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J Appl Physiol 99: 1226-1232, 2005. First published May 12, 2005; doi:10.1152/japplphysiol.01105.2004
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HIGHLIGHTED TOPICS
Biomechanics and Mechanotransduction in Cells and Tissues

Reactive oxidant and p42/44 MAP kinase signaling is necessary for mechanical strain-induced proliferation in pulmonary epithelial cells

Patricia R. Chess,1,2 Michael A. O'Reilly,1,3 Fredrick Sachs,4 and Jacob N. Finkelstein1,3

Departments of 1Pediatrics, 2Biomedical Engineering, and 3Environmental Medicine, University of Rochester, Rochester, New York; and 4Department of Physiology and Biophysics, State University of New York Buffalo, Buffalo, New York

Submitted 1 October 2004 ; accepted in final form 5 May 2005

Mechanical strain is necessary for normal lung growth and development. Individuals with respiratory failure are supported with mechanical ventilation, leading to altered lung growth and injury. Understanding signaling pathways initiated by mechanical strain in lung epithelial cells will help guide development of strategies aimed at optimizing strain-induced lung growth while mitigating ventilator-induced lung injury. To study strain-induced proliferative signaling, focusing on the role of reactive oxidant species (ROS) and p42/44 mitogen-activated protein (MAP) kinase, human pulmonary epithelial H441 and MLE15 cells were exposed to equibiaxial cyclic mechanical strain. ROS were increased within 15 min of strain. N-acetylcysteine inactivated strain-induced ROS and inhibited p42/44 MAP kinase phosphorylation and strain-induced proliferation. PD98059 and UO126, p42/44 MAP kinase inhibitors, blocked strain-induced proliferation. To verify the specificity of p42/44 MAP kinase inhibition, cells were transfected with dominant-negative mitogen-activated protein kinase kinase-1 plasmid DNA. Transfected cells did not proliferate in response to mechanical strain. To determine whether strain-induced tyrosine kinase activity is necessary for strain-induced ROS-p42/44 MAP kinase signaling, genistein, a tyrosine kinase inhibitor, was used. Genistein did not block strain-induced ROS production or p42/44 MAP kinase phosphorylation. Gadolinium, a mechanosensitive calcium channel blocker, blocked strain-induced ROS production and p42/44 MAP kinase phosphorylation but not strain-induced tyrosine phosphorylation. These data support ROS production and p42/44 MAP kinase phosphorylation being involved in a common strain-induced signaling pathway, necessary for strain-induced proliferation in pulmonary epithelial cells, with a parallel strain-induced tyrosine kinase pathway.

pulmonary epithelium; reactive oxygen species


Address for reprint requests and other correspondence: P. R. Chess, Box 850, 601 Elmwood Ave., Rochester, New York 14642 (e-mail: patricia_chess{at}urmc.rochester.edu)




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