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Published ahead of print on June 19, 2003, doi:10.1164/rccm.200208-964OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1051-1059, (2003)
© 2003 American Thoracic Society

Early Changes in Lung Gene Expression due to High Tidal Volume

Ian B. Copland, Brian P. Kavanagh, Doreen Engelberts, Colin McKerlie, Jaques Belik and Martin Post

Program in Lung Biology and Department of Critical Care Medicine, The Hospital for Sick Children, and Departments of Laboratory Medicine and Pathobiology, and Pediatrics, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Martin Post, Ph.D., Lung Biology Program, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. E-mail: martin.post{at}sickkids.ca

The purpose of this study was to use gene expression profiling to understand how adult rat lung responds to high tidal volume (HV) ventilation in vivo. HV ventilation for 30 minutes did not cause discernable lung injury (in terms of altered mechanics or histology) but caused obvious injury when continued for 90 minutes. However, at 30-minute ventilation, HV caused significant upregulation of 10 genes and suppression of 12 genes. Among the upregulated genes were transcription factors, stress proteins, and inflammatory mediators; the downregulated genes were exemplified by metabolic regulatory genes. On the basis of cluster analysis, we studied Egr-1, c-Jun, heat shock protein 70, and interleukin (IL)-1ß in further detail. Temporal studies demonstrated that Egr-1 and c-Jun were increased early and before heat shock protein 70 and IL-1ß. Spatial studies using in situ hybridization and laser capture microscopy revealed that all four genes were upregulated primarily in the bronchiolar airway epithelium. Furthermore, at 90 minutes of HV ventilation, a significant increase in intracellular IL-1ß protein was observed. Although there are limitations to gene array methodology, the current data suggest a global hypothesis that (1) the effects of HV are cumulative; (2) specific patterns of gene activation and suppression precede lung injury; and (3) alteration of gene expression after mechanical stretch is pathogenic.

Key Words: ventilation • gene expression profiling




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