期刊
JOURNAL OF APPLIED PHYSIOLOGY
卷 99, 期 1, 页码 298-307出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/japplphysiol.01360.2004
关键词
lung injury; bleomycin; growth factors; receptor tyrosine kinases; neuregulin
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-beta(1) 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-beta(1) 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.
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