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

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.

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

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.26.4.4594 ◽

2002 ◽

Vol 26 (4) ◽

pp. 430-437 ◽

Cited By ~ 21

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

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.5.l1045 ◽

1999 ◽

Vol 277 (5) ◽

pp. L1045-L1050 ◽

Cited By ~ 11

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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