A disintegrin and metalloproteinase domain-8: A novel protective proteinase in chronic obstructive pulmonary disease

Francesca Polverino, Joselyn Rojas-Quintero, Xiaoyun Wang, Hans Petersen, Li Zhang, Xiaoyan Gai, Andrew Higham, Duo Zhang, Kushagra Gupta, Amit Rout, Ilyas Yambayev, Victor Pinto-Plata, Lynette M. Sholl, Danen Cunoosamy, Bartolomé R. Celli, James Goldring, Dave Singh, Yohannes Tesfaigzi, Jadwiga Wedzicha, Henric OlssonCaroline A. Owen

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Rationale:ADAM8(a disintegrin and metalloproteinase domain-8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of chronic obstructive pulmonary disease (COPD) is unknown. Objectives: To determine whether the expression of ADAM8 is increased in the lungs of patients with COPD and cigarette smoke (CS)-exposed mice, and whether ADAM8 promotes the development of COPD. Methods: ADAM8 levels were measured in lung, sputum, plasma, and/or BAL fluid samples from patients with COPD, smokers, and nonsmokers, and wild-type (WT) mice exposed to CS versus air. COPD-like lung pathologies were compared in CS-exposed WT versus Adam8-/- mice. Measurements and Main Results: ADAM8 immunostaining was reduced in macrophages, and alveolar and bronchial epithelial cells in the lungs of patients with COPD versus control subjects, and CS-versus air-exposed WT mice. ADAM8 levels were similar in plasma, sputum, and BAL fluid samples from patients with COPD and control subjects. CS-exposed Adam8-/- mice had greater airspace enlargement and airway mucus cell metaplasia than WT mice, but similar small airway fibrosis. CS-exposed Adam8-/- mice had higher lung macrophage counts, oxidative stress levels, and alveolar septal cell death rates, but lower alveolar septal cell proliferation rates and soluble epidermal growth factor receptor BAL fluid levels than WT mice. Adam8 deficiency increased lung inflammation by reducing CS-induced activation of the intrinsic apoptosis pathway in macrophages. Human ADAM8 proteolytically shed the epidermal growth factor receptor from bronchial epithelial cells to reduce mucin expression in vitro. Adam8 bone marrow chimera studies revealed that Adam8 deficiency in leukocytes and lung parenchymal cells contributed to the exaggerated COPD-like disease in Adam8-/- mice. Conclusions: Adam8 deficiency increases CS-induced lung inflammation, emphysema, and airway mucus cell metaplasia. Strategies that increase or prolong ADAM8's expression in the lung may have therapeutic efficacy in COPD.

Original languageEnglish (US)
Pages (from-to)1254-1267
Number of pages14
JournalAmerican journal of respiratory and critical care medicine
Issue number10
StatePublished - Nov 15 2018
Externally publishedYes


  • Airway mucus cell metaplasia
  • EGFR shedding
  • Intrinsic apoptosis pathway
  • Lung inflammation
  • Macrophage

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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