Semester

Spring

Date of Graduation

2006

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Vincent Castranova.

Abstract

Incidences of high levels of air pollution have been correlated with increased morbidity and mortality in susceptible populations. Inhalation of the combustion-derived pollutant, residual oil fly ash (ROFA), has been shown to impair lung defense mechanisms in laboratory animals and susceptible populations. The hypothesis of these studies was that the soluble metals in ROFA would increase susceptibility to pulmonary infection in rats, and that the primary metal responsible for the increase is soluble Ni. To investigate the hypothesis, three specific aims were established: (1) determine if soluble metals in ROFA cause a decrease in bacterial clearance from the lungs of rats, (2) determine the potential mechanisms by which the soluble metals suppress the innate and adaptive pulmonary immune response to infection, and (3) establish what metal or metal combination would account for the alterations in pulmonary host defense.;To investigate this, an in vivo infectivity model was employed where adult rats were intratracheally instilled with ROFA (R-Total), soluble (R-Soluble) or insoluble ROFA (R-Insoluble), or the major individual soluble metals or metal combinations in ROFA on day 0. Control groups included the vehicle control (phosphate-buffered saline) and the soluble ROFA sample after metals had been extracted from the solution by chelation (R-Chelex). On day 3, rats were intratracheally inoculated with Listeria monocytogenes as the model pathogen. Pulmonary clearance, morbidity, cellular profiles and phenotypes, lung injury parameters, and cytokine and oxidant production were monitored on day 3 prior to infection, and for 1 week after infection (days 6, 8, and 10).;The first study revealed that the primary metal constituents of ROFA were iron (Fe), nickel (Ni), vanadium (V), aluminum (Al), and zinc (Zn). The soluble fraction of ROFA contained Fe, Ni, Al, and Zn, but very little V. R-Soluble was found to significantly decrease bacterial clearance from the lungs of rats to a similar degree as R-Total, whereas R-Insoluble did not alter clearance of bacteria when compared to control. In addition, removal of the metals from R-Soluble abolished the increase in susceptibility to infection. In study 2, the R-Soluble sample was shown to induce a lung injury and inflammation prior to and post-infection which was comparable to, if not more severe than, R-Total. Post-infection, R-Soluble was found to increase neutrophil, macrophage, and lymphocyte influx into the lungs, and to increase NO and IL-6 production, indicating an exacerbated acute phase response and excess inflammation in this group. In addition, macrophage function appeared to be inhibited, as indicated by the increased bacterial burdens at all time points in the R-Soluble group, and T cell activity was also suppressed, demonstrated as reduced interleukin (IL)-2 and IL-4. (Abstract shortened by UMI.).

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