A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease

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

doi:10.1164/rccm.201707-1331oc

Cited by 33 publications

(29 citation statements)

References 54 publications

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“…The balance of proteinases and anti-proteinases is a classic concept in the pathogenesis of COPD [90]. Two recent murine studies have demonstrated the potential role of a disintegrin and a metalloproteinase domain-8 (ADAM8) and ADAM9 in cigarette smoke induced COPD-like pathology [91, 92]. In one study, cigarette smoke exposed ADAM8 knockout mice had greater lung inflammation, airspace enlargement and small airway goblet cell metaplasia compared to cigarette smoke exposed wildtype mice.…”

Section: Histopathological Features Of Small Airway Disease In Copdmentioning

confidence: 99%

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The pathology of small airways disease in COPD: historical aspects and future directions

et al. 2019

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Small airways disease (SAD) is a cardinal feature of chronic obstructive pulmonary disease (COPD) first recognized in the nineteenth century. The diverse histopathological features associated with SAD underpin the heterogeneous nature of COPD. Our understanding of the key molecular mechanisms which drive the pathological changes are not complete. In this article we will provide a historical overview of key histopathological studies which have helped shape our understanding of SAD and discuss the hallmark features of airway remodelling, mucous plugging and inflammation. We focus on the relationship between SAD and emphysema, SAD in the early stages of COPD, and the mechanisms which cause SAD progression, including bacterial colonization and exacerbations. We discuss the need to specifically target SAD to attenuate the progression of COPD.

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Section: Histopathological Features Of Small Airway Disease In Copdmentioning

confidence: 99%

“…Interestingly there was no difference in the extent of small airway fibrosis. ADAM8 expression was also reduced in COPD patients compared to controls [91]. In contrast, ADAM9 was shown to promote airspace enlargement, goblet cell metaplasia and fibrosis.…”

Section: Histopathological Features Of Small Airway Disease In Copdmentioning

confidence: 99%

The pathology of small airways disease in COPD: historical aspects and future directions

et al. 2019

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“…Proteases and their regulators, such as AAT (alpha-1 antitrypsin), have garnered recent interest for their role in COPD pathogenesis. Polverino and colleagues reported that the expression of ADAM8 (ADAM metallopeptidase domain 8), a metalloproteinase, was higher in the airway epithelia of nonsmokers than in smokers without COPD and was further decreased in individuals with COPD (12). Similarly, cigarette smoke-exposed mice had decreased ADAM8 expression, and ADAM8 knockout mice developed more emphysema after cigarette smoke exposure than wild-type mice.…”

Section: Protease-antiprotease Balancementioning

confidence: 99%

“…Similarly, cigarette smoke-exposed mice had decreased ADAM8 expression, and ADAM8 knockout mice developed more emphysema after cigarette smoke exposure than wild-type mice. ADAM8 induced epidermal growth factor receptor shedding from airway epithelial cells, leading to decreased mucin gene expression (11,12). In contrast, Wang and colleagues reported higher ADAM9 expression in airway epithelia from patients with COPD than from nonsmokers and smokers without COPD (14).…”

Section: Protease-antiprotease Balancementioning

confidence: 99%

Update in Chronic Obstructive Pulmonary Disease 2018

Labaki

Kimmig

Mutlu

et al. 2019

Am J Respir Crit Care Med

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“…Most prior studies of proteinases in the pathogenesis of COPD have focused on the contributions of serine proteinases, matrix metalloproteinases (MMPs), and cysteine proteinases [ 4 ]. However, the family of ADAM proteinases (a d isintegrin a nd m etalloproteinase domain) are emerging as key contributors to COPD as two family members (ADAM8 and ADAM9) have been recently strongly linked to COPD [ 6 , 7 ]. ADAMs are multi-domain proteinases that are expressed on cell surfaces [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction

et al. 2020

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Background A d isintegrin a nd m etalloproteinase domain-15 (ADAM15) is expressed by activated leukocytes, and fibroblasts in vitro. Whether ADAM15 expression is increased in the lungs of COPD patients is not known. Methods ADAM15 gene expression and/or protein levels were measured in whole lung and bronchoalveolar lavage (BAL) macrophage samples obtained from COPD patients, smokers, and non-smokers. Soluble ADAM15 protein levels were measured in BAL fluid (BALF) and plasma samples from COPD patients and controls. Cells expressing ADAM15 in the lungs were identified using immunostaining. Staining for ADAM15 in different cells in the lungs was related to forced expiratory volume in 1 s (FEV 1 ), ratio of FEV 1 to forced vital capacity (FEV 1 /FVC), and pack-years of smoking history. Results ADAM15 gene expression and/or protein levels were increased in alveolar macrophages and whole lung samples from COPD patients versus smokers and non-smokers. Soluble ADAM15 protein levels were similar in BALF and plasma samples from COPD patients and controls. ADAM15 immunostaining was increased in macrophages, CD8 + T cells, epithelial cells, and airway α-smooth muscle (α-SMA)-positive cells in the lungs of COPD patients. ADAM15 immunostaining in macrophages, CD8 + T cells and bronchial (but not alveolar) epithelial cells was related inversely to FEV 1 and FEV 1 /FVC, but not to pack-years of smoking history. ADAM15 staining levels in airway α-SMA-positive cells was directly related to FEV 1 /FVC. Over-expressing ADAM15 in THP-1 cells reduced their release of matrix metalloproteinases and CCL2. Conclusions These results link increased ADAM15 expression especially in lung leukocytes and bronchial epithelial cells to the pathogenesis of COPD.

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A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease

Abstract: 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.

Cited by 33 publications

References 54 publications

The pathology of small airways disease in COPD: historical aspects and future directions

The pathology of small airways disease in COPD: historical aspects and future directions

Update in Chronic Obstructive Pulmonary Disease 2018

ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction

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