Constrictive Bronchiolitis in Cystic Fibrosis Adolescents with Refractory Pulmonary Decline

Abstract

Rationale: Refractory lung function decline in association with recurrent pulmonary exacerbations is a common, yet poorly explained finding in cystic fibrosis (CF). To investigate the histopathologic mechanisms of pulmonary deterioration during adolescence and early adulthood, we reviewed clinicallyindicated lung biopsy specimens obtained during a period of persistent decline.Objectives: To determine if peribronchiolar remodeling is prominent in lung biopsy specimens obtained in adolescents with CF refractory to conventional therapy.Methods: Six adolescents with CF (mean age, 16.2 y; mean FEV 1 , 52% predicted at biopsy) with significant pulmonary deterioration over 12-24 months (mean FEV 1 decline of 14% predicted/year) despite aggressive intervention underwent computed tomography imaging and ultimately lung biopsy to aid clinical management. In addition to routine clinical evaluation, histopathologic investigation included staining for transforming growth factor-b (TGF-b, a genetic modifier of CF lung disease), collagen deposition (a marker of fibrosis), elastin (to evaluate for bronchiectasis), and a-smooth muscle actin (to identify myofibroblasts).

MicroRNA-145 Antagonism Reverses TGF-β Inhibition of F508del CFTR Correction in Airway Epithelia

“…Although F508del correctors have generated in vitro promise, the in vivo response has not been as robust as desired (24,26,57). Our previous data on increased TGF-b in CF (36,53,58,59) suggest that some of the suboptimal in vivo results of lumacaftor may be influenced by increased TGF-b signaling in CF lungs. The present findings in both non-CF and CF primary epithelia reinforce this concern and suggest that modulator efficacy should be evaluated in the setting of CF pulmonary conditions that are known to influence CFTR stability.…”

New insights into TGF-β/Smad signaling in tissue fibrosis

“…Taken together, TGF-β was associated with pulmonary fibrosis in multiple animal models and in IPF and drives myofibroblast differentiation. Activation of TGF-β signaling were associated with fibrosis area and myofibroblast differentiation, furthermore, that constrictive bronchiolitis in lung biopsies was linked to myofibroblast differentiation potentially induced through TGF-β [58].…”

Fibrocyte accumulation in the lungs of cystic fibrosis patients

“…CF lung disease in humans shares several features of fibrotic remodeling seen in IPF, including myofibroblast accumulation and excessive collagen deposition [48] . Fibrocytes have been implicated in the pathogenesis of several chronic inflammatory diseases such as necrotizing enterocolitis (NEC), asthma, Graves' disease, and rheumatoid arthritis [49][50][51][52] .…”