Defining the Aryl Hydrocarbon Receptor as a Driver of Pulmonary Fibrosis
Bibliographic record
Abstract
Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is the most common and severe interstitial lung disease (ILD), carrying a median survival of 3 years after diagnosis. In IPF, dysregulation of signaling pathways involved in extracellular matrix (ECM) production, such as transforming growth factor-β (TGF-β) signaling, lead to persistent activation of lung fibroblasts and results in the overproduction of ECM proteins such as collagen. We hypothesized that the aryl hydrocarbon receptor (AhR), a transcription factor originally characterized as a mediator of xenobiotic metabolism, is mechanistically involved in the development of fibrosis. To address this hypothesis, we evaluated the role of the AhR in fibroblast-mediated fibrotic outcomes in in-vitro and in-vivo models of pulmonary fibrosis. Methods: Primary mouse lung fibroblasts (MLFs) from AhR wild-type (Ahr+/+) and AhR knock-out (Ahr-/-) mice were treated with TGF-β (5 ng/mL) for 48 hours with or without the AhR inhibitor CH223191 (10µM). Collagen 1A1 (Col1a1) and α-smooth muscle actin (α-SMA) protein were measured via immunoblot. We performed proteomic analysis of cell lysate from Ahr+/+ and Ahr-/- MLFs treated with or without TGF-β via liquid chromatography-mass spectrometry (LC/MS). As a complement, the AhR was also knocked down in primary human lung fibroblasts (HLFs) using AhR-targeting siRNA. TGF-β-stimulated Col1a1 production was then evaluated via immunoblot. To evaluate AhR-dependency of pulmonary fibrosis in-vivo, Ahr+/+ and Ahr-/- mice were treated with bleomycin (2 mg/kg) via oropharyngeal administration and lung collagen deposition was evaluated 21 days later via Masson's Trichrome and quantified with hydroxyproline assay. Results: Col1a1 protein is reduced in Ahr-/- MLFs compared to Ahr+/+ controls both at baseline and in response to TGF-β. CH223191 attenuated TGF-β-stimulated Col1a1 production by Ahr+/+ MLFs. HLFs treated with AhR-targeting siRNA have reduced Col1a1 production compared to cells treated with siRNA controls. Proteomic analysis revealed reduced levels of proteins involved in collagen biosynthesis (Serpinh1, Plod3, Mia3, Colgalt1, Crtap, Ph31), actin polymerization (Cotl1, Arap1, Stmn1, Swap70, Flna), and mechanotransduction (Thy1, Rhog, Itga5, Itgb5) in AhR-deficient cells. Furthermore, Ahr-/- mice appear to be resistant to bleomycin-induced pulmonary fibrosis compared to Ahr+/+ controls. Conclusions: Our findings suggest that the AhR is essential for the development of the fibrotic phenotype in in-vitro and in-vivo models of pulmonary fibrosis. Future work will determine whether AhR antagonism can reverse the fibrotic phenotype, aiming to establish a novel therapeutic approach for combating fibrosis.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".