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Chronic LPS Inhalation Causes Emphysema-Like Changes in Mouse Lung that Are Associated with Apoptosis

¹ Environmental Lung Diseases Research Group, Laboratory of Respiratory Biology, National Heart Lung and Blood Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; and ² Division of Pulmonary, Allergy, and Critical Care Medicine, and ³ Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina

Correspondence and requests for reprints should be addressed to David M. Brass, PhD, Duke University Medical Center, Department of Pediatrics, Neonatal Perinatal Research Institute, 403 Alex R. Sands Laboratory Bldg., DUMC Box 3373, Durham, NC 27710. E-mail: david.brass{at}duke.edu

Lipopolysaccharide (LPS) is ubiquitous in the environment. Recent epidemiologic data suggest that occupational exposure to inhaled LPS can contribute to the progression of chronic obstructive pulmonary disease. To address the hypothesis that inhaled LPS can cause emphysema-like changes in mouse pulmonary parenchyma, we exposed C57BL/6 mice to aerosolized LPS daily for 4 weeks. By 3 days after the end of the 4-week exposure, LPS-exposed mice developed enlarged airspaces that persisted in the 4-week recovered mice. These architectural alterations in the lung are associated with enhanced type I, III, and IV procollagen mRNA as well as elevated levels of matrix metalloproteinase (MMP)-9 mRNA, all of which have been previously associated with human emphysema. Interestingly, MMP-9–deficient mice were not protected from the development of LPS-induced emphysema. However, we demonstrate that LPS-induced airspace enlargement was associated with apoptosis within the lung parenchyma, as shown by prominent TUNEL staining and elevated cleaved caspase 3 immunoreactivity. Antineutrophil antiserum-treated mice were partially protected from the lung destruction caused by chronic inhalation of LPS. Taken together, these findings demonstrate that inhaled LPS can cause neutrophil-dependent emphysematous changes in lung architecture that are associated with apoptosis and that these changes may be occurring through mechanisms different than those induced by cigarette smoke.

CLINICAL RELEVANCE These findings provide further experimental support for the observation that not all chronic obstructive pulmonary disease is induced by cigarette smoke and that other environmental exposures are likely important in the etiology of this disease.

 

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