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

Department of Pediatrics, University of Rochester, New York, USA.
Journal of Applied Physiology (Impact Factor: 3.06). 10/2005; 99(3):1226-32. DOI: 10.1152/japplphysiol.01105.2004
Source: PubMed


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.

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    • "In cells representative of those in the mature lung, stretch has been shown to exert potent effects on growth, structure, homeostasis and differentiated function. Cyclic stretch drives the production of reactive oxygen species (ROS) in distal lung epithelial cells (Chapman et al. 2005) necessary for stretch-induced cellular proliferation (Chess et al. 2005). The growth regulation of epithelial cells by stretch also requires contributions from Src, FAK, and ERK, emphasizing the complex interplay of regulatory signals governing cellular proliferation in response to mechanical stimulation (Chaturvedi et al. 2007). "
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    ABSTRACT: Lung function is inextricably linked to mechanics. On short timescales every breath generates dynamic cycles of cell and matrix stretch, along with convection of fluids in the airways and vasculature. Perturbations such airway smooth muscle shortening or surfactant dysfunction rapidly alter respiratory mechanics, with profound influence on lung function. On longer timescales, lung development, maturation, and remodeling all strongly depend on cues from the mechanical environment. Thus mechanics has long played a central role in our developing understanding of lung biology and respiratory physiology. This concise review focuses on progress over the past 5 years in elucidating the molecular origins of lung mechanical behavior, and the cellular signaling events triggered by mechanical perturbations that contribute to lung development, homeostasis, and injury. Special emphasis is placed on the tools and approaches opening new avenues for investigation of lung behavior at integrative cellular and molecular scales. We conclude with a brief summary of selected opportunities and challenges that lie ahead for the lung mechanobiology research community.
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    • "This can not only induce lipid peroxidation and DNA damage (Casalino et al., 1997; El-Maraghy et al., 2001; Fotakis et al., 2005; Palus et al., 2003), and increase the mutation rate, but also act as signaling molecules (Carmody and Cotter, 2001), resulting in the initiation and promotion of tumor growth (Achanzar et al., 2000; Joseph et al., 2001; Wang and Templeton, 1998). N-Acetylcysteine (NAC) is an antioxidant with ROS scavenging ability, and has been shown to be effective for suppressing cell proliferation by many carcinogens (Arora-Kuruganti et al., 1999; Chess et al., 2005; Velarde et al., 2004; Wei et al., 2005). DNA methylation is a naturally occurring modification of DNA that involves an addition of a methyl group to the 5-position carbon of the cytosine ring to form 5-methylcytosine (5-MeC). "
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