Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice

2005 ◽  
Vol 99 (1) ◽  
pp. 298-307 ◽  
Author(s):  
David E. Nethery ◽  
Bethany B. Moore ◽  
George Minowada ◽  
James Carroll ◽  
Jihane A. Faress ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lavage Fluid ◽  
Dominant Negative ◽  
Nontransgenic Littermate

Neuregulin-1 (NRG-1), binding to the human epidermal growth factor receptor HER2/HER3, plays a role in pulmonary epithelial cell proliferation and recovery from injury in vitro. We hypothesized that activation of HER2/HER3 by NRG-1 would also play a role in recovery from in vivo lung injury. We tested this hypothesis using bleomycin lung injury of transgenic mice incapable of signaling through HER2/HER3 due to lung-specific dominant-negative HER3 (DNHER3) expression. In animals expressing DNHER3, protein leak, cell infiltration, and NRG-1 levels in bronchoalveolar lavage fluid increased after injury, similar to that in nontransgenic littermate control animals. However, HER2/HER3 was not activated, and DNHER3 animals displayed fewer lung morphological changes at 10 and 21 days after injury ( P = 0.01). In addition, they contained 51% less collagen in injured lungs ( P = 0.04). Transforming growth factor-β1 did not increase in bronchoalveolar lavage fluid from DNHER3 mice compared with nontransgenic littermate mice ( P = 0.001), suggesting that a mechanism for the decreased fibrosis was lack of transforming growth factor-β1 induction in DNHER3 mice. Severe lung injury (0.08 units bleomycin) resulted in 80% mortality of nontransgenic mice, but only 35% mortality of DNHER3 transgenic mice ( P = 0.04). Thus inhibition of HER2/HER3 signaling protects against pulmonary fibrosis and improves survival.

Transforming growth factor-β1in bronchoalveolar lavage fluid from children with cystic fibrosis

2009 ◽  
Vol 44 (11) ◽  
pp. 1057-1064 ◽  
Author(s):  
William T. Harris ◽  
Marianne S. Muhlebach ◽  
Robert A. Oster ◽  
Michael R. Knowles ◽  
Terry L. Noah
Keyword(s):  
Cystic Fibrosis ◽  
Growth Factor ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Lavage Fluid

Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo

2000 ◽  
Vol 278 (5) ◽  
pp. L914-L922 ◽  
Author(s):  
Toru Arai ◽  
Kin'Ya Abe ◽  
Hiroto Matsuoka ◽  
Mitsuhiro Yoshida ◽  
Masahide Mori ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Mrna Expression ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Type I ◽  
Myeloperoxidase Activity ◽  
Human Lung Fibroblast

Interleukin (IL)-10 has been shown to reduce many inflammatory reactions. We investigated the in vivo effects of IL-10 on a bleomycin-induced lung injury model. Hemagglutinating virus of Japan (HVJ)-liposomes containing a human IL-10 expression vector (hIL10-HVJ) or a balanced salt solution as a control (Cont-HVJ) was intraperitoneally injected into mice on day −3. This was followed by intratracheal instillation of bleomycin (0.8 mg/kg) on day 0. Myeloperoxidase activity of bronchoalveolar lavage fluid and tumor necrosis factor-α mRNA expression in bronchoalveolar lavage fluid cells on day 7 and hydroxyproline content of the whole lung on day 21 were inhibited significantly by hIL10-HVJ treatment. However, Cont-HVJ treatment could not suppress any of these parameters. We also examined the in vitro effects of IL-10 on the human lung fibroblast cell line WI-38. IL-10 significantly reduced constitutive and transforming growth factor-β-stimulated type I collagen mRNA expression. However, IL-10 did not affect the proliferation of WI-38 cells induced by platelet-derived growth factor. These data suggested that exogenous IL-10 may be useful in the treatment of pulmonary fibrosis.

