Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 169, Issue 4, Pages 518-524Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200305-660OC
Keywords
chemokine; mitogen-activated protein kinase; lung stretch
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Funding
- NHLBI NIH HHS [HL67371, HL039020, HL61688] Funding Source: Medline
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Positive pressure ventilation with large VTS has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human interleukin-8. The mechanisms regulating ventilation-induced cytokine production are unclear. Based on our previous in vitro model of lung cell stretch, we hypothesized that high VT ventilation-induced MIP-2 production is dependent on the activation of the c-Jun N-terminal kinase (JNK). We exposed C57BL/6 mice to high VT (30 ml/kg) or low VT (6 ml/kg) mechanical ventilation for 5 hours. High VT ventilation-induced neutrophil migration into the lung, MIP-2 protein production, MIP-2 messenger RNA expression, and JNK activation. Large VT ventilation of JNK knockout mice and pharmacologic JNK inhibition with SP600125 attenuated neutrophil sequestration and blocked MIP-2 messenger RNA expression and MIP-2 production. We conclude that lung cell stretch in vivo results in increased lung neutrophil sequestration and increased MIP-2 production, which was, at least in part, dependent upon the JNK pathway.
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