TGFβ1 Mediates Airway Remodeling Caused by Mechanical Stress during Inspiratory Resistive Breathing

Abstract

Mechanical stress emerging in the airways during acute or persistent bronchoconstriction is considered to be one of the key mechanisms that may foster airway inflammation and remodeling. TGFβ1is a potent mediator of airway remodeling exerting its pro-fibrotic effect by stimulation of fibroblasts proliferation and enhanced deposition of extracellular matrix. The aim of this study was to investigate the association between airway response to inspiratory resistive breathing, TGFβ1production and severity of airway remodeling. A total of 212 subjects (mean age 47.4±1.10 years, 57% males) including 123 patients with asthma (mostly mild-to moderate) and 89 patients with COPD (GOLD stage II – 53%) were enrolled in the study. All the patients underwent a challenge test with 5-min isocapnic (5% CO2) inspiratory resistive breathing with load at 45% of maximum inspiratory pressure to induce mechanical stress in the airways. Lung function parameters including specific airway conductance (sGaw) were measured before and after the test by body plethysmography. Total TGFβ1was assayed by ELISA in exhaled breath condensate collected before and after the inspiratory resistive breathing. Wall thickness (WT) and area (WA) of the apical (b1) and posterior basal (b10) segmental bronchi were calculated automatically based on CT scans data. We found that 24% of patients responded to experimental mechanical stress by ≥20% reduction in sGaw (group I). At the same time, 18.4% of patients demonstrated ≥20% increase in sGaw after the test (group II). There was no difference in the ratio of high amplitude (≥20%) changes of sGaw between asthma and COPD. However, COPD patients more commonly had low amplitude (<20%) response as compared to asthma (66.3% vs. 51.2%, p=0.03). ΔsGaw negatively correlated with WTb1 (R=-0.16, p=0.04), WAb1 (R=-0.17, p=0.03) and WAb10 (R=-0.17, p=0.03). Group I patients had higher degree of airway remodeling than the patients in group II (WTb1 2.4 (2.1-3.1) mm vs. 2.1 (2.0-2.4) mm, p=0.02; WAb1 69.4 (63.7-75.6)% vs. 63.1 (60.4-67.7)%, p=0.01; WAb10 67.0 (56.0-71.8)% vs. 57.5 (54.9-63.6)%, p=0.03). The changes of TGFβ1level in response to mechanical stress (ΔTGFβ1) significantly correlated with ΔsGaw (R=-0.15, p=0.04). The patients from group I were predominantly characterized by increase in TGFβ1concentration after the test (ΔTGFβ1 8.6 (-13.2-29.8)%) while in group II the level of TGFβ1declined (-12.1 (-30.8-14.3)%, p=0.02). Moreover, the patients with ≥20% increase in TGFβ1after the resistive breathing had more pronounced signs of airway remodeling when compared to those with <20% TGFβ1dynamics (WTb10 2.5 (2.3-2.9) mm vs. 2.3 (2.1-2.7) mm, p=0.04; WAb10 65.7 (58.5-70.8)% vs. 60.2 (54.8-80.5)%, p=0.01). Thus, asthma and COPD patients with ≥20% drop in sGaw in response to 5-min test with inspiratory resistive breathing are more predisposed to airway remodeling. As suggested by the obtained results, this phenomenon is likely mediated by TGFβ1which production is associated both with the decrease in airway conductivity and development of the remodeling.