Lysosomotropic drugs inhibit maturation of transforming growth factor-β

2008 ◽  
Vol 86 (9) ◽  
pp. 606-612 ◽  
Author(s):  
Julie Basque ◽  
Marc Martel ◽  
Richard Leduc ◽  
André M. Cantin
Keyword(s):  
Growth Factor ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Brefeldin A ◽  
Transforming Growth Factor Β ◽  
Lavage Fluid ◽  
Biologically Active ◽  
Alveolar Epithelial ◽  
Golgi Network ◽  
Human A549

Transforming growth factor-β (TGFβ) is synthesized as a precursor protein, pro-TGFβ, that must be cleaved by a furin-like proteinase before it becomes biologically active. We hypothesized that alkalinization of the trans-Golgi network (TGN)/endosome system may suppress pro-TGFβ processing and decrease TGFβ secretion. This hypothesis was tested in human A549 alveolar epithelial and T98G glioblastoma cell lines and in C57BL/6 mice. Inhibition of furin-like activity with decanoyl-RVKR chloromethylketone suppressed pro-TGFβ processing, thereby significantly reducing the levels of secreted TGFβ. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGFβ processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGFβ. Reduced levels of secreted TGFβ were also associated with a decrease in Smad2 signaling. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFβ. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGFβ processing.

scholarly journals Overexpression of a Kinase-deficient Transforming Growth Factor-β Type II Receptor in Mouse Mammary Stroma Results in Increased Epithelial Branching

1999 ◽  
Vol 10 (4) ◽  
pp. 1221-1234 ◽  
Author(s):  
Heather Joseph ◽  
Agnieszka E. Gorska ◽  
Philip Sohn ◽  
Harold L. Moses ◽  
Rosa Serra
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Branching Morphogenesis ◽  
Mammary Glands ◽  
Dominant Negative ◽  
Type Ii ◽  
Ductal Epithelium ◽  
Lateral Branching

Members of the transforming growth factor-β (TGF-β) superfamily signal through heteromeric type I and type II serine/threonine kinase receptors. Transgenic mice that overexpress a dominant-negative mutation of the TGF-β type II receptor (DNIIR) under the control of a metallothionein-derived promoter (MT-DNIIR) were used to determine the role of endogenous TGF-βs in the developing mammary gland. The expression of the dominant-negative receptor was induced with zinc and was primarily localized to the stroma underlying the ductal epithelium in the mammary glands of virgin transgenic mice from two separate mouse lines. In MT-DNIIR virgin females treated with zinc, there was an increase in lateral branching of the ductal epithelium. We tested the hypothesis that expression of the dominant-negative receptor may alter expression of genes that are expressed in the stroma and regulated by TGF-βs, potentially resulting in the increased lateral branching seen in the MT-DNIIR mammary glands. The expression of hepatocyte growth factor mRNA was increased in mammary glands from transgenic animals relative to the wild-type controls, suggesting that this factor may play a role in TGF-β-mediated regulation of lateral branching. Loss of responsiveness to TGF-βs in the mammary stroma resulted in increased branching in mammary epithelium, suggesting that TGF-βs play an important role in the stromal–epithelial interactions required for branching morphogenesis.

Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-α

1999 ◽  
Vol 277 (5) ◽  
pp. L1045-L1050 ◽  
Author(s):  
William D. Hardie ◽  
Daniel R. Prows ◽  
George D. Leikauf ◽  
Thomas R. Korfhagen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Lavage Fluid ◽  
Transforming Growth Factor Α ◽  
Factor Α ◽  
Mouse Lines

Transforming growth factor-α (TGF-α) is produced in the lung in experimental and human lung diseases; however, its physiological actions after lung injury are not understood. To determine the influence of TGF-α on acute lung injury, transgenic mouse lines expressing differing levels of human TGF-α in distal pulmonary epithelial cells under control of the surfactant protein C gene promoter were generated. TGF-α transgenic and nontransgenic control mice were exposed to polytetrafluoroethylene (PTFE; Teflon) fumes to induce acute lung injury. Length of survival of four separate TGF-α transgenic mouse lines was significantly longer than that of nontransgenic control mice, and survival correlated with the levels of TGF-α expression in the lung. The transgenic line expressing the highest level of TGF-α (line 28) and nontransgenic control mice were then compared at time intervals of 2, 4, and 6 h of PTFE exposure for differences in pulmonary function, lung histology, bronchoalveolar lavage fluid protein and cell differential, and lung homogenate proinflammatory cytokines. Line 28 TGF-α transgenic mice demonstrated reduced histological changes, decreased bronchoalveolar lavage fluid total protein and neutrophils, and delayed alterations in pulmonary function measures of airway obstruction compared with those in nontransgenic control mice. Both line 28 and nontransgenic control mice had similar increases in interleukin-1β protein levels in lung homogenates. In contrast, interleukin-6 and macrophage inflammatory protein-2 levels were significantly reduced in line 28 transgenic mice compared with those in nontransgenic control mice. In the transgenic mouse model, TGF-α protects against PTFE-induced acute lung injury, at least in part, by attenuating the inflammatory response.

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