PMID- 30813222 OWN - NLM STAT- MEDLINE DCOM- 20190607 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 4 DP - 2019 Feb 22 TI - HER2 Signaling Implicated in Regulating Alveolar Epithelial Permeability with Cyclic Stretch. LID - 10.3390/ijms20040948 [doi] LID - 948 AB - Mechanical ventilation can be damaging, and can cause or exacerbate ventilator-induced lung injury (VILI). The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) activates HER2 heterodimerization with HER3, and has been implicated in inflammatory injuries. We hypothesized that HER2 activation contributes to VILI. We analyzed a database of differentially expressed genes between cyclically stretched and unstretched rat alveolar epithelial cells (RAEC) for HER ligands and validated the differential expression. The effect of the ligand and HER2 inhibition on RAEC permeability was tested, and in vivo relevance was assessed in a rat model of VILI. Analysis of our expression array revealed the upregulation of NRG1 and amphiregulin (AREG) with stretch. NRG1 protein, but not AREG, increased after stretch in culture media. Treatment with an NRG1-cleavage inhibitor (TAPI2) or an inhibitor of NRG1-binding (anti-HER3 antibody) reduced HER2 phosphorylation and partially mitigated stretch-induced permeability, with the upregulation of claudin-7. The results were reproduced by treatment with a direct inhibitor of HER2 phosphorylation (AG825). The transfection of microRNA miR-15b, predicted to negatively regulate NRG1, also attenuated stretch-induced permeability, and was associated with lower NRG1 mRNA levels. In rats ventilated at damaging tidal volumes, AG825 partly attenuated VILI. We concluded that cyclic stretch activates HER2 via the HER3 ligand NRG1, leading to increased permeability. Outcomes were mitigated by the downregulation of NRG1, prevention of NRG1 binding, and most strongly by the direct inhibition of HER2. In vivo HER2 inhibition also attenuated VILI. Ligand-dependent HER2 activation is a potential target for reducing VILI. FAU - Yehya, Nadir AU - Yehya N AUID- ORCID: 0000-0002-2996-217X AD - Department of Bioengineering, University of Pennsylvania, 40 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104, USA. yehyan@email.chop.edu. AD - Department of Anesthesiology and Critical Care Medicine, Children' Hospital of Philadelphia and University of Pennsylvania, Suite 7C-26, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA. yehyan@email.chop.edu. FAU - Song, Min Jae AU - Song MJ AUID- ORCID: 0000-0003-1744-0806 AD - Department of Bioengineering, University of Pennsylvania, 40 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104, USA. minjae.song@nih.gov. FAU - Lawrence, Gladys G AU - Lawrence GG AD - Department of Bioengineering, University of Pennsylvania, 40 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104, USA. ggb@seas.upenn.edu. FAU - Margulies, Susan S AU - Margulies SS AUID- ORCID: 0000-0002-3615-7902 AD - Department of Bioengineering, University of Pennsylvania, 40 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104, USA. susan.margulies@gatech.edu. AD - Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering, Emory University School of Medicine, Atlanta, GA 30332, USA. susan.margulies@gatech.edu. LA - eng GR - K23 HL136688/HL/NHLBI NIH HHS/United States GR - R01-HL57204/National Institutes of Health/ GR - K12-HL109009/National Institutes of Health/ GR - K23-Hl136688/National Institutes of Health/ PT - Journal Article DEP - 20190222 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Ligands) RN - 0 (MicroRNAs) RN - 0 (Neuregulin-1) RN - 0 (Nrg1 protein, rat) RN - 0 (RNA, Messenger) RN - 0 (mirn15 microRNA, rat) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM MH - Alveolar Epithelial Cells/*metabolism/*pathology MH - Animals MH - *Cell Membrane Permeability MH - Ligands MH - Male MH - MicroRNAs/metabolism MH - Neuregulin-1/metabolism MH - RNA, Messenger/genetics/metabolism MH - Rats, Sprague-Dawley MH - Receptor, ErbB-2/*metabolism MH - *Signal Transduction MH - *Stress, Mechanical MH - Ventilator-Induced Lung Injury/metabolism PMC - PMC6412492 OTO - NOTNLM OT - HER2 OT - HER3 OT - NRG1 OT - VILI OT - neuregulin-1 OT - ventilator-induced lung injury COIS- The authors declare no conflict of interest, and the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/03/01 06:00 MHDA- 2019/06/08 06:00 PMCR- 2019/02/01 CRDT- 2019/03/01 06:00 PHST- 2019/01/22 00:00 [received] PHST- 2019/02/11 00:00 [revised] PHST- 2019/02/19 00:00 [accepted] PHST- 2019/03/01 06:00 [entrez] PHST- 2019/03/01 06:00 [pubmed] PHST- 2019/06/08 06:00 [medline] PHST- 2019/02/01 00:00 [pmc-release] AID - ijms20040948 [pii] AID - ijms-20-00948 [pii] AID - 10.3390/ijms20040948 [doi] PST - epublish SO - Int J Mol Sci. 2019 Feb 22;20(4):948. doi: 10.3390/ijms20040948.