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Published ahead of print on June 19, 2003, doi:10.1164/rccm.200208-964OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 9, November 2003, 1051-1059

A more recent version of this article appeared on November 1, 2003
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Submitted on September 4, 2002
Accepted on June 12, 2003

Early Changes in Lung Gene Expression due to High Tidal Volume

Ian B Copland1, Brian P Kavanagh2, Doreen Engelberts3, Colin McKerlie1, Jaques Belik4, and Martin Post5*

1 Program in Lung Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, 2 Program in Lung Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Critical Care Medicine, Hospital for Sick Children, Toronto, Ontario, Canada, 3 Program in Lung Biology, Hospital for Sick Children, Toronto, Ontario, Canada, 4 Program in Lung Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Pediatrics, University of Toronto, Toronto, Ontario, Canada, 5 Program in Lung Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Pediatrics, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: martin.post{at}sickkids.ca.

The purpose of this study was to utilize gene-expression profiling to understand how adult rat lung responds to high tidal volume (HV) ventilation in vivo. HV ventilation for 30 min did not cause discernable lung injury (in terms of altered mechanics or histology), but caused obvious injury when continued for 90 min. However at 30 min, HV caused significant up-regulation of 10 genes, and suppression of 12 genes. Among the up-regulated genes were transcription factors, stress proteins and inflammatory mediators; the down-regulated genes were exemplified by metabolic regulatory genes. Based on cluster analysis we studied Egr-1, c-Jun, HSP70 and IL-1{beta} in further detail. Temporal studies demonstrated that Egr-1 and c-Jun were increased early, and prior to HSP70 and IL-1{beta}. Spatial studies using in situ hybridization and laser capture microscopy revealed that all four genes were up-regulated primarily in the bronchiolar airway epithelium. Furthermore, at 90 min of HV ventilation a significant increase in intracellular IL-1{beta} protein was observed. Although there are significant 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 following mechanical stretch is pathogenic.
Key words: Intermittent positive-pressure ventilation gene expression profiling




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