Mechanical stretch activates nuclear factor-kappaB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma.
We investigated the effects of mechanical stretch and induced stimulation of lung parenchyma on the activation of proinflammatory transcription factors in normal mice and in a mouse model of asthma. Mechanical stretching of lung parenchyma led to increased activation of NF-kappaB and AP-1 transcription factors. Incubation of lung parenchyma with methacholine increased the activation of NF-kappaB, which was further augmented by stretch. Activation of NF-kappaB in response to mechanical stretch was associated with the phosphorylation and degradation of IkappaBalpha and the activation of IkappaB kinase. Stretch-induced activation of NF-kappaB involves activation of stretch-activated (SA) channels and the production of free radicals. Mechanical stretch and/or treatment with methacholine resulted in an increased activation of ERK1/2 and p38 MAP kinase, and the inhibition of the activity of these kinases partially blocked the stretch-induced NF-kappaB and AP-1 activation. A greater level of NF-kappaB and ERK1/2 activity was observed in the asthmatic mice, which was further increased by mechanical stretching. The level of cyclooxygenase-2, an NF-kappaB-regulated enzyme, was also higher in lung parenchyma from asthmatic mice than in normal mice. Our data suggest that mechanical stretching of lung parenchyma activates NF-kappaB and AP-1, at least in part, through the activation of MAP kinase signaling pathways.
D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000378:metabolism*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D046508:Culture Techniques; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D005609:Free Radicals / Q000378:metabolism; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D046911:Macromolecular Substances; D026901:Membrane Transport Proteins / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013314:Stress, Mechanical; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D016085:Bronchoconstrictor Agents; D005609:Free Radicals; D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D018808:Transcription Factor AP-1; D016210:Methacholine Chloride; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases