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, LPS, and cyclic stretch
1 Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
2 Critical Care, St. Michael’s Hospital, Toronto, Ontario, Canada
3 Research Center Borstel, Division of Pulmonary Pharmacology, Borstel, Germany
4 Thoracic Diseases Research Unit, Mayo Clinic, Rochester, Minnesota
5 Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
6 Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Recent evidence suggests that alveolar epithelial cells (AECs) may contribute to the development, propagation, and resolution of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Proinflammatory cytokines, pathogen products, and injurious mechanical ventilation are important contributors of excessive inflammatory responses in the lung. In the present study, we used cDNA microarrays to define the gene expression patterns of A549 cells (an AEC line) in the early stages of three models of pulmonary parenchymal cell activation: cells treated with tumor necrosis factor-
(TNF) (20 ng/ml), lipopolysaccharide (LPS, 1 µg/ml), or cyclic stretch (20% elongation) for either 1 h or 4 h. Differential gene expression profiles were determined by gene array analysis. TNF induced an inflammatory response pattern, including induction of genes for chemokines, inflammatory mediators, and cell surface membrane proteins. TNF also increased genes related to pro- and anti-apoptotic proteins, signal transduction proteins, and transcriptional factors. TNF further induced a group of genes that may form a negative feedback loop to silence the NF
B pathway. Stimulation of AECs with mechanical stretch changed cell morphology and activated Src protein tyrosine kinase. The combination of TNF plus stretch enhanced or attenuated expression of multiple genes. LPS decreased microfilament polymerization but had less impact on NFB translocation and gene expression. Results from this study indicate that AECs can tailor their response to different stimuli or/and combination of stimuli and subsequently play an important role in acute inflammatory responses in the lung.
acute respiratory distress syndrome; acute lung injury; ventilator-induced lung injury; mechanotransduction; significant analysis of microarray
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