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.

Dose-dependent lung remodeling in transgenic mice expressing transforming growth factor-α

2001 ◽  
Vol 281 (5) ◽  
pp. L1088-L1094 ◽  
Author(s):  
William D. Hardie ◽  
Alyssa Piljan-Gentle ◽  
Michelle R. Dunlavy ◽  
Machiko Ikegami ◽  
Thomas R. Korfhagen
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Lavage Fluid ◽  
Proliferating Cells ◽  
Transforming Growth Factor Α ◽  
Lung Remodeling ◽  
Transgenic Lines ◽  
Factor Α ◽  
Dose Dependent

Transgenic mice overexpressing human transforming growth factor-α (TGF-α) develop emphysema and fibrosis during postnatal alveologenesis. To assess dose-related pulmonary alterations, four distinct transgenic lines expressing different amounts of TGF-α in the distal lung under control of the surfactant protein C (SP-C) promoter were characterized. Mean lung homogenate TGF-α levels ranged from 388 ± 40 pg/ml in the lowest expressing line to 1,247 ± 33 pg/ml in the highest expressing line. Histological assessment demonstrated progressive alveolar airspace size changes that were more severe in the higher expressing TGF-α lines. Pleural and parenchymal fibrosis were only detected in the highest expressing line ( line 28), and increasing terminal airspace area was associated with increasing TGF-α expression. Hysteresis on pressure-volume curves was significantly reduced in line 28 mice compared with other lines of mice. There were no differences in bronchoalveolar lavage fluid cell count or differential that would indicate any evidence of lung inflammation among all transgenic lines. Proliferating cells were increased in line 28 without alterations of numbers of type II cells. We conclude that TGF-α lung remodeling in transgenic mice is dose dependent and is independent of pulmonary inflammation.

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.

Dose-Related Protection from Nickel-Induced Lung Injury in Transgenic Mice Expressing Human Transforming Growth Factor- α

2002 ◽  
Vol 26 (4) ◽  
pp. 430-437 ◽  
Author(s):  
William D. Hardie ◽  
Daniel R. Prows ◽  
Alyssa Piljan-Gentle ◽  
Michelle R. Dunlavy ◽  
Scott C. Wesselkamper ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Α ◽  
Factor Α

Soluble Transforming Growth Factor-α Is Present in the Pulmonary Edema Fluid of Patients With Acute Lung Injury

CHEST Journal ◽  
1997 ◽  
Vol 111 (3) ◽  
pp. 652-656 ◽  
Author(s):  
Asha N. Chesnutt ◽  
Farrah Kheradmand ◽  
Hans G. Folkesson ◽  
Michael Alberts ◽  
Michael A. Matthay
Keyword(s):  
Acute Lung Injury ◽  
Growth Factor ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Α ◽  
Edema Fluid ◽  
Factor Α

Interleukin-1β augments in vitro alveolar epithelial repair

2000 ◽  
Vol 279 (6) ◽  
pp. L1184-L1190 ◽  
Author(s):  
Thomas Geiser ◽  
Pierre-Henri Jarreau ◽  
Kamran Atabai ◽  
Michael A. Matthay
Keyword(s):  
Acute Lung Injury ◽  
Growth Factor ◽  
Lung Injury ◽  
Wound Repair ◽  
Transforming Growth Factor ◽  
Epithelial Repair ◽  
Transforming Growth Factor Α ◽  
Alveolar Epithelial ◽  
Factor Α

Biologically active interleukin (IL)-1β is present in the pulmonary edema fluid obtained from patients with acute lung injury and has been implicated as an important early mediator of nonpulmonary epithelial wound repair. Therefore, we tested the hypothesis that IL-1β would enhance wound repair in cultured monolayers from rat alveolar epithelial type II cells. IL-1β (20 ng/ml) increased the rate of in vitro alveolar epithelial repair by 118 ± 11% compared with that in serum-free medium control cells ( P < 0.01). IL-1β induced cell spreading and migration at the edge of the wound but not proliferation. Neutralizing antibodies to epidermal growth factor (EGF) and transforming growth factor-α or inhibition of the EGF receptor by tyrphostin AG-1478 or genistein inhibited IL-1β-induced alveolar epithelial repair, indicating that IL-1β enhances in vitro alveolar epithelial repair by an EGF- or transforming growth factor-α-dependent mechanism. Moreover, the mitogen-activated protein kinase pathway is involved in IL-1β-induced alveolar epithelial repair because inhibition of extracellular signal-regulated kinase activation by PD-98059 inhibited IL-1β-induced alveolar epithelial repair. In conclusion, IL-1β augments in vitro alveolar epithelial repair, indicating a possible novel role for IL-1β in the early repair process of the alveolar epithelium in acute lung injury.

scholarly journals Mammary Carcinogenesis Is Preceded by Altered Epithelial Cell Turnover in Transforming Growth Factor-α and c-myc Transgenic Mice

2006 ◽  
Vol 169 (5) ◽  
pp. 1821-1832 ◽  
Author(s):  
Teresa A. Rose-Hellekant ◽  
Kristin M. Wentworth ◽  
Sarah Nikolai ◽  
Donald W. Kundel ◽  
Eric P. Sandgren
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Transgenic Mice ◽  
Transforming Growth Factor ◽  
Mammary Carcinogenesis ◽  
Cell Turnover ◽  
Transforming Growth Factor Α ◽  
Factor Α

Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

2021 ◽  
Author(s):  
Irina N. Baranova ◽  
Alexander V. Bocharov ◽  
Tatyana G. Vishnyakova ◽  
Zhigang Chen ◽  
Anna A. Birukova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protective Role ◽  
Lung Damage ◽  
Wild Type ◽  
Class B ◽  
Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

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