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Background: Long‐term trajectories of asthma with fixed airflow obstruction (FAO) may reveal links to inflammatory endotypes. Objective: We investigated whether measures of asthma control and airway inflammation and remodelling differed by long‐term FAO status in moderate‐to‐severe asthma. Methods: Adults enrolled in the Difficult Asthma Study assessed initially using serial Asthma Control Questionnaire (ACQ), exacerbation history, spirometry and sputum cytology over 12 months, as well as endoscopic bronchial biopsy with airway smooth muscle (ASM) quantification, were revaluated three or more years later with questionnaires and spirometry. FAO was defined as a persistent post‐bronchodilator forced expired volume in one second (FEV1)‐to‐forced vital capacity ratio below 0.70. Results: Sixty‐two participants (mean ± SD age 48 ± 11 years; 50% female; 75% atopic; asthma duration 24 ± 14 years) returned for follow‐up assessment (median interval 7.9 years; IQR: 5.4‐8.8 years). Compared to participants without FAO (n = 28), those with FAO at baseline and long‐term follow‐up (n = 18) had higher baseline sputum neutrophil content and ASM, and a higher exacerbation frequency that persisted at long‐term follow‐up. Sputum eosinophils, ACQ and long‐term FEV1 decline did not differ. Participants with incident FAO at long‐term follow‐up (n = 16) had higher baseline exacerbation frequency, sputum eosinophil content, higher ACQ scores and greater decline in FEV1, whereas baseline ASM was similar to those without FAO. Conclusion: In moderate‐to‐severe asthma, long‐term FAO is characterized by neutrophilic sputum inflammation and airway remodelling, but FEV1 decline is similar to those without FAO. Long‐term incident FAO is preceded by higher exacerbation frequency, higher sputum eosinophil content and significant FEV1 decline. [ABSTRACT FROM AUTHOR]

Background: Airway fibroblasts are major contributors to the histopathological feature of airway remodeling in asthma by their implication in the cell invasiveness and profibrogenic secretory phenotype observed in subepithelial fibrosis. 1,25 Dihydroxy vitamin D3 (1,25(OH)2D3) is an important therapeutic agent that blocks many features of airway remodeling induced by profibrogenic mediators, such as transforming growth factor beta 1 (TGF-β 1) or T helper type 1 inflammatory cytokines. Objective: We hypothesized that 1,25(OH)2D3 opposes the TGF-β 1 or tumor necrosis factor alpha (TNF-α)-Interleukin 1 beta (IL-1β) stimulation on airway fibroblast profibrogenic secretory phenotype observed in severe asthmatic patients. Our aim was to investigate the anti-fibrogenic effect of 1,25(OH)2D3 in TGF-β 1 or TNF-α-IL-1β-stimulated human bronchial fibroblast cells (HBFCs) from severe asthmatic compared with non-asthmatic subjects. Patients and Methods: All experiments were performed on primary HBFCs from asthmatic (DHBFCs, n=4) and non-asthmatic subjects (NHBFCs, n=4). mRNA expression and protein quantification of key fibrogenic markers were analyzed by RT-qPCR and ELISA, comparing HBFCs from asthmatic and non-asthmatic subjects. Vitamin D receptor (VDR) mRNA expression and its functionality in HBFCs were assessed by RT-qPCR. HBFCs proliferation was assessed by flow cytometry using BrdU-FITC/7AAD bivariate staining, while HBFCs apoptosis by Annexin V-FITC/7AAD. Results: VDR is constitutively expressed in HBFCs and the addition of 1,25(OH)2D3 significantly increased mRNA expression of CYP24A1 (a direct VDRs' target gene) in both HBFCs groups. DHBFCs cultured in the presence of TGF-β 1 or TNF-α-IL-1β showed increased mRNA expression and protein secretion of fibrogenic markers when compared to NHBFCs. Additionally, we observed decreased mRNA expression of FN 1, LUM, BGN, MMP2, COL5A1, TIMP1 and CC-chemokines (CCL2, CCL5, CCL11) in response to 1,25(OH)2D3 addition to the TGF-β 1 or TNF-α-IL-1β-stimulated HBFCs. Cell culture media obtained from TGF-β 1 or TNF-α-IL-1β-stimulated DHBFCs showed decreased protein secretion (fibronectin 1, lumican, MCP1, RANTES and eotaxin-1) in response to 1,25(OH)2D3 when compared to NHBFCs. 1,25(OH)2D3 inhibited proliferation in TGF-β 1-stimulated HBFCs through G0/G1 cell cycle arrest and these effects were not correlated with the induction of apoptosis. Conclusion: DHBFCs under TGF-β 1 or TNF-α-IL-1β stimulation showed higher fibrogenic capacity when compared to NHBFCs. 1,25(OH)2D3 significantly blocked these effects and highlight 1,25(OH)2D3 as a possible therapeutic target for severe asthma. [ABSTRACT FROM AUTHOR]

