Chronic Endotoxin Exposure Produces Airflow Obstruction and Lung Dendritic Cell Expansion

Abstract

Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.Keywords: airway resistance; inhalation; neutrophils; macrophages; dendritic cells; endotoxin Endotoxin (lipopolysaccharide, or LPS) is a cell-wall component of Gram-negative bacteria, and is ubiquitous in the environment. Occupational settings in which the ambient concentration of endotoxin is markedly increased include swine farms, sewage treatment plants, humidified buildings, and the processing of organic materials (in particular, cotton), where exposure levels can exceed 5,900 EU/m 3 (1). Endotoxin is also an important component of indoor air pollution in homes burning biomass fuel (2).Human studies have demonstrated a relationship between occupational endotoxin exposure and the development of airflow obstruction, and suggest that sufficient endotoxin exists in cotton dust to cause respiratory symptoms (often as part of a syndrome termed "byssinosis") and a decline in pulmonary function test results (3, 4). Importantly, the endotoxin concentration in cotton dust, and not the dust concentration, is correlated with the decline in lung function (5). Although most studies in humans examined the acute response to airborne endotoxin, some studies suggest that long-term exposure to cotton dust is associated with a loss of lung function, with symptoms and pulmonary function test results similar to those observed in chronic obstructive CLINICAL RELEVANCEOccupat...

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