Date of Graduation

2003

Document Type

Thesis

Abstract

Pulmonary fibrosis due to acute or chronic occupational exposures is the leading cause of work-related illness in the U.S. according to the 2002 report by the American Lung Association. Asbestosis and silicosis are well described lung diseases that result from asbestos fiber or crystalline silica inhalation, respectively. This study investigated the underlying lung inflammatory and fibrotic mechanisms involved in the response caused by exposure to crystalline silica (α-quartz) or JM-100 glass, chrysotile asbestos, and ceramic fibers. Two topics were investigated: (1) The role of fiber dimension and chemical composition in the response of alveolar macrophages (AMs). (2) The role of inducible nitric oxide synthase (iNOS) derived nitric oxide (NO) in silica-induced lung inflammation and fibrosis. The second topic examined silica-induced responses as well as an experimental model of lung damage and inflammation, lipopolysaccharide (LPS) + interferon-γ (IFN-γ) exposure. Therefore, this investigation involves a common theme that includes lung damage, inflammation, and resulting fibrosis. The first topic revealed fiber length and chemical composition are important factors in fiber-induced cellular effects. Cellular effects of length-classified glass fibers (7 and 17 μm) or three types of fibers (glass, chrysotile, or ceramic) of similar lengths were monitored in primary rat AMs in vitro. Longer (17 μm) fibers that were unable to be fully engulfed by AMs (i.e. frustrated phagocytosis) caused greater mediator production than short (7 μm) fibers. Fibers of the same length but different chemical compositions also resulted in differential mediator production and cytotoxicity; however, the contribution of length to fiber potency appears greater than chemistry. Human AMs were also used to determine the effects of length-classified JM-100 glass fibers (8, 10, 16, 20 μm) due to the fact that human AMs are larger in comparison to the rat, approximately 18 μm as compared to 13 μm, respectively. In human AMs, all fiber length fractions tested were completely engulfed and exhibited equal cytotoxicity in the same dose-dependent fashion. Therefore, the data indicate that, because human AMs are larger than rat AMs, they are able to phagocytize longer fibers and the absence of frustrated phagocytosis results in lower fiber toxicity in human AMs. These differences in the AM response to long fibers between human and rat phagocytes are pertinent to the assessment of fiber-induced health effects. The role of iNOS derived NO in pulmonary disease states remains unresolved with both anti-inflammatory [scavenging radicals and inhibiting nuclear factor-κB (NF-κB) activation] and pro-inflammatory (forming highly reactive peroxynitrite and augmenting NF-κB activation by inflammatory agents) actions reported. Therefore, a series of studies have been initiated to determine whether deletion of the iNOS gene in the C57BL/6J mouse alters the pulmonary response to silica or LPS + IFN-γ. Data show that increased inflammation and damage due to acute exposure to LPS + IFN-γ was evident in the iNOS knockout (KO) compared to wild type (WT) mice. On the other hand, attenuation of sub-chronic silica-induced lung effects was observed in the iNOS KO mice. The differential responses of the iNOS KO and WT mice to various stimuli could be attributed to factors related to the complex nature of the signaling pathways for toll-like versus scavenger receptors and/or the inflammatory and immune response to these stimuli.

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