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Molecular mechanisms of nitrogen dioxide induced epithelial injury in the lung

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Abstract

The lung can be exposed to a variety of reactive nitrogen intermediates through the inhalation of environmental oxidants and those produced during inflammation. Reactive nitrogen species (RNS) include, nitrogen dioxide (·NO2) and peroxynitrite (ONOO–). Classically known as a major component of both indoor and outdoor air pollution, ·NO2 is a toxic free radical gas. ·NO2 can also be formed during inflammation by the decomposition of ONOO– or through peroxidase-catalyzed reactions. Due to their reactive nature, RNS may play an important role in disease pathology. Depending on the dose and the duration of administration, ·NO2 has been documented to cause pulmonary injury in both animal and human studies. Injury to the lung epithelial cells following exposure to ·NO2 is characterized by airway denudation followed by compensatory proliferation. The persistent injury and repair process may contribute to airway remodeling, including the development of fibrosis. To better understand the signaling pathways involved in epithelial cell death by ·NO2 or other RNS, we routinely expose cells in culture to continuous gas-phase ·NO2. Studies using the ·NO2 exposure system revealed that lung epithelial cell death occurs in a density dependent manner. In wound healing experiments, ·NO2 induced cell death is limited to cells localized in the leading edge of the wound. Importantly, ·NO2-induced death does not appear to be dependent on oxidative stress per se. Potential cell signaling mechanisms will be discussed, which include the mitogen activated protein kinase, c-Jun N-terminal Kinase and the Fas/Fas ligand pathways. During periods of epithelial loss and regeneration that occur in diseases such as asthma or during lung development, epithelial cells in the lung may be uniquely susceptible to death. Understanding the molecular mechanisms of epithelial cell death associated with the exposure to ·NO2 will be important in designing therapeutics aimed at protecting the lung from persistent injury and repair.

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  1. Department of Environmental Health, School of Public Health and Community Medicine, University of Washington, Seattle, WA, USA

    Rebecca L. Persinger

  2. Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA

    Matthew E. Poynter, Karina Ckless & Yvonne M.W. Janssen-Heininger

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  1. Rebecca L. Persinger
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Persinger, R.L., Poynter, M.E., Ckless, K. et al. Molecular mechanisms of nitrogen dioxide induced epithelial injury in the lung. Mol Cell Biochem 234, 71–80 (2002). https://doi.org/10.1023/A:1015973530559

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