Date of Graduation

2017

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Rosana Schafer

Committee Co-Chair

Christopher F Cuff

Committee Member

Jeffrey S Fedan

Committee Member

Jenny R Roberts

Committee Member

James M Sheil

Committee Member

Paul D Siegel

Abstract

Crystalline silica (SIL) and diesel particulate matter (DPM) are each well-recognized for their potential to cause pulmonary toxicity following inhalation. However, these particulates have also been identified as coexisting in mixtures of respirable aerosols at a variety of industrial settings: mining, oil and gas extraction, construction, road construction, tunneling, excavation, foundry, and sandblasting. In order to characterize the potential for increased pulmonary health effects when these particulates are inhaled in a mixture, a battery of acute and subacute in vivo exposure studies were conducted. The current studies examined co-exposure to SIL and DPM at doses that were derived from field measures collected during industrial activities. The project had three major aims: (1a) Characterize the pulmonary response to an acute co-exposure to DPM and SIL at varying doses; (1b) characterize the pulmonary response to a repeated co-exposure to DPM and SIL in order to determine if subacute exposure vs. acute exposure altered the effects observed for 1a; (2) establish if susceptibility to an acute respiratory infection was altered following a co-exposure of DPM and SIL; and (3) determine whether clearance of particulate in a co-exposure to DPM and SIL was altered compared with the clearance rate of either particle individually to assess the effect of particle load in toxicity. Co-exposure of rats to SIL and DPM had the capability to enhance indicators of inflammation, injury, oxidant production by phagocytes, onset of the initiation of fibrosis, and differentially alter immunological responses when administered in combination, compared to either particle individually. In acute infection models examining respiratory susceptibility following exposure to particles, the highest dose of DPM was shown to suppress bacterial clearance in the innate phase of the immune response as compared to SIL. It was determined that although some macrophage functions were reduced by the presence of DPM early in the time course (1 to 3 days following infection), all groups cleared the infection at a similar rate in the adaptive phase of the immune response. Further, it was determined that some effects in the co-exposure group were associated with the presence of SIL and the overall particle load over time, particularly tissue remodeling and the development of fibrosis; whereas other effects were due to specific characteristics of DPM including inflammation, injury, and oxidant production. Overall, the studies indicate that silica-exposed workers may be at an increased risk for adverse health effects when concomitantly exposed to diesel particulate, even doses that cause low toxicity in individual exposures.

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