Action of 1,25(OH)2D3 on Human Asthmatic Bronchial Fibroblasts: Implications for Airway Remodeling in Asthma
Bibliographic record
Abstract
Maria Plesa,1 Mellissa Gaudet,1 Andrea Mogas,1 Ronald Olivenstein,1,2 Saba Al Heialy,1,3 Qutayba Hamid1,2,4 1Translational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montréal, QC, Canada; 2Faculty of Medicine, McGill University, Montréal, QC, Canada; 3Mohammed Bin Rashid University of Medicine and Health Sciences, College of Medicine, Dubai, United Arab Emirates; 4College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesCorrespondence: Qutayba HamidTranslational Research in Respiratory Diseases, Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, 1001 Boulevard Decarie, Montréal, QC H4A 3J1, CanadaTel +1-514-934-1934 ext 76121Email qutayba.hamid@mcgill.caBackground: 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.Keywords: 1,25(OH)2D3, 1,25 dihydroxy vitamin D3 or calcitriol, asthma airway remodeling, fibrogenic markers, human airway fibroblasts, cell proliferation, apoptosis
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".