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Stretch-Induced Mitogen-Activated Protein Kinase Activation and Interleukin-8 Production in Type II Alveolar Cells^*

^* From the Pulmonary/Critical Care, Renal, and Cardiology Units, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Correspondence to: D. Quinn, MD, Pulmonary/Critical Care, Renal, and Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

The treatment of ARDS requires the use of positive pressure mechanical ventilation with high levels of inspired oxygen to provide adequate oxygenation to vital organs. Since ARDS is an inhomogenous disease, some areas are less affected and therefore more compliant. These areas may be mechanically overdistended by ventilator breaths. This ventilator-induced lung injury in animal models is characterized by noncardiogenic pulmonary edema, release of inflammatory cytokines, and subsequent influx of neutrophils that may worsen lung injury. Interleukin-8 (IL-8) is an inflammatory cytokine and chemoattractant for neutrophils in the lung. The mitogen-activated protein (MAP) kinases, including stress-activated protein kinase (SAPK), p38, and extracellular signal-regulated kinase (ERK)1/2, regulate cellular response to extracellular stimuli, such as oxidant stress, heat shock, growth factors, and radiation. We hypothesized that lung cell stretch induces IL-8 production, which is dependent on activation of the stress-responsive MAP kinases, SAPK, and/or p38. To examine the effects of stretch at the cellular level, we used a cell stretch device that applies uniform biaxial strain to flexible cell culture membranes. A549 cells, a type II alveolar cell line, were grown on fibronectin-coated silicone elastomeric membranes. Cells were exposed to cell stretch at 5% and 15% strain at 12 cycles per minute for 30 min and 2 h. Kinase activity was determined in immune complex kinase assays. IL-8 was determined in cell supernatants by enzyme-linked immunosorbent assay. Total messenger RNA (mRNA) was extracted and probed for IL-8 mRNA. Five percent strain induced release of IL-8, but 15% strain did more (196 ± 42 pg/mL vs 279 ± 49 vs 381 ± 73, p < 0.05). Levels of IL-8 mRNA were increased after both 5% and 15% strain for 2 h. SAPK activity was increased after 15% strain at 30 min (168%) and at 2 h (237%), and after 5% strain at 2 h (137%). In contrast, p38 was only increased after 15% strain at 2 h (468%). ERK1/2 was not activated by cell stretch. We conclude that cell stretch induces IL-8 production in A549 cells, by increasing transcription of IL-8 mRNA. This increase in IL-8 production is accompanied by an activation of SAPK and p38 activity. Cell stretch-induced IL-8 production and MAP kinase activation may be important in ventilator-induced lung injury.

Footnotes

Supported by grants HL09572, DK50282, and HL39150.

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