Inhalation of Asbestos Fibers and Consequent Expression of Peptide Growth Factors

Abstract

It would be impossible to completely review this broad topic in the space and time allowed, lust as we must make choices when focusing on a research topic, this brief overview of particles and fibrosis deals with a small corner of our current thinking on the molecular mechanisms through which inhaled particles mediate fibroproliferative lung disease. At some point, there must be a common pathway of action because the fundamental process after any exposure involves fibroblast proliferation and production of extracellular matrix, that is, scar tissue. Thus, if we can understand how to control the fibroblast cell cycle and those genes that code for matrix components, it may be possible to develop effective therapeutic modalities for pulmonary fibrosis where none now exist. To control cell cycle and matrix genes that are expressed due to particle exposure, investigators have focused on certain peptide growth factors. The genes that code for these factors as well as the genes and oncogenes that are expressed when the peptides bind to their cognate receptors offer the best opportunities for understanding the molecular mechanisms of particle-induced lung fibrosis. As an example, mice with the genes knocked out for both the 55- and 75-kD receptors for tumor necrosis factor-alpha (TNF-α) are protected from the fibrogenic effects of inhaled asbestos and silica. Expression of other peptide growth factors in these animals is reduced, leading to a central working hypothesis, that TNF-α is a “master switch” that controls the expression of other more downstream factors that mediate components of the fibrogenic process. There is ample evidence of TNF-α expression in animal models and in populations of dust-exposed workers to support this postulate. In addition, it appears that transforming growth factor beta (TGF-β) is the primary peptide that controls production of extracellular matrix. Blocking of TGF-β expression in animal models prevents fibrosis, and the use of specific antisense RNA blocks both TGF-β and collagen gene expression in primary lung fibroblasts. Conversely, an adenovirus vector that transduces expression of TGF-β to the bronchiolar-alveolar epithelium induces diffuse fibrogenesis in rats and mice. Thus, particle-induced pulmonary fibrosis is a complex process that will be understood only after we dissect and elucidate the signal transduction pathways that control growth factor and matrix gene expression. The emerging technologies for developing transgenic and knockout mice, viral vectors for gene transduction, antisense approaches, and microarray gene analysis will finally allow us to accomplish these goals.