Early changes in lung gene expression due to high tidal volume.
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)-1beta in further detail. Temporal studies demonstrated that Egr-1 and c-Jun were increased early and before heat shock protein 70 and IL-1beta. 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-1beta 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.
Copland
Ian B
IB
Department of Critical Care, The Hospital for Sick Children, University of Toronto, Ontario, Canada.
Kavanagh
Brian P
BP
Engelberts
Doreen
D
McKerlie
Colin
C
Belik
Jaques
J
Post
Martin
M
D000818:Animals; D015152:Blotting, Northern; D040502:Calgranulin B / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D017874:Immediate-Early Proteins; D007375:Interleukin-1 / Q000235:genetics; D008168:Lung / Q000503:physiopathology*; D055370:Lung Injury; D008297:Male; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial; D013990:Tidal Volume / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
D040502:Calgranulin B; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D018840:HSP70 Heat-Shock Proteins; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors