Protein’s Activity Tied to Emphysema, May Link COPD to Lung Cancer
The protein ADAM17 appears to serve as a switch for chronic obstructive pulmonary disease (COPD), a study in a mouse model of emphysema reports, promoting COPD’s development when activated and alleviating disease features when deficient.
An increase in active ADAM17 is also associated with lung cancer, and may underlie the development of this cancer in COPD patients.
A team led by investigators at Hudson Institute, in Australia, suggest these findings highlight ADAM17 as a potential way of treating COPD.
“This is the first time that ADAM17 inhibition has been shown to be a promising treatment strategy for COPD and emphysema,” Brendan Jenkins, PhD, a study co-author, said in a press release. Emphysema, a severe form of COPD characterized by shortness of breath, causes damage to lung alveoli (air sacs).
The study reporting the findings, “ADAM17 Deficiency Protects Against Pulmonary Emphysema,” was published in the American Journal of Respiratory Cell and Molecular Biology.
COPD is a major risk factor for lung cancer. Current treatments for COPD and emphysema target disease symptoms and complications, but are unable to prevent a long-term decline in lung function.
ADAM17, an enzyme that regulates numerous cell functions through the processing of proteins, is expressed in lung tissue and elevated in animal models of lung diseases, including COPD, asthma, and lung cancer.
ADAM17’s activity is enhanced by a process called phosphorylation that is mediated by the MAPK family of proteins, including ERK, p38 MAPK, and PKC-epsilon.
Researchers assessed the role that ADAM17 plays in emphysema. The team used a mouse model engineered to spontaneously develop emphysema at 6 months of age, as well as tumor-free tissues collected from lung cancer patients with no or mild-to-moderate COPD.
Results showed that while ADAM17 protein expression was comparable in lung cells of emphysema patients and those without emphysema, the proportion of cells expressing phosphorylated (active) ADAM17 was 1.9 times higher in emphysema patient lungs.
Similarly, ADAM17 was expressed at comparable levels in lung cells of the spontaneous emphysema mice model and wild-type (non-mutant) control mice at the pre-emphysema stage (3 months old) and after emphysema onset at 6 months. However, active ADAM17 expression in spontaneous emphysema mice was 3.5 times higher than in controls at age 3 months, and three times higher at 6 months, suggesting that in mice and humans ADAM17 plays a role in emphysema’s development.
At age 6 months, the activity of p38 and ERK1/2 MAPKs, which both activate ADAM17, was impaired in the lungs of emphysema mice compared with controls. Conversely, PKC-epsilon activity was elevated in the 6-month-old emphysema mice, indicating that ADAM17 in the lungs may be activated by the PKC-epsilon signaling pathway during emphysema’s development.
To assess the effects of ADAM17 on emphysema onset, the researchers crossed a mouse with global ADAM17 deficiency with the spontaneous emphysema mouse to generate an ADAM17-deficient emphysema mouse model.
Loss of ADAM17 alleviated the spontaneous development of emphysema in these 6-month-old mice, with evidence of reduced changes in alveolar (lung air sac) structure and lesser airflow impairment. While the emphysema mice experienced loss of alveolar tissue involved in gas exchange in the lungs, emphysema mice without ADAM17 experienced no such changes.
In lung emphysema tissue, alveolar cells undergo apoptosis, a distinct programmed cell death process. In emphysema mice lacking ADAM17, a 60.8% reduction in total apoptotic cells and 43.9% reduction in apoptotic alveolar cells was observed in comparison to emphysema mice with ADAM17.
In other words, the number of surviving alveolar cells was significantly higher in the lungs of ADAM17-deficient mice than in ADAM17-expressing mice. These results suggest that ADAM17 mediates emphysema development by inducing alveolar cell apoptosis.
“Developing effective treatments for COPD and its major debilitating component, pulmonary emphysema, requires an understanding of how alterations at the molecular level affect lung macroscopic architecture,” the scientists wrote. “In this regard, we provide in vivo evidence implicating the protease ADAM17 as a pivotal molecular switch that orchestrates pulmonary emphysema, thus evoking the therapeutic potential of ADAM17 inhibition in the management of COPD.”
Because COPD is frequently linked to smoking, a control mice group was exposed to cigarette smoke for four days. No difference in lung levels of ADAM17 protein was seen in these animals compared with another non-mutant mouse group exposed only to air. However, the lungs of smoke-exposed mice had 2.4 times the active ADAM17 levels of air-exposed mice.
Similar to the engineered emphysema mouse model, smoke-exposed mice — compared with controls — had increased activation of PKC-epsilon, but not other ADAM17-activating MAPKs.
Exposure to cigarette smoke induces characteristics of emphysema in mice, including alveolar cell apoptosis and lung inflammation. In mice lacking ADAM17, smoke exposure failed to induce emphysema features, such that smoke-exposed ADAM17-deficient mice had apoptotic alveolar cell levels and inflammation comparable to air-exposed controls.
“Our study places the protease ADAM17 as a pivotal inducer of pulmonary emphysema and a central mechanistic link between cigarette smoke, COPD (emphysema) and lung cancer,” said Mohamed Saad, PhD, the study’s first author.
According to the team, these data pave “the way for using ADAM17 inhibitors as potential therapeutic agents to treat COPD and emphysema.”
Saad believes it possible “to test whether newly-developed ADAM17 inhibitors will effectively block emphysema and COPD in pre-clinical models, paving the way for these inhibitors to be considered in the future to treat patients,” he said.
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