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Early changes in lung gene expression due to high tidal volume
Ian B Copland1, Brian P Kavanagh, Doreen Engelberts
1Department of Critical Care, The Hospital for Sick Children, University of Toronto, Ontario, Canada.
Summary
High tidal volume (HV) ventilation in rats triggers early gene expression changes in lung airways, preceding observable injury. These molecular responses suggest mechanical stretch is pathogenic and effects are cumulative.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Genomics
Background:
- Mechanical ventilation is critical in critical care but can induce lung injury.
- Understanding the molecular mechanisms of ventilator-induced lung injury (VILI) is crucial for developing protective strategies.
Purpose of the Study:
- To investigate the early gene expression profile of adult rat lungs subjected to high tidal volume (HV) ventilation.
- To identify specific genes and pathways involved in the lung's response to mechanical stretch.
Main Methods:
- Gene expression profiling using microarrays in adult rats ventilated with HV.
- Temporal and spatial analysis of key genes (Egr-1, c-Jun, HSP70, IL-1beta) using in situ hybridization and laser capture microscopy.
- Assessment of lung mechanics and histology at different ventilation durations.
Main Results:
- HV ventilation for 30 minutes induced significant upregulation of 10 genes and downregulation of 12 genes, without causing mechanical or histological injury.
- Upregulated genes included transcription factors, stress proteins, and inflammatory mediators; downregulated genes were involved in metabolic regulation.
- Early increases in Egr-1 and c-Jun preceded increases in heat shock protein 70 and interleukin (IL)-1beta, primarily within the bronchiolar epithelium.
- Prolonged HV ventilation (90 minutes) led to observable lung injury and increased intracellular IL-1beta protein.
Conclusions:
- The effects of high tidal volume ventilation are cumulative.
- Distinct patterns of gene activation and suppression occur before the onset of lung injury.
- Alterations in gene expression following mechanical stretch contribute to the pathogenesis of ventilator-induced lung injury.