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NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells
  1. Yaxun Jing1,
  2. Joao Antonio Gimenes2,
  3. Rahul Mishra1,
  4. Duc Pham1,
  5. Adam T Comstock1,
  6. Daohai Yu3,
  7. Umadevi Sajjan1,2,4
  1. 1 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
  2. 2 Department of Thoracic Surgery and Medicine, Temple University, Philadelphia, Pennsylvania, USA
  3. 3 Department of Clinical Sciences, Temple University, Philadelphia, Pennsylvania, USA
  4. 4 Department of Physiology, Temple University, Philadelphia, Pennsylvania, USA
  1. Correspondence to Professor Umadevi Sajjan, Departments of Physiology, and Thoracic Medicine and Surgery, Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz Medical School, Temple University, Philadelphia PA 19140, USA; uma.sajjan{at}


Rationale Goblet cell hyperplasia (GCH) is one of the cardinal features of chronic obstructive pulmonary disease (COPD) and contributes to airways obstruction. Rhinovirus (RV), which causes acute exacerbations in patients with COPD, also causes prolonged airways obstruction. Previously, we showed that RV enhances mucin gene expression and increases goblet cell number in a COPD mouse model. This study examines whether RV causes sustained GCH in relevant models of COPD.

Methods Mucociliary-differentiated COPD and normal airway epithelial cell cultures and mice with normal or COPD phenotype were infected with RV or sham and examined for GCH by immunofluorescence and/or mucin gene expression. In some experiments, RV-infected COPD cells and mice with COPD phenotype were treated with γ-secretase inhibitor or interleukin-13 neutralising antibody and assessed for GCH. To determine the contribution of NOTCH1/3 in RV-induced GCH, COPD cells transduced with NOTCH1/3 shRNA were used.

Results RV-infected COPD, but not normal cell cultures, showed sustained GCH and increased mucin genes expression. Microarray analysis indicated increased expression of NOTCH1, NOTCH3 and HEY1 only in RV-infected COPD cells. Blocking NOTCH3, but not NOTCH1, attenuated RV-induced GCH in vitro. Inhibition of NOTCH signalling by γ-secretase inhibitor, but not neutralising antibody to IL-13, abrogated RV-induced GCH and mucin gene expression.

Conclusions RV induces sustained GCH via NOTCH3 particularly in COPD cells or mice with COPD phenotype. This may be one of the mechanisms that may contribute to RV-induced prolonged airways obstruction in COPD.

  • airway epithelium
  • viral infection
  • copd pathology

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  • Contributors YJ and JAG designed and performed experiments. RM, DP and ATM provided technical assistance with cell culture and animal work. DY performed statistical analysis and wrote description of statistical analysis. US conceived the idea for the manuscript, helped to design appropriate experiments and prepared the manuscript.

  • Funding This work was supported by National Institutes of Health grants HL897720, AT004793 and AT007620 to US.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional regulatory board, University of Michigan, Ann Arbor, Michigan.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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