temporal changes in diaphragmatic gene expression during controlled mechanical ventilation in the rat. Methods: Adult Sprague-Dawley rats were assigned to either control or mechanical ventilation groups (n=5/group). Mechanically ventilated animals were anesthetized, tracheostomized, and ventilated with room air for 6 or 18 hours. Animals in the control group were acutely anesthetized but not exposed to mechanical ventilation. Measurements and Main Results: Compared to control diaphragms, microarray analysis identified 354 differentially expressed, unique gene products following 6 and 18 hours of mechanical ventilation. In general, genes in the cell growth/cell maintenance, stress response, and nucleic acid metabolism categories showed predominant upregulation whereas genes in the structural protein and energy metabolism categories were predominantly downregulated. Conclusions: We conclude that mechanical ventilation results in rapid changes in diaphragmatic gene expression and, subsequently, many of these changes may contribute to atrophy and muscle fiber remodeling associated with unloading this primary inspiratory muscle. Importantly, this study also provides new insights into why the diaphragm, following the onset of contractile inactivity, atrophies more rapidly than locomotor skeletal muscles and also highlights unique differences that exist between these muscles in the mRNA response to inactivity. Key words: respiratory muscle, muscle atrophy, weaning from mechanical ventilation, gene expression, microarray
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