PS4/USBM 4204 - Dust Center Project Reports - Characterization of the Mechanism of Lung Injury

"INTRODUCTION The major objective of our research is to help reduce the incidence and severity of coal worker's pneumoconiosis (CWP). To that end, this project is designed to improve our understanding of the processes that lead to pulmonary dysfunction following mine dust exposure, and how those processes might be interrupted or attenuated. The response of the lung ' to inhaled particles is complex, and the course of development of disabling CWP is slow and unpredictable. From among the numerous cellular and molecular interactions involved in the pulmonary response to inhaled particles, this project is focussed on the role that the pulmonary alveolar macrophage (PAM) may play in regulating the activity of fibroblasts.The PAM is the lung cell that has the most immediate and the most obvious interaction with inhaled particles. Within a short period after particles are arrested in the alveolus of the lung, they are phagocytized (engulfed) by these specialized cells. The PAM then has a diverse potential repertoire of subsequent activities. Which reaction actually ensues is determined, in large part, by the nature of the phagocytized _particles. Activated PAMs produce a variety of products that may affect adjacent lung tissue, including superoxide free radical, elastase, collagenase, prostaglandins, platelet activating factor, etc. Those may well be important in the pathogenesis of CWP, but they are beyond the scope of this project. Background information that is cogent to this project has come primarily from investigations using animal models of silicosis and asbestosis. PAMs that have ingested silica particles synthesize and release molecules that control the behavior of surrounding cells. One such mediator is interleukin-1 (IL-1), a molecule that plays a central role in many aspects of the response to injury. It can stimulate fibroblasts (the cells that help to hold tissues together) to release the enzyme collagenase, resulting in breakdown of the structural collagen fibers that support the lung tissue. IL-1 also stimulates fibroblasts to undergo mitosis and to proliferate, which is an initial stage of fibrosis. Certain stimulants cause PAMs to release fibroblast growth factors (FGFs) that are distinct- from IL-1. Under other circumstances activated PAMs synthesize and release molecules that stimulate fibroblasts to accelerate synthesis of collagen fibers, thus contributing to fibrosis. Although these observations provide a valuable precedent for analysis of the mechanisms involved in CWP, their relevance to CWP cannot be assumed since most of those studies involved macrophages or fibroblasts obtained from tissues other than the lung, and because almost none of them have used CMD as the stimulating particles. Therefore, the goal of this project is to learn how exposure to CMD affects the behavior of PAMs, and in turn how products of dust-exposed PAMs affect fibroblasts and the process of fibrosis in the lung."