Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase.
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.
Li
Li-Fu
LF
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Yu
Lunyin
L
Quinn
Deborah A
DA
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002452:Cell Count; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000473:pathology*; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases
D000873:Anthracenes; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D012333:RNA, Messenger; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; C482625:MAP3K3 protein, human; C482626:Map3k3 protein, mouse