Treatment with an interleukin-6 neutralizing antibody significantly reduced airway mucus hypersecretion (AMH) in chronic obstructive pulmonary disease (COPD), based on data from human and mouse cells in a human organoid model.
AMH plays a large part in aggravating airway obstruction in patients with COPD, Yuan-Yuan Wei, MD, of First Affiliated Hospital of Anhui Medical University, Hefei, China, and colleagues wrote.
Current pharmacotherapies relieve COPD symptoms and improve exercise tolerance, but have not proven effective for relieving the airflow limitations caused by mucus accumulation that “leads to irreversible structural damage and an unfavorable prognosis,” the researchers said. Although reducing AMH could help manage COPD, the molecular mechanisms of action have not been fully explored.
In a study published in Biomedicine & Pharmacotherapy , the researchers examined the relationship between IL-6 and AMH. Since IL-6 has been shown to cause overexpression of the mucin-type protein known as Muc5ac, they hypothesized that IL-6 antibodies (IL-6Ab) might block this protein elevation.
The researchers recruited 30 adults with COPD and 30 controls from a single center. Bronchial epithelial cells were isolated from the participants and measured the levels of Muc5ac protein and mRNA in the lung tissue. Compared with controls, COPD patients had elevated Muc5ac positively correlated with IL-6.
The researchers then created an organoid model of a trachea for COPD patients and controls. In the model, Muc5ac was similarly elevated in COPD patients, compared with controls. “Furthermore, IL-6 significantly induced excessive secretion of mucus in the organoid model of trachea in COPD patients as observed under electron microscope, and IL-6Ab attenuated these effects,” they noted.
IL-6 significantly increased both Muc5ac mRNA and protein expression in the organoid model of trachea (P < .0001 and P < .005, respectively), but both of these significantly decreased when treated with IL-6Ab (P < .0001 and P < .05, respectively).
The researchers also examined human and mouse cells to explore the mechanism of action of IL-6Ab. Using high-throughput sequencing, they found that the IL-6Ab induced nuclear translocation of the Nrt2 gene in COPD patients, and that this action promoted the effect of IL-6Ab on excessive mucus secretion.
The study findings were limited by the relatively small study population from a single center, the researchers noted.
However, the results support the potential of IL-6Ab as “a novel therapeutic strategy in the treatment of IL-6–induced hypersecretion of airway mucus so as to improve airflow limitations in COPD,” they concluded.
The study was supported by supported by the National Natural Science Foundation of China and the Scientific Research Project of Education Department of Anhui Province. The researchers had no financial conflicts to disclose.