TNF-α Receptor Knockout Mice Are Protected from the Fibroproliferative Effects of Inhaled Asbestos Fibers

Abstract

We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alphaRKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obtained by in situ hybridization showing that expression of the genes coding for transforming growth factor alpha (TGF-alpha) and platelet-derived growth factor A-chain (PDGF-A) is reduced in the TNF-alphaRKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-alphaRKO mice show no increases over unexposed control animals. In contrast, wild-type control mice exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and consequently develop fibrogenic lesions. Even though the levels of TNF-alpha gene expression and protein production were increased in the asbestos-exposed TNF-alphaRKO mice, the lack of receptor signaling protected the mice from developing fibroproliferative lesions. We agree with the view that TNF-alpha is essential for the development of interstitial pulmonary fibrosis and postulate that TNF-alpha mediates its effects through activation of other growth factors such as PDGF and TGF-alpha that control cell growth and matrix production.

Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases

“…As a consequence, a large amount of extracellular matrix (ECM) is produced, and the lungs reach a state of fibrosis and asbestosis [6,7]. In particular, TNF-a plays a role in production of transforming growth factor-beta (TGF)-b, which induces production of ECM, and previous studies have demonstrated that TNF-a receptor knockout mice showed decreases in production of TGF-b and accumulation of ECM after exposure to asbestos [6,8]. Moreover, asbestos exposure causes apoptosis of lung epithelial cells, mesothelial cells, and AM [9], and it has been reported that intratracheal instillation with apoptotic cells of macrophages induces increased production of TGF-b and fibrosis of the lungs [10].…”

Asbestos-derived reactive oxygen species activate TGF-β1

“…In as much as chrysotile is the most commonly used form of asbestos worldwide, 6 we typically use this variety of fiber for both in vitro and in vivo studies. 7 We have primarily used chrysotile in the studies reported here and have compared these findings with crocidolite asbestos, a fiber with iron as a component of its chemical formula. 6 A number of cytokines are thought to be significant contributors in the development of human interstitial fibrosis and in models of pulmonary fibrogenesis.…”

“…6 A number of cytokines are thought to be significant contributors in the development of human interstitial fibrosis and in models of pulmonary fibrogenesis. For example, it has been demonstrated that inhalation of asbestos enhances tumor necrosis factor-a (TNF-a), 7 transforming growth factor-a (TGF-a), 8 platelet-derived growth factor (PDGF) isoforms, 9 transforming growth factor beta (TGF-b), 10,11 as well as fibronectin expression at sites of fiber deposition, 10 correlating with elevated levels of cellular proliferation, 9 and extracellular matrix (ECM) deposition in both rats 10,12 and mice. 11 Of these factors, TGF-b 1 is the most potent in upregulating genes involved in collagen and fibronectin biosynthesis.…”

The controversial role of tumor necrosis factor α in fibrotic diseases

“…In contrast to experiments with TNF␣-transgenic mice, these studies demonstrated uniformly that inhibition of signaling via TNFRI and TNFRII prevents the development of fibrosis. For instance, TNFRI Ϫ/Ϫ /II -/-mice were protected from experimental pulmonary fibrosis induced by silica, asbestos, and bleomycin (52)(53)(54). In contrast to WT mice, TNFRI Ϫ/Ϫ /II -/-mice did not demonstrate significant inflammation or increased proliferation in the lungs after exposure to profibrotic agents, the induction of TNF␣ was diminished, and there was no increased deposition of ECM.…”