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
asbestos-induced 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 (TNFα) appears to play a crucial role, since mice with TNFα receptor genes knocked out are resistant to
asbestos-induced
fibrosis. However, many man-made
mineral fibers (MMVF) are able to generate ROS, cell signaling factors, and proinflammatory
cytokines (probably every fiber causes expression of TNFα), 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 TNFα expression, and nonfibrogenic dusts induce fibrogenic mediators such as
transforming growth factor-beta (TCFβ) 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.