Semester

Spring

Date of Graduation

2004

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Vincent Castranova.

Abstract

Evidence suggests that hyperproduction of reactive oxidants and inflammatory mediators plays a critical role in adverse pulmonary responses to silica or lipopolysaccharide (LPS). The main objective of this study was to contribute to advancing the understanding of the role of AM's and type II (TII) cells in the induction of pulmonary inflammation and injury in response to silica and LPS, and improve our understanding of the interaction between AM's and TII cells which would occur in vivo. To reach this objective, three aims were put forth. (1) Determine the relative responsiveness of primary rat AM's, primary rat TII cells and RLE-6TN, a rat TII cell line to silica and LPS under comparable conditions. (2) Determine if AM/TII intercellular interactions exist and under what conditions they can be demonstrated. (3) Attempt to identify the mediator(s) responsible for this interaction. The following findings were made: (1) although AM's were generally found to release more inflammatory mediators than TII cells following LPS or silica exposures, primary TII cells clearly produced significant levels of mediators which could be capable of contributing considerably to lung inflammation and injury. (2) Since the RLE-6TN cell line responses to LPS and silica exposures were generally considerably less intense and required higher doses of stimulant than those measured in primary TII cells, RLE-6TN cells may not be a good substitute for primary TII cells in studying the pulmonary epithelium. (3) LPS was more potent than silica in inducing inflammatory cytokines from the three cell types. However, silica was found to be as potent as LPS or even slightly more potent as an inducer of cellular oxidants, especially from primary TII cells. (4) Surfactant appears to be an inhibitory mediator released from TII cells and acts on AM's. (5) Basal transwell co-culture conditions are better than mixed co-culture conditions to study AM/TII cell interactions since the inhibitory effect of the surfactant in the transwell co-culture is minimized. (6) Oxidants, TNF-alpha, IL-1beta, prostaglandins and leukotrienes, probably do not directly affect the AM/TII intercellular interaction; instead, they (and especially TNF-alpha) appear to indirectly modulate the complex pathways of the AM/TII communication.

Download

Share

COinS