A new study led by researchers at Yale School of Medicine in Connecticut and Brown University in Rhode Island recently revealed that cigarette smoke interferes with a specific protein that plays a key role in the development of chronic obstructive pulmonary disease (COPD). The study is entitled “Suppression of NLRX1 in chronic obstructive pulmonary disease” and was published in the Journal of Clinical Investigation.

COPD is one of the most common lung diseases and a major cause of morbidity and mortality worldwide, being the third leading cause of death in the United States. It is a progressive disease in which individuals develop serious problems in breathing with obstruction of the airways, shortness of breath (dyspnea) and acute exacerbations. Smoking is considered to be the leading cause of COPD.

It has been previously shown that in COPD patients, cigarette smoke triggers an immune response pathway, known as MAVS/RIG-I-like helicase (MAVS/RLH), that induces inflammation and damage to the lung tissue. The mechanisms that control the activation and repression of this pathway are poorly elucidated, but the protein NLRX1 (nucleotide-binding domain and leucine-rich repeat–containing protein X1) has been reported to act as an inhibitor of the MAVS/RLH pathway, preventing its activation.

In this study, researchers hypothesized that cigarette smoke could target NLRX1, abrogating its activity causing the lung tissue damage typically seen in COPD patients. The team assessed NLRX1 expression in three COPD patient cohorts and analyzed the possible relationship between cigarette smoke, NLRX1 expression, MAVS/RLH pathway and disease severity in mice models.

Researchers found that in the analyzed COPD patients, the expression of NLRX1was markedly reduced, and that this reduction directly correlated with disease severity and a poorer pulmonary function, prognosis and quality of life. “We observed that the levels of this molecule could explain diverse aspects of disease severity and patient’s symptoms,” said the study’s lead author Dr. Min-Jong Kang in a news release.

Using mice models, researchers found that cigarette smoke inhibits NLRX1 expression. Animals lacking NLRX1 exhibited pulmonary inflammation, alveolar destruction, protease proteins induction and high levels of lung cell death. Interestingly, when NLRX1was overexpressed in mice exposed to cigarette smoke, the MAVS/RLH pathway was inhibited, halting disease progression and improving the pulmonary condition of the animals. The research team has filed for a provisional patent based on this finding.

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“NLRX1 is a critical inhibitor of MAVS/RIG-like helicase signaling that is affected by cigarette smoking exposure,” concluded Dr. Kang. The team proposed that NLRX1 levels could be used as a potential predictor of a patient’s risk for developing COPD and of disease severity.

The research team concluded that cigarette smoke inhibits NLRX1, facilitating MAVS/RHL activation and subsequent inflammation, remodeling and cell death responses in the lungs of COPD patients. One of the team’s next goals is to determine how cigarette smoke suppresses NLRX1 expression in patients.