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
Source: PubMed


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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    ABSTRACT: Bleomycin produces DNA damage, apoptosis and senescence, all of which play crucial roles in the development of pulmonary fibrosis. Recently, close attention has been paid to a DNA damage-induced phenotypic change (senescence-associated secretory phenotype; SASP) as a trigger for the secretion of various mediators which modify the processes of tissue injury, inflammation, repair and fibrosis. We characterized the SASP in a murine model of bleomycin-induced lung injury. Mice were intratracheally administered bleomycin or control saline, and the lungs were obtained on days 7, 14 and 21. The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining. γH2AX immunostaining of the bleomycin-treated lungs revealed double-strand breaks (DSBs), largely within E-cadherin-positive, β4-integirn-positive alveolar epithelial cells. The DSBs were associated with phosphorylation of ATM/ATR, a central signal transducer mediating the DNA damage response, and upregulation of the cyclin-dependent kinase inhibitor p21(CIP1). The DSBs persisted for at least 21 days after the bleomycin exposure, although it began to wane after 7 days. A subpopulation of the γH2AX-positive, DNA-damaged cells exhibited the SASP, characterized by overexpression of IL-6, TNFα, MMP-2 and MMP-9, in association with the phosphorylation of IKKα/β and p38 MAPK. Persistent DNA damage and the SASP are induced in the process of bleomycin-induced lung injury and repair, suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin-induced pneumopathy.
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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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    ABSTRACT: Interstitial lung disease (ILD) represents a severe manifestation in connective tissue diseases (CTD), with an overall incidence of 15%, and it is still a challenge for clinicians evaluation and management. ILD is the most common manifestation of lung involvement in Rheumatoid Arthritis (RA), observed in up to 80% of biopsies, 50% of chest Computed Tomography (CT) and only 5% of chest radiographs. Histopatological patterns of ILD in RA may present with different patterns, such as: usual interstitial pneumonia, non specific interstitial pneumonia, desquamative interstitial pneumonia, organizing pneumonia, and eosinophilic infiltration. The incidence of ILD in RA patients is not only related to the disease itself, many drugs may be in fact associated with the development of pulmonary damage. Some reports suggest a causative role for TNFα inhibitors in RA-ILD development/worsening, anyway, no definitive statement can be drawn thus data are incomplete and affected by several variables. A tight control (pulmonary function tests and/or HRCT) is mandatory in patients with preexisting ILD, but it should be also performed in those presenting risk factors for ILD and mild respiratory symptoms. Biologic therapy should be interrupted, and, after excluding triggering infections, corticosteroids should be administered.
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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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