Early Changes in Lung Gene Expression due to High Tidal Volume

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Abstract
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 media- tors; the downregulated genes were exemplified by metabolic regu- latory genes. On the basis of cluster analysis, we studied Egr-1, c-Jun, heat shock protein 70, and interleukin (IL)-1 in further detail. Temporal studies demonstrated that Egr-1 and c-Jun were increased early and before heat shock protein 70 and IL-1. 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-1 protein was observed. Although there are limitations to gene array methodology, the cur- rent 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 me- Our knowledge about the role played by specific mediators in the pathogenesis of stretch-induced lung injury is rapidly ex- panding but is not comprehensive (1-4). The precise role of individual mediators is confounded by the use of ex vivo models that induce extreme degrees of injury or that involve pretreat- ment with either bacterial products or saline lavage. In addition, the exploration of specific mediators has been driven by the a priori knowledge of currently identified cytokines as well as by the availability of validated assays. Thus, several issues are unresolved. First, there is fundamental disagreement in terms of which mediators are released (1-4). Second, although stretch is clearly associated with release of several mediators, the tempo- ral relationship (a requirement for inferring cause and effect) of these mediators has not been clearly defined. Third, current data are based on subjective expectations and availability of specific assays. Finally, although studies have focused on estab- lished or evolving injury, no studies to date have reported on the gene activation induced by mechanical stretch that occurs in the absence of physiologic or structural impairment. Therefore, in