Expression of a tumor necrosis factor-α transgene in murine lung causes lymphocytic and fibrosing alveolitis: A mouse model of progressive pulmonary fibrosis

Department of Pathology, University of Geneva, Switzerland.
Journal of Clinical Investigation (Impact Factor: 13.77). 08/1995; 96(1):250-9. DOI: 10.1172/JCI118029
Source: PubMed

ABSTRACT 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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Available from: Irene Garcia, Aug 19, 2015
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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; DOI:10.1016/j.etp.2013.04.001 · 2.01 Impact Factor
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    • "Further, it has been established that TNF-α and IL-1β promote anchorage-independent growth of immortalized human mesothelial cells treated with erionite in vitro, and may therefore contribute to the pathogenesis of MM (Wang et al. 2004). In vivo models utilizing transgenic mice overexpressing TNF-α in type II alveolar epithelial cells spontaneously develop fibrotic lesions similar to those observed in asbestosis (Miyazaki et al. 1995). Finally, TNF-α receptor knockout mice fail to develop the fibrosis seen in wild-type mice following chrysotile asbestos exposure (Liu et al. 1998). "
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    Journal of Toxicology and Environmental Health Part A 02/2010; 73(5):423-36. DOI:10.1080/15287390903486568 · 1.83 Impact Factor
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    • "In addition, intra-cellular signal transduction generated by TNF-alpha elicits a wide spectrum of other cellular responses, including modulation of differentiation and proliferation of a variety of cell types, and induction of apoptosis (Aggarwal, 2003). Lung-specific ectopic over-expression of Tnf-alpha (Miyazaki et al., 1995) and other inflammatory cytokines inhibits branching morphogenesis (DiCosmo et al., 1994; Ray et al., 1997). Signal transduction in the TNF-alpha pathway occurs partly through the activity of the NF-kB family of transcriptional factors. "
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