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J Appl Physiol (February 24, 2005). doi:10.1152/japplphysiol.01360.2004
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Submitted on December 7, 2004
Accepted on February 19, 2005

Expression of Mutant Human Epidermal Receptor 3 Attenuates Lung Fibrosis and Improves Survival in Mice

David E. Nethery1, Bethany B. Moore2, George Minowada1, James Carroll3, Jihane A. Faress1, and Jeffrey A. Kern1*

1 Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
2 Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI, USA
3 Department of Internal Medicine, Pulmonary and Critical Care Division, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA

* To whom correspondence should be addressed. E-mail: jeffrey.kern{at}uhhs.com.

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 (BALF) increased after injury similar to non-transgenic littermate control animals. However, HER2/HER3 was not activated and DNHER3 animals displayed fewer lung morphologic changes at 10 and 21 days after injury (p<0.01). In addition, they contained 51% less collagen in injured lungs (p<0.05). TGF{beta}-1 did not increase in BALF from DNHER3 mice compared to non-transgenic littermate mice (p<0.05), suggesting a mechanism for the decreased fibrosis was lack of TGF{beta}-1 induction in DNHER3 mice. Severe lung injury (0.08 units bleomycin) resulted in 80% mortality of non-transgenic mice, but only 35% mortality in DNHER3 transgenic mice (p=0.04). Thus, inhibition of HER2/HER3 signaling protects against pulmonary fibrosis and improves survival.




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