Background: Bronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure. Methods: Patients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 ?g beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on longacting- b2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT. Results: 45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group. Conclusions: The absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years. [ABSTRACT FROM AUTHOR]

Background: Airway fibroblasts are major contributors to the histopathological feature of airway remodeling in asthma by their implication in the cell invasiveness and profibrogenic secretory phenotype observed in subepithelial fibrosis. 1,25 Dihydroxy vitamin D 3 (1,25(OH) 2 D 3 ) is an important therapeutic agent that blocks many features of airway remodeling induced by profibrogenic mediators, such as transforming growth factor beta 1 (TGF-β1) or T helper type 1 inflammatory cytokines., Objective: We hypothesized that 1,25(OH) 2 D 3 opposes the TGF-β1 or tumor necrosis factor alpha (TNF-α)-Interleukin 1 beta (IL-1β) stimulation on airway fibroblast profibrogenic secretory phenotype observed in severe asthmatic patients. Our aim was to investigate the anti-fibrogenic effect of 1,25(OH) 2 D 3 in TGF-β1 or TNF-α-IL-1β-stimulated human bronchial fibroblast cells (HBFCs) from severe asthmatic compared with non-asthmatic subjects., Patients and Methods: All experiments were performed on primary HBFCs from asthmatic (DHBFCs, n=4) and non-asthmatic subjects (NHBFCs, n=4). mRNA expression and protein quantification of key fibrogenic markers were analyzed by RT-qPCR and ELISA, comparing HBFCs from asthmatic and non-asthmatic subjects. Vitamin D receptor ( VDR ) mRNA expression and its functionality in HBFCs were assessed by RT-qPCR. HBFCs proliferation was assessed by flow cytometry using BrdU-FITC/7AAD bivariate staining, while HBFCs apoptosis by Annexin V-FITC/7AAD., Results: VDR is constitutively expressed in HBFCs and the addition of 1,25(OH) 2 D 3 significantly increased mRNA expression of CYP24A1 (a direct VDRs' target gene) in both HBFCs groups. DHBFCs cultured in the presence of TGF-β1 or TNF-α-IL-1β showed increased mRNA expression and protein secretion of fibrogenic markers when compared to NHBFCs. Additionally, we observed decreased mRNA expression of FN 1, LUM, BGN, MMP2, COL5A1, TIMP1 and CC-chemokines ( CCL2, CCL5 , CCL11) in response to 1,25(OH) 2 D 3 addition to the TGF-β1 or TNF-α-IL-1β-stimulated HBFCs. Cell culture media obtained from TGF-β1 or TNF-α-IL-1β-stimulated DHBFCs showed decreased protein secretion (fibronectin 1, lumican, MCP1, RANTES and eotaxin-1) in response to 1,25(OH) 2 D 3 when compared to NHBFCs. 1,25(OH) 2 D 3 inhibited proliferation in TGF-β1-stimulated HBFCs through G0/G1 cell cycle arrest and these effects were not correlated with the induction of apoptosis., Conclusion: DHBFCs under TGF-β1 or TNF-α-IL-1β stimulation showed higher fibrogenic capacity when compared to NHBFCs. 1,25(OH) 2 D 3 significantly blocked these effects and highlight 1,25(OH) 2 D 3 as a possible therapeutic target for severe asthma., Competing Interests: Ronald Olivenstein reports personal fees from GSK, outside the submitted work. The authors report no other potential conflicts of interest in this work., (© 2020 Plesa et al.)