TY - JOUR
T1 - A disintegrin and metalloproteinase domain-8
T2 - A novel protective proteinase in chronic obstructive pulmonary disease
AU - Polverino, Francesca
AU - Rojas-Quintero, Joselyn
AU - Wang, Xiaoyun
AU - Petersen, Hans
AU - Zhang, Li
AU - Gai, Xiaoyan
AU - Higham, Andrew
AU - Zhang, Duo
AU - Gupta, Kushagra
AU - Rout, Amit
AU - Yambayev, Ilyas
AU - Pinto-Plata, Victor
AU - Sholl, Lynette M.
AU - Cunoosamy, Danen
AU - Celli, Bartolomé R.
AU - Goldring, James
AU - Singh, Dave
AU - Tesfaigzi, Yohannes
AU - Wedzicha, Jadwiga
AU - Olsson, Henric
AU - Owen, Caroline A.
N1 - Publisher Copyright:
© 2018 by the American Thoracic Society.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - 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.
AB - 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.
KW - Airway mucus cell metaplasia
KW - EGFR shedding
KW - Intrinsic apoptosis pathway
KW - Lung inflammation
KW - Macrophage
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U2 - 10.1164/rccm.201707-1331OC
DO - 10.1164/rccm.201707-1331OC
M3 - Article
C2 - 29750543
AN - SCOPUS:85056630729
SN - 1073-449X
VL - 198
SP - 1254
EP - 1267
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 10
ER -