D21-05 Leptin- and Oxidative Stress-induced Periostin Secretion in Airway Fibroblasts Is Associated With 129XeMRI-localized Abnormal Airway Regions in Asthma With Comorbid Obesity

Abstract Rationale Obesity, a prevalent comorbidity of asthma, worsens disease severity and blunts responses to asthma therapies. Airway remodeling and subepithelial fibrosis are key features of asthma but remain poorly defined in asthma with comorbid obesity. Conventional spirometry fails to localize sites of remodeling, underscoring the need for imaging-guided approaches. Emerging evidence from studies of asthma participants utilizing 129Xe magnetic resonance imaging (129XeMRI) reveals distinct regions of ventilation defects, potentially reflecting localized remodeling. We hypothesized that, in asthma participants with obesity, airway fibroblasts isolated from 129XeMRI-defined abnormal airway regions display enhanced periostin secretion in response to obesity-associated profibrotic mediators, such as leptin and oxidative stress. Methods Asthma (n = 12) and non-asthma (n = 5) participants with obesity underwent 129Xe MRI pre- and post-bronchodilator to identify target (abnormal 129XeMRI Vent, RBC or Membrane signaling) and control (normal and bronchodilator-responsive) airway regions. Airway biopsies and bronchoalveolar lavage fluid (BALF) were collected at these specific sites via endobronchial bronchoscopy. Primary airway fibroblasts from these regions were cultured from biopsies and incubated with or without leptin (20 ng/mL), H2O2 (100µM), and/or IL-13 (50 ng/mL) (interleukin-13 - a key profibrotic mediator of asthma). Periostin levels in fibroblast supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). Relationships between periostin secretion, pre-bronchodilator ventilation defect percentage (VDP) at the target and control sites, and BALF adiponectin were evaluated using t-test, Wilcoxon signed rank test or single linear regression with F-test. Results Pre-bronchodilator VDP did not differ between target and control site in asthma or non-asthma (p = 0.72, each comparison). In asthma, baseline periostin levels in airway fibroblasts derived from target site biopsies, but not control site biopsies, positively correlated with segmental pre-bronchodilator VDP (p = 0.037). Airway fibroblasts derived from asthma participants demonstrated increased periostin secretion in target site cells compared with control site cells following combined leptin + H2O2 and leptin + H2O2 + IL-13 exposures (p = 0.046 and p = 0.044, respectively), and the difference between target and control sites for these exposures was significantly greater than baseline (p = 0.02, each comparison). Leptin-induced periostin responses in airway fibroblasts at target and control sites in asthma participants were inversely correlated with BALF adiponectin levels at corresponding target and control sites (p = 0.02). All comparisons were non-significant in non-asthma participants’ airway fibroblasts. Conclusions These findings indicate that fibroblasts isolated from regions of abnormal 129XeMRI-defined lung function in asthma participants with obesity exhibit elevated leptin and oxidative stress-driven periostin production, suggesting a potential mechanistic connection between metabolic dysfunction and regional airway remodeling. This abstract is funded by: NIH/NHLBI 1R01HL153641