Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice
| Autor: | George Minowada, Jihane Faress, Jeffrey A. Kern, James Carroll, Bethany B. Moore, David Nethery |
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| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Receptor ErbB-3 Receptor ErbB-2 Physiology Pulmonary Fibrosis medicine.medical_treatment Mice Transgenic Lung injury Bleomycin Receptor tyrosine kinase Mice chemistry.chemical_compound Physiology (medical) Internal medicine Pulmonary fibrosis medicine Animals Humans skin and connective tissue diseases Receptor Lung biology Growth factor Genetic Therapy medicine.disease Survival Analysis Recombinant Proteins Mice Inbred C57BL Survival Rate Treatment Outcome Endocrinology chemistry Trk receptor biology.protein Cancer research Neuregulin |
| Zdroj: | Journal of Applied Physiology. 99:298-307 |
| ISSN: | 1522-1601 8750-7587 |
| DOI: | 10.1152/japplphysiol.01360.2004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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