Overexpression of Tumor Necrosis Factor-α Diminishes Pulmonary Fibrosis Induced by Bleomycin or Transforming Growth Factor-β

Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 01/2004; 29(6):669-76. DOI: 10.1165/rcmb.2002-0046OC
Source: PubMed


Tumor necrosis factor-alpha (TNF-alpha) is thought to be important in the development of pulmonary fibrosis. However, surfactant protein-C/TNF-alpha transgenic mice do not spontaneously develop pulmonary fibrosis but instead develop alveolar enlargement and loss of elastic recoil. We hypothesized that overexpression of TNF-alpha in the lung requires an additional insult to produce fibrosis. In this study we evaluated whether TNF-alpha overexpression altered the development of pulmonary fibrosis due to bleomycin or transforming growth factor-beta (TGF-beta). Either 0.2 U bleomycin or saline was administered into left lung of TNF-alpha transgenic mice and their transgene-negative littermates. To overexpress TGF-beta, an adenovirus vector containing either active TGF-beta (AdTGF-beta) or LacZ was administered at a dose of 3 x 108 plaque-forming units per mouse. Fibrosis was assessed histologically and by measurement of hydroxyproline. TNF-alpha transgenic mice tolerated bleomycin or AdTGF-beta, whereas the transgene-negative littermates demonstrated severe pulmonary fibrosis after either agent. An increase in prostaglandin E2 and downregulation of TNF receptor I expression were observed in the TNF-alpha transgenic mice. In addition, recombinant human TNF-alpha attenuated bleomycin-induced pulmonary fibrosis. TNF-alpha has a complex role in the development of pulmonary fibrosis. Endogenous TNF-alpha may be important in the development of fibrosis as indicated in other reports, but overexpression of TNF-alpha or exogenous TNF-alpha limits pulmonary fibrosis in mice.

