Miyazaki, Y. et al. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. J. Clin. Invest. 96, 250-259

Department of Pathology, University of Geneva, Switzerland.
Journal of Clinical Investigation (Impact Factor: 13.22). 08/1995; 96(1):250-9. DOI: 10.1172/JCI118029
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The murine TNF-alpha gene was expressed under the control of the human surfactant protein SP-C promoter in transgenic mice. A number of the SP-C TNF-alpha mice died at birth or after a few weeks with very severe lung lesions. Surviving mice transmitted a pulmonary disease to their offspring, the severity and evolution of which was related to the level of TNF-alpha mRNA in the lung; TNF-alpha RNA was detected in alveolar epithelium, presumably in type II epithelial cells. In a longitudinal study of two independent mouse lines, pulmonary pathology, at 1-2 mo of age, consisted of a leukocytic alveolitis with a predominance of T lymphocytes. Leukocyte infiltration was associated with endothelial changes and increased levels of mRNA for the endothelial adhesion molecule VCAM-1. In the following months, alveolar spaces enlarged in association with thickening of the alveolar walls due to an accumulation of desmin-containing fibroblasts, collagen fibers, and lymphocytes. Alveolar surfaces were lined by regenerating type II epithelial cells, and alveolar spaces contained desquamating epithelial cells in places. Platelet trapping in the damaged alveolar capillaries was observed. Pulmonary pathology in the SP-C TNF-alpha mice bears a striking resemblance to human idiopathic pulmonary fibrosis, in which increased expression of TNF-alpha in type II epithelial cells has also been noted. These mice provide a valuable animal model for understanding the pathogenesis of pulmonary fibrosis and exploring possible therapeutic approaches.

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    • "The upregulated secretion of IL-6 and TNF␣ exacerbates bleomycin-induced lung injury by recruiting inflammatory cells (Wynn and Ramalingam, 2012). This notion is supported by previous reports indicating that mice that overexpress TNF␣ develop progressive pulmonary fibrosis (Miyazaki et al., 1995), and that anti-TNF␣ antibody prevents bleomycin-induced fibrosis (Piguet et al., 1989). Similar to the studies on TNF␣, other studies have also documented the profibrotic activity of IL-6, e.g., the study showing that the development of bleomycin-induced pulmonary fibrosis was attenuated in IL- 6-deficient mice (Saito et al., 2008). "
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    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 05/2013; 65(7). DOI:10.1016/j.etp.2013.04.001 · 1.86 Impact Factor
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    • "Transgenic mice overexpressing murine TNFα in the lung develop a chronic lymphocytic alveolitis which severity correlates with the expression of TNFα mRNA. Moreover, TNFα may upregulate TGFb1 expression in the lungs via the activation of regulated kinase pathway in fibroblasts [36, 37]. On the other hand, mice KO for TNFα develop a bleomycin-induced pulmonary fibrosis that may be reverted by the administration of TNFα [38]; TNF-α is also able to block the synthesis of collagen production and inhibits α2 collagen gene transcription in human dermal fibroblasts [39]. "
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    Pulmonary Medicine 12/2011; 2011(2):931342. DOI:10.1155/2011/931342
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    • "TNF-α is one of most important cytokines in the early immune response to a variety of inflammatory disorders, and is a critical mediator in the pathogenesis of pulmonary fibrosis.4 TNF-α can directly stimulate the secretion of matrix proteins, increase fibroblast proliferation, and promote induction of matrix-degrading gelatinases that can facilitate fibroblast migration to site of injury.5 Increased expression of TNF-α gene is observed in fibrotic human lungs as well as animal models of lung fibrosis, and inhibition of TNF-α expression can significantly reduce the incidence of pulmonary fibrosis.6 "
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