Abstract:
INTRODUCTION:Proteinases with a disintegrin and a metalloproteinase domain (ADAMs) have not been well studied in COPD. We investigated whether ADAM9 is linked to COPD in humans and mice. METHODS:ADAM9 blood and lung levels were measured in COPD patients versus controls, and air- versus cigarette smoke (CS)-exposed wild-type (WT) mice. WT and Adam9-/- mice were exposed to air or CS for 1-6 months, and COPD-like lung pathologies were measured. RESULTS:ADAM9 staining was increased in lung epithelial cells and macrophages in smokers and even more so in COPD patients and correlated directly with pack-year smoking history and inversely with airflow obstruction and/or FEV1 % predicted. Bronchial epithelial cell ADAM9 mRNA levels were higher in COPD patients than controls and correlated directly with pack-year smoking history. Plasma, BALF and sputum ADAM9 levels were similar in COPD patients and controls. CS exposure increased Adam9 levels in WT murine lungs. Adam9-/- mice were protected from emphysema development, small airway fibrosis, and airway mucus metaplasia. CS-exposed Adam9-/- mice had reduced lung macrophage counts, alveolar septal cell apoptosis, lung elastin degradation, and shedding of VEGFR2 and EGFR in BALF samples. Recombinant ADAM9 sheds EGF and VEGF receptors from epithelial cells to reduce activation of the Akt pro-survival pathway and increase cellular apoptosis. CONCLUSIONS:ADAM9 levels are increased in COPD lungs and linked to key clinical variables. Adam9 promotes emphysema development, and large and small airway disease in mice. Inhibition of ADAM9 could be a therapeutic approach for multiple COPD phenotypes.
journal_name
Am J Respir Crit Care Medauthors
Wang X,Polverino F,Rojas-Quintero J,Zhang D,Sánchez J,Yambayev I,Lindqvist E,Virtala R,Djukanovic R,Davies DE,Wilson S,O'Donnell R,Cunoosamy D,Hazon P,Higham A,Singh D,Olsson H,Owen CAdoi
10.1164/rccm.201711-2300OCsubject
Has Abstractpub_date
2018-06-04 00:00:00eissn
1073-449Xissn
1535-4970pub_type
杂志文章abstract::Long-term cognitive impairment is common among ICU survivors, but its natural history remains unclear. In this systematic review, we report the frequency of cognitive impairment in ICU survivors across various time points after ICU discharge that were extracted from 46 of the 3,350 screened records. Prior studies used...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
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abstract::The role of strain difference in the response to cigarette smoke was investigated in mice. Mice of the strains DBA/2 and C57BL/6J responded to acute cigarette smoke with a decrease of the antioxidant defenses of their bronchoalveolar lavage (BAL) fluids. On the other hand, under these conditions ICR mice increased the...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
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journal_title:American journal of respiratory and critical care medicine
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doi:10.1164/ajrccm.150.3.8087340
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abstract::Increased serum levels of mucin-associated antigen have been previously demonstrated in patients with cystic fibrosis (CF) and interstitial pneumonia, and in lung-transplant recipients. The present study assessed the serum airway mucin levels in patients with acute respiratory distress syndrome (ARDS). An enzyme-linke...
journal_title:American journal of respiratory and critical care medicine
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pub_type: 杂志文章,评审
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abstract:RATIONALE:Although the transplantation of induced pluripotent stem cell (iPSC)-derived cells harbors enormous potential for the treatment of pulmonary diseases, in vivo data demonstrating clear therapeutic benefits of human iPSC-derived cells in lung disease models are missing. OBJECTIVES:We have tested the therapeuti...
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journal_title:American journal of respiratory and critical care medicine
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更新日期:1998-02-01 00:00:00
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journal_title:American journal of respiratory and critical care medicine
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doi:10.1164/rccm.201105-0784OC
更新日期:2012-02-15 00:00:00
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更新日期:2001-10-15 00:00:00
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更新日期:2000-07-01 00:00:00
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更新日期:2000-02-01 00:00:00
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更新日期:2011-05-01 00:00:00
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更新日期:2006-12-15 00:00:00
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abstract::To determine the status of activation of lymphocytes and the role of cytokines on the inflammatory response of the bronchial mucosa in toluene diisocyanate (TDI) asthma, we performed a quantitative analysis of bronchial biopsies obtained from 15 subjects with TDI-induced asthma and seven normal control subjects. Marke...
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abstract::Idiopathic pulmonary fibrosis (IPF) is a generally fatal disorder with a reported median survival of 3 to 6 yr. This has been based on relatively few studies with diagnoses inconsistently confirmed by adequate lung biopsy. Retrospective analysis of 104 patients with IPF who had open lung biopsy (OLB) at Mayo Medical C...
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更新日期:1995-04-01 00:00:00
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journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:2004-10-01 00:00:00
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更新日期:2001-09-15 00:00:00
abstract:RATIONALE:Venous thromboembolism is difficult to diagnose in critically ill patients and may increase morbidity and mortality. OBJECTIVES:To evaluate the cost-effectiveness of strategies to reduce morbidity from venous thromboembolism in critically ill patients. METHODS:A Markov decision analytic model to compare wee...
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更新日期:2011-12-01 00:00:00
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journal_title:American journal of respiratory and critical care medicine
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journal_title:American journal of respiratory and critical care medicine
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更新日期:2016-06-01 00:00:00
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journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1164/ajrccm.150.3.8087360
更新日期:1994-09-01 00:00:00
abstract:RATIONALE:Childhood sleep-disordered breathing ranges in severity from primary snoring to obstructive sleep apnea and is associated with behavioral and neurocognitive deficits. It remains unknown why children with primary snoring, who do not experience peripheral oxygen desaturation or sleep fragmentation, experience s...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
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更新日期:2018-06-01 00:00:00
abstract::To determine if gastric intramucosal pH changes during weaning from mechanical ventilation are related to gastric mucosal blood flow modifications, we studied 16 ventilator-supported patients with chronic obstructive pulmonary disease (COPD) who tolerated a 2-h trial of spontaneous breathing with pressure support vent...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.160.5.9901018
更新日期:1999-11-01 00:00:00