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.—Kumar, A., Lnu, S., Malya, R., Barron, D., Moore, J., Corry, D. B., Boriek, A. M. Mechanical stretch activates nuclear factor‐kappaB, activator protein‐1, and mitogen‐activated protein kinases in lung parenchyma: implications in asthma. FASEB J. 17, 1800–1811 (2003)