Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice.
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-beta1 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-beta1 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.
Nethery
David E
DE
Dept. of Internal Medicine, Pulmonary and Critical Care Division, Univ. Hospitals of Cleveland, Cleveland, OH 44106, USA.
Moore
Bethany B
BB
Minowada
George
G
Carroll
James
J
Faress
Jihane A
JA
Kern
Jeffrey A
JA
D000818:Animals; D001761:Bleomycin; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome
D001761:Bleomycin; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins