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DIESEL EXHAUST PARTICLES INDUCE ABERRANT ALVEOLAR EPITHELIAL DIRECTED CELL MOVEMENT BY DISRUPTION OF POLARITY MECHANISMS
LaGier, A. J., N. D. Manzo, AND J. A. DYE. DIESEL EXHAUST PARTICLES INDUCE ABERRANT ALVEOLAR EPITHELIAL DIRECTED CELL MOVEMENT BY DISRUPTION OF POLARITY MECHANISMS. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. Taylor & Francis, Inc., Philadelphia, PA, 76(2):71-85, (2013).
Disruption of the respiratory epithelium contributes to the progression of a variety of respiratory diseases that are aggravated by exposure to air pollutants, specifically traffic-based pollutants such as diesel exhaust particles (DEP). Recognizing that lung repair following injury requires efficient and directed alveolar epithelial cell migration, the goal for this study was to understand how alveolar epithelial cells respond to DEP, in particular when exposure is accompanied with comorbid lung insult or injury. Separate mechanistic steps of directed migration were investigated in confluent murine LA-4 cells exposed to increasing concentrations (0-25 ug/cm2) of particles, either automobile-emitted diesel exhaust particles (DEPA) or carbon black (CB) particles. BCECF ratio fluorimetry was used to monitor intracellular pH (pHi) and a scratch wound model was used to ascertain how DEP exposure affected directional cell migration. Cells were immunostained with giantin to assess cell polarity and paxillin to assess focal cell adhesions. In addition, cells were immunoblotted for ezrin/radixin/moesin (ERM) levels to assess cytoskeletal anchoring. We demonstrate herein that at non-cytotoxic concentrations, exposure of LA-4 cells to DEPA (but not CB) resulted in disrupted regulation of pHi, delayed directional cell migration, altered Golgi polarity of leading edge cells, modified focal adhesions, impaired de-adhesion of the trailing edge cell processes, decreased cytoskeletal anchoring, and reduced levels of ERM. The ability of DEP to disrupt directed cell migration at multiple levels suggests that signaling pathways such as ERM/Rho are critical for transduction of ion transport signals into cytoskeletal arrangement responses. As part of a larger effort to develop whole cell-based biosensors to predict pollutant-induced effects on lung growth and repair, these results provide insights into the mechanisms by which chronic exposure to traffic-based emissions may result in decrements in lung capacity.
This manuscript shows that, in addition to identifying mechanisms by which DEP exposure may induce direct epithelial cell injury, we further show that at lesser concentrations, DEP exposure may interfere with cellular events essential for lung epithelial repair -effects that together, likely contribute to pathologic lung or airway remodeling. By extension, we hypothesize that in susceptible individuals, repeated exposure to traffic-based emissions sets up a continuous cycle of"lung injury with dysregulated epithelial repair" that in turn to increases epithelial susceptibility to additional environmental insults (e.g., other gaseous air pollutants, infectious agents, or allergens). Collectively, our data provide biologic plausibility for the epidemiologic reports associating chronic exposure to traffic-based emissions with long-standing decrements in lung capacity.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
ENVIRONMENTAL PUBLIC HEALTH DIVISION
CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH