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Int J Physiol Pathophysiol Pharmacol 2011;3(3):167-175.

Original Article
Gene expression profile in the diaphragm following contractile inactivity during
thoracic surgery

Willem N Welvaart, Marinus A Paul, Diederik WD Kuster, Wessel N van Wieringen, Francois Rustenburg, Ger JM Stienen, Anton
Vonk-Noordegraaf, Coen AC Ottenheijm

Departments of Surgery, Physiology, Epidemiology and Biostatistics, Pathology,  Pulmonology, VU University Medical Center/ Institute
for Cardiovascular Research, Dept of Surgery, Rivierenland hospital, The Netherlands.

Received July 3, 2011; accepted August 29, 2011; Epub September 7, 2011; Published September 30, 2011

Abstract: Introduction: Recent work revealed the development of marked muscle fiber weakness in the diaphragm, but not in the
non-respiratory latissimus dorsi, during thoracic surgery. To disentangle the molecular processes that underlie the development of
diaphragm muscle fiber weakness during thoracic surgery, we studied changes in the gene expression profile. Methods: Serial
biopsies from the diaphragm and the latissimus dorsi muscle were obtained from four patients during thoracotomy for resection of a
tumor in the right lung. Biopsies were taken as soon as the diaphragm had been exposed (t0) and again after two hours (t2). Gobal
differences in gene expression in diaphragm biopsies were assessed by microarray analysis. Results: 346 differentially expressed
gene transcripts were found in the diaphragm at t2 vs. t0. Pathway analysis revealed that genes associated with inflammation (83
genes; p<0.0001) and cell death (118 genes, p<0.0001) pathways were significantly overexpressed at t2. Of the 346 differentially
expressed genes in the diaphragm at t2, 258 were also differential in the latissimus dorsi muscle, with the direction of change being
identical for all differentially expressed genes. In addition, latissimus dorsi showed exclusive upregulaton of negative regulators of cell
death. Conclusion: Two hours of thoracic surgery result in rapid and profound changes in expression of inflammatory response and
apoptotic genes in the diaphragm. The apoptotic response was stronger in the diaphragm than in the latissiums dorsi. These findings
suggest that the development of selective diaphragm muscle fiber weakness in these patients might be related to an exaggerated
apoptotic response. (IJPPP1107001).

Keywords: thoracic surgery, mechanical ventilation, diaphragm, gene expression

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Address all correspondence to:
Coen Ottenheijm, PhD
VU University Medical Center
Department of Physiology
Van der Boechorststraat 7
1081 BT  Amsterdam        
The Netherlands
tel.: +31 20 44 48123
fax: +31 20 44 48255