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1 Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States; Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
2 Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
3 Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
4 Pathology, Johns Hopkins University, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: bsimon{at}jhmi.edu.
Human acute lung injury is characterized by heterogeneous tissue involvement, leading to the potential for extremes of mechanical stress and tissue injury when mechanical ventilation, required to support critically ill patients, is employed. Our goal was to establish whether regional cellular responses to these disparate local mechanical conditions could be determined as a novel approach towards understanding the mechanism of development of ventilator-associated lung injury. We utilized cross-species genomic microarrays in a unilateral model of ventilator-associated lung injury in anesthetized dogs to assess regional cellular responses to local mechanical conditions which potentially contribute pathogenic mechanisms of injury. Highly significant regional differences in gene expression were observed between lung apex/base regions as well as between gravitationally dependent/non-dependent regions of the base, with 367 and 1544 genes differentially regulated between these regions, respectively. Major functional groupings of differentially regulated genes included inflammation and immune responses, cell proliferation, adhesion, and signaling, and apoptosis. Expression of genes encoding both acute lung injury-associated inflammatory cytokines and protective acute response genes were markedly different in the non-dependent compared to the dependent regions of the lung base. We conclude that there are significant differences in the local responses to stress within the lung, and consequently insights into the cellular responses that contribute to ventilator-associated lung injury development must be sought in the context of the mechanical heterogeneity that characterizes this syndrome.
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