A76-10 N-actylcysteine Is More Effective Than Rhdnase in Decreasing the Abnormal Elastic Behavior of Sputum From COPD and Bronchiectasis Patients

Rationale Pathologic mucus in muco-obstructive lung diseases, including chronic obstructive pulmonary disease (COPD) and non-CF bronchiectasis, is characterized by increased elastic modulus (G’) which contributes to poor mucus clearance and mucus plugging. DNA and mucin polymers contribute to high G’ values of pathologic airway mucus and mucolytics drugs that cleave DNA or mucin disulfide bridges are potential mucoactive drug strategies. We set out here to conduct ex vivo experiments in sputum from patients with COPD and bronchiectasis to compare the relative effects of recombinant human deoxyribonuclease I (rhDNase) and N-acetyl cysteine (NAC) on the G’ of COPD and bronchiectasis sputum. Methods Spontaneously expectorated sputum was collected from 8 patients with COPD and 12 patients with non-CF bronchiectasis. Using rheology methods previously described (Addante et al. Eur Respir J 2023; 61: 2202022), the effects of NAC and rhDNase on the elastic modulus (G′) of sputum were determined. Briefly, a cone and plate rheometer was used to measure the G′ of the sputum samples at baseline in a frequency sweep from 0.1 to 50 Hz at 5% strain, followed by addition and manual mixing of the test agents at 10% v/w (PBS control, rhDNase, NAC). Drugs were applied, and changes in G’ were measured at 2-minute intervals for 60 minutes. To accommodate baseline variability in sputum G′, the data was normalized using a generalized additive modelling framework (GAM), which generated a smooth term, βj, as function of time (aka normalized G′). Results In sputum from patients with COPD and bronchiectasis, compared to the effects of PBS control, NAC caused a larger decrease in sputum G′, was faster in decreasing sputum G′ by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. In contrast, the effects of rhDANase were not significantly greater than the effects of PBS. Conclusion N-acetylcysteine is more effective than rhDNAse in normalizing the G’ of sputum from patients with COPD and bronchiectasis. These data indicate that disulfide cross linked mucins contribute more than DNA polymers to the abnormal elastic properties of airway mucus in COPD and bronchiectasis.