The objective of the proposed research is to investigate the effects of diesel exhaust particles (DEP) on the development of chronic lung diseases in animal models. Preliminary studies in rates showed that DEP induced pulmonary inflammation and inhibited alveolar macrophage (AM) host defense function. Specifically, DEP inhibited AM secretion of cytokines in response to endotoxin stimulation, and resulted din altered thiol (cysteine and glutathione) levels that are known to regulate T lymphocyte function. These results indicate that DEP can change the susceptibility of the lung to bacterial infection and allergic sensitization. The proposed research will study the mechanism of the DEP effects indicated in the preliminary studies based on the following hypotheses. (1) DEP impair cell-mediated immunity in the lung, which can be illustrated by measuring the weakened host defense against the obligate intercellular pathogen, listeria monocytogens; (2) DEP augment antigen- elicited humoral immune responses, increasing the likelihood and severity of sensitization, and worsening the clinical outcome. Theses hypotheses will be tested using a L. Monocytogens rate model for cell-mediated immunity and the Brown-Norway rate (BNR) model for allergic sensitization. Exposure of rates to DEP will be carried out by inhalation. The DEP effects will be assessed with an acute and a sub-chronic exposure protocol, via the following studies: (a) to establish the effects of inhalation DEP exposure on pulmonary inflammation; (b) to characterize the pulmonary immune-inflammatory responses to L. Monocytogens and the effect of DEP on the host defense mechanism; to assess the integrative effect of DEP and antigen sensitization on airway hyper reactivity; and (d) to establish the DEP effects on T lymphocyte function, AM- regulated thiol levels and cytokine productions in the BNR model. In year 1, studies will be focused on the effects of DEP on Listeria infection and allergic sensitization via acute DEP exposure. A sub-chronic exposure protocol will be established. In years 2 and 3, studies will be focused on the interactive effects of the disease state with sub-chronic DEP exposure and the mechanism(s) by which DEP alter pulmonary immunity. By using the two disease models, this research will characterize the cellular (TH1) and humoral (TH2) responses to DEP exposure, and test the hypothesis that DEP suppress the cellular buy enhance humoral immune responses by altering AM-regulated thiol homeostasis in the lung. The strengths of this proposal are 1) the strong and robust assumptions underlying the hypotheses, 2) the extent of preliminary data available, 3) the investigator's experience in these methods and preparations, and 4) the inhalation system, which is proven. The weaknesses of this proposal are 1) its complexity and the complicated logistics required for execution, and 2) uncertainties in extrapolation to human exposure and expression of disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062630-02
Application #
6315585
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Croxton, Thomas
Project Start
2000-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$255,500
Indirect Cost
Name
West Virginia University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Yin, Xuejun J; Dong, Caroline C; Ma, Jane Y C et al. (2007) Suppression of phagocytic and bactericidal functions of rat alveolar macrophages by the organic component of diesel exhaust particles. J Toxicol Environ Health A 70:820-8
Dong, Caroline C; Yin, Xuejun J; Ma, Jane Y C et al. (2005) Exposure of brown Norway rats to diesel exhaust particles prior to ovalbumin (OVA) sensitization elicits IgE adjuvant activity but attenuates OVA-induced airway inflammation. Toxicol Sci 88:150-60
Dong, Caroline C; Yin, Xuejun J; Ma, Jane Y C et al. (2005) Effect of diesel exhaust particles on allergic reactions and airway responsiveness in ovalbumin-sensitized brown Norway rats. Toxicol Sci 88:202-12
Yin, Xuejun J; Dong, Caroline C; Ma, Jane Y C et al. (2005) Sustained effect of inhaled diesel exhaust particles on T-lymphocyte-mediated immune responses against Listeria monocytogenes. Toxicol Sci 88:73-81
Yin, Xuejun J; Dong, Caroline C; Ma, Jane Y C et al. (2004) Suppression of cell-mediated immune responses to listeria infection by repeated exposure to diesel exhaust particles in brown Norway rats. Toxicol Sci 77:263-71
Yin, Xuejun J; Ma, Jane Y C; Antonini, James M et al. (2004) Roles of reactive oxygen species and heme oxygenase-1 in modulation of alveolar macrophage-mediated pulmonary immune responses to Listeria monocytogenes by diesel exhaust particles. Toxicol Sci 82:143-53
Rengasamy, A; Barger, M W; Kane, E et al. (2003) Diesel exhaust particle-induced alterations of pulmonary phase I and phase II enzymes of rats. J Toxicol Environ Health A 66:153-67
Yin, Xue-Jun; Schafer, Rosana; Ma, Jane Y C et al. (2003) Alteration of pulmonary immunity to Listeria monocytogenes by diesel exhaust particles (DEPs). II. Effects of DEPs on T-cell-mediated immune responses in rats. Environ Health Perspect 111:524-30
Yang, Xiao-Dong; Ma, Jane Y C; Barger, Mark W et al. (2002) Transport and utilization of arginine and arginine-containing peptides by rat alveolar macrophages. Pharm Res 19:825-31
Al-Humadi, Nabil H; Siegel, Paul D; Lewis, Daniel M et al. (2002) Alteration of intracellular cysteine and glutathione levels in alveolar macrophages and lymphocytes by diesel exhaust particle exposure. Environ Health Perspect 110:349-53

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