B29-12 Airway Smooth Muscle Tone Contributes to Ventilation Heterogeneity in Healthy But Not Asthmatic Lungs

Rationale Asthma is a heterogeneous disease characterized by regional differences in airway inflammation, airway remodeling, and airway smooth muscle tone within the lung. Ventilation heterogeneity (VH), defined as the non-uniform distribution of airflow throughout the lungs, is markedly increased in asthma and impairs lung function by limiting gas transport and exchange. Airway hyperreactivity and mucus plugging likely contribute to the VH seen in asthma, but the relative contribution of each is unknown. We hypothesized that a decrease in airway smooth muscle tone would decrease airway hyperreactivity and improve VH in the presence of airway remodeling and inflammation. Methods C57BL/6 mice (12 weeks) were used in the standard acute OVA model of airway inflammation. The day following the final challenge, formoterol, a beta-2 agonist known to ease smooth muscle tone, was instilled intranasally. Thirty minutes after formoterol treatment, 4DMedical functional lung imaging was performed to visualize and quantify VH. Airway hyperreactivity was measured using flexiVent. Bronchoalveolar lavage was performed to collect immune cells, followed by lung harvest to quantify airway remodeling by histological analysis and flow cytometry. Results As expected, formoterol treatment decreased airway hyperreactivity in the OVA model, confirming the presence of pre-constricted airway smooth muscle (Rrs (cmH2O·s/mL), mean ± SEM: without formoterol 2.15 ± 0.45; with formoterol 1.23 ± 0.12, n = 4, p = 0.02). VH was also increased in OVA mice compared to naïve animals (VH (%): OVA 43.82 ± 5.85; naïve 32.93 ± 2.69, n = 4-5, p = 0.03). Formoterol-treated naïve mice showed significant decreases in the VH of large airways and the ventilation defect percentage compared to untreated naïve mice (VH large, naïve: without formoterol 24.89 ± 2.29; with formoterol 18.39 ± 1.26, n = 5, p = 0.03). In contrast, OVA mice treated with formoterol showed no change in VH compared to untreated OVA mice (VH large, OVA: without formoterol 33.01 ± 5.61; with formoterol 30.89 ± 3.07, n = 4, p = 0.66). High eosinophilic inflammation, robust goblet cell metaplasia, increased collagen synthesis by airway smooth muscle cells, and smooth muscle hypertrophy were present in OVA mice compared to naïve mice. Conclusion Formoterol treatment reduced airway hyperreactivity but had no significant effects on VH in asthmatic lungs. Contrarily, healthy lungs exhibited a more uniform ventilation distribution in response to formoterol treatment. These findings suggest that airway smooth muscle tone has a minimal contribution to VH attributed to asthma but contributes to physiological VH. Inflammation and airway remodeling, but not smooth muscle tone, drive VH in murine asthmatic lungs. This abstract is funded by: None