Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice

Abstract

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.

Neuregulin-1-Human Epidermal Receptor-2 Signaling Is a Central Regulator of Pulmonary Epithelial Permeability and Acute Lung Injury

“…Murine bleomycin lung injury has an early, inflammatory phase marked by epithelial damage and loss of barrier function followed by fibrosis, closely modeling some features of human ALI (20). Inactivation of HER2 signaling in transgenic mice or pharmacologic blockade of the NRG-1-HER2 pathway prior to bleomycin injury attenuated pulmonary fibrosis in mice at 21 days as well as decreased bron-choalveolar lavage (BAL) protein at 3 days, suggesting that HER2 might participate in signaling relevant to late and early phases of injury (21,22).…”

“…Western Blotting-Western blotting was performed as described previously (21,22). For all experimental conditions, cells were pretreated with specific inhibitors for 2 h before IL-1␤ stimulation: AG825 (10 M) and TAPI-2 (100 M).…”

“…Murine Lung Injury Models-Bleomycin-induced lung injury was performed in mice as described previously (21,22). Control animals were injected with an equal volume of PBS.…”

“…Injury was assessed on day 3. Indices of lung injury (BAL, lung collection, and histology) were performed as described previously (21,22).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…In intact mice, lung injury by bleomycin resulted in Erbb3 activation as part of the response, along with inflammatory cell infiltration and collagen deposition. 370 In mice where Erbb3-mediated effects were blocked in lung by a dominant-negative Erbb3 transgene, these outcomes were diminished after bleomycin and survival was improved. Blockade of Erbb2/Erbb3 signaling with the 2C4 monoclonal antibody had a similar effect.…”