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-κB and AP-1 transcription factors. Incubation of lung parenchyma with methacholine increased the activation of NF-κB, which was further augmented by stretch. Activation of NF-κB in response to mechanical stretch was associated with the phosphorylation and degradation of IκBα and the activation of IκB kinase. Stretch-induced activation of NF-κB 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-κB and AP-1 activation. A greater level of NF-κB and ERK1/2 activity was observed in the asthmatic mice, which was further increased by mechanical stretching. The level of cyclooxygenase-2, an NF-κB-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-κB and AP-1, at least in part, through the activation of MAP kinase signaling pathways.