Full-text preview

Available from:
  • Source
    • "MDA is a biomarker for lipid peroxidation generated by ROS, which are critically controlled by NOX, the reduced form of NADPH oxidase (Cui et al., 2011; Levitan et al., 2010). NO is a typical indicator of reactive oxygen species (ROS), and lipid peroxidation is an indicator of oxidative stress in the BDL model (Alptekin et al., 1997; Desmet et al., 1995; Fujita et al., 2003). Immunochemistry staining against 4-HNE demonstrated the lipid peroxidation inside cells (Poli and Schaur, 2000), and BDL treatment strongly enhanced the 4-HNE expression compared to the sham group. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Artemisia capillaris has been widely used as a traditional herbal medicine in the treatment of liver diseases. However, no previous study has investigated whether A. capillaries alone is effective in treating pathological conditions associated with cholestatic liver injury. In the present study, we evaluated the anti-hepatofibrotic effects of A. capillaris (aqueous extract, WAC) in a bile duct ligation (BDL)-induced cholestatic fibrosis model. After BDL, rats were given WAC (25 or 50mg/kg) or urosodeoxycholic acid (UDCA, 25mg/kg) orally for 2 weeks (once per day). The serum cholestatic markers, malondialdehyde, and liver hydroxyproline levels were drastically increased in the BDL group, while administering WAC significantly reduced these alterations. Administering WAC also restored the BDL-induced depletion of glutathione content and glutathione peroxidase activity. Cholestatic liver injury and collagen deposition were markedly attenuated by WAC treatment, and these changes were paralleled by the significantly suppressed expression of fibrogenic factors, including hepatic alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-β). The beneficial effects of WAC administration are associated with antifibrotic properties via both upregulation of antioxidant activities and downregulation of ECM protein production in the rat BDL model.
    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 01/2013; 65(6). DOI:10.1016/j.etp.2012.12.002 · 1.86 Impact Factor
  • Source
    • "Tumor necrosis factor alpha (TNF-α) is important in the development of pulmonary fibrosis. Since chronic overexpression of TNF-α alone did not produce pulmonary fibrosis, we hypothesized that chronic overexpression of TNF-α might make the lungs more susceptible to BL or TGF-β1 [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT: Interstitial pulmonary fibrosis is characterized by an altered cellular composition of the alveolar region with excessive deposition of collagen. Lung inflammation is also common in pulmonary fibrosis. This study aims to test the inhibition of 5-lipooxygenase (5-LOX) by boswellic acid (BA) extract in an experimental model of pulmonary fibrosis using bleomycin (BL). Boswellic acid extract (1 g/kg) was force-fed to rats seven days prior to administration of BL or gamma irradiation or both. BL (0.15 U/rat) in 25 μl of 0.9% normal saline (NS) or 0.9% NS alone was administered intratracheally. Rats were exposed to two fractionated doses of gamma irradiation (0.5 Gy/dose/week) with a gamma cell-40 (Cesium-137 irradiation units, Canada) during the last two weeks of the experiment. BA was administered during BL or irradiation treatment or both. After the animals were sacrificed, bronchoalveolar lavage was performed; lungs were weighed and processed separately for biochemical and histological studies. In rats treated with BL, levels of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were significantly elevated (P = 0.05 and P = 0.005). Hydroxyproline was highly and extensively expressed. Immunoreactive compounds were abundantly expressed, represented in the levels of macrophages infiltrate, accumulation of eosinophils and neutrophils in the lung as well as the aggregation of fibroblasts in the fibrotic area. The levels of lipoxygenase enzyme activity were significantly increased (P = 0.005). Antioxidant activities measured in BL-treated rats deteriorated, coupled with the elevation of both levels of plasma lipid peroxide (LP) content and bronchoalveolar lavage lactate dehydrogenase activity. BA-treated rats had reduced number of macrophages, (P = 0.01), neutrophils in bronchoalveolar lavage (P = 0.01) and protein (P = 0.0001). Moreover, the hydroxyproline content was significantly lowered in BA-treated rats (P = 0.005). BA extract inhibited the TGF-ß induced fibrosis (P = 0.01) and 5-LOX activity levels (P = 0.005).Histologically, BA reduced the number of infiltrating cells, ameliorated the destruction of lung architecture and attenuated lung fibrosis. BA attenuates the BL-induced injury response in rats, such as collagen accumulation, airway dysfunction and injury. This study suggests that the blocking of 5-LOX may prevent the progression of fibrosis.
    Chinese Medicine 09/2011; 6(1):36. DOI:10.1186/1749-8546-6-36 · 1.49 Impact Factor
  • Source
    • "Tumor necrosis factor-α (TNF-α), a ligand for the death receptors, as well as death receptors themselves, are increased in the lung tissue of patients with IPF19, 20, 21. Data indicate many of the same factors identified in human lung fibrosis are also increased in animal models of the disease22, 23, 24, 25, 26, 27, 28, 29. The imbalance of homeostatic factors created by increased production of pro-apoptotic factors is further exacerbated by a decrease in the production of factors that sustain epithelial and endothelial cell survival, including hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF)30, 31, 32, 33, 34. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary remodeling is characterized by the permanent and progressive loss of the normal alveolar architecture, especially the loss of alveolar epithelial and endothelial cells, persistent proliferation of activated fibroblasts, or myofibroblasts, and alteration of extracellular matrix. Hepatocyte growth factor (HGF) is a pleiotropic factor, which induces cellular motility, survival, proliferation, and morphogenesis, depending upon the cell type. In the adult, HGF has been demonstrated to play a critical role in tissue repair, including in the lung. Administration of HGF protein or ectopic expression of HGF has been demonstrated in animal models of pulmonary fibrosis to induce normal tissue repair and to prevent fibrotic remodeling. HGF-induced inhibition of fibrotic remodeling may occur via multiple direct and indirect mechanisms including the induction of cell survival and proliferation of pulmonary epithelial and endothelial cells, and the reduction of myofibroblast accumulation.
    Acta Pharmacologica Sinica 01/2011; 32(1):12-20. DOI:10.1038/aps.2010.90 · 2.91 Impact Factor
Show more