PATHOGENESIS OF FIBROSIS PRODUCED BY ASBESTOS AND MAN-MADE MINERAL FIBERS: What Makes a Fiber Fibrogenic?

Author： Churg A. Wright J. Gilks B. Dai J.

ISSN： 1091-7691

Source： Inhalation Toxicology, Vol.12, Iss.10, 2000-10, pp. : 15-26

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Abstract

Recent studies have revealed a wide array of molecular and cellular changes in cells and whole lungs exposed to asbestos fibers, changes that are presumed to be related to asbestosinduced fibrogenesis. These include generation of reactive oxygen species (ROS), induction of cell signaling factors and proinflammatory cytokines, and induction of fibrogenic mediators. Tumor necrosis factor-alpha (TNFalpha) appears to play a crucial role, since mice with TNFalpha receptor genes knocked out are resistant to asbestos-induced fibrosis. However, many man-made mineral fibers (MMVF) are able to generate ROS, cellsignaling factors, and proinflammatory cytokines (probably every fiber causes expression of TNFalpha ), but there is no clear correlation between the ability of MMVF to initiate these events and their ability to produce fibrosis. Moreover, asbestos produces fibrosis in tracheal explant systems without increasing TNFalpha expression, and nonfibrogenic dusts induce fibrogenic mediators such as transforming growth factor-beta (TGFbeta) and platelet-derived growth factor (PDGF) but not procollagen in such systems. It remains uncertain whether alveolar macrophages are central to fibrosis, as is often assumed, or whether fibers penetrating tissue are the real effector agents. Fiber length, biopersistence, and dose clearly do play a very important role in fibrogenesis, since short fibers, readily degraded fibers, and small numbers of fibers of any type are nonfibrogenic. There is some evidence to suggest that short and nonpersistent fibers produce quantitatively less of the mediators just described, but the ability of macrophages to clear fibers is probably crucial to preventing fibrosis. Thus, molecular and cellular events must combine in as yet uncertain ways with abnormalities at a more '''macroscopic'' level before fibrosis can become established.