ADAM9: A Damaging Player in Chronic Obstructive Pulmonary Disease
Year: 2018
Type: editorial
Abstract: A Damaging Player in Chronic Obstructive Pulmonary DiseaseThe inflammatory smoking-associated condition chronic obstructive pulmonary disease (COPD) can be broadly conceived as simple alveolar enlargement coupled with airway inflammation (1), which together culminate in airflow obstruction (2).However, underlying these qualitative changes in the lungs of COPD sufferers is a host of complex, interdependent processes combined in a sometimes paradoxical fashion, all of which conspire to increase airway resistance.The emphysema seen in COPD is a wellknown example of excessive extracellular matrix degradation leading to proteolytic tissue loss (3).In part because of this loss of matrix anchoring (4), and in part because of reduced resiliency (and a tendency toward apoptosis) of the alveolar pneumocytes ( 5), the cellular units that overlie these septae also are lost in COPD, causing emphysema.However, it is now established that COPD is also associated with excesses of abnormal extracellular matrix deposition in the pulmonary parenchyma (6), which, probably along with other mechanisms (7, 8), culminates in dramatic pruning of the small airways.The third major pathophysiologic derangement of COPD pertains to the larger airways, which undergo hypertrophic and metaplastic remodeling, causing increased mucus production and large-airway inflammation, that is, chronic bronchitis.These complex and seemingly disparate disease characteristics, as well as a predisposition to local and systemic inflammation, generally carry forward in patients, albeit at a slower rate, even if smoking cessation is achieved once COPD has become established (9, 10).In this issue of the Journal, Wang and colleagues (pp.1500-1518) describe a mediator, ADAM9 (a disintegrin and metalloprotease domain-9), that was previously linked to acute lung injury (11) and appears to be upregulated in inflammatory cells in response to cigarette smoke (CS) injury ( 12).They relate the activity of this enzyme to a surprising number of the diverse pathologies seen in COPD . . .almost one for each of the seven functional domains on this pleiotropic enzyme.This suggests a potential proximity of ADAM9 to the pathogenetic epicenter of COPD, and thus implies that ADAM9 has considerable potential as a therapeutic target in these wide-ranging dysfunctions.The authors used a combination of ADAM9 2/2 CS-exposed animals, enzymologic studies, and studies of tissue, cells, and clinical samples from subjects with and without various degrees of COPD and/or CS exposure to demonstrate these findings in vivo and in vitro.The findings include multiple distinct effects of ADAM9 on all three of the key pathophysiologic mechanisms of COPD mentioned above (Figure 1): 1) emphysema (direct elastolysis, excessive alveolar pneumocyte apoptosis, and increased accumulation of leukocytes, especially alveolar macrophages); 2) small-airways fibrosis (which may be due to both the
Authors: Derek W. Russell, Amit Gaggar
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2903643417