The Potential Role of GPR87 in the Development of Pulmonary Fibrosis
Bibliographic record
Abstract
Abstract Background: G-protein Coupled receptor 87 (GPR87), an orphan lysophosphatidic acid (LPA) receptor, was reported in idiopathic pulmonary fibrosis (IPF) airway basal cells. We have previously reported that GPR87 is highly expressed in IPF, mainly in airway basal and aberrant basaloid cells, and correlates with disease severity, and that GPR87 knockdown using siRNA leads to under-expression of fibrosis related genes, proteins and microRNA in induced pluripotent stem cells (iPSC) derived basal cells (iBC) through PI3K pathway, as well as mTOR and TNFα pathways. Here we discuss its rule as a therapeutic target. Methods: iBC cell cultures were treated PI3K stimulator 740Y-P, or PI3K inhibitor A66. GPR87 gene was knocked down using siRNA. Gene expression was measured using qPCR and bulk RNA sequencing. Normal human lung precision cut lung slices (PCLS) were cultured with fibrotic cocktail (TNFα, PDGF, TGFβ and LPA) for 5 days. GPR87 siRNA or nintedanib were added at day 3. IPF PCLS were cultured for 5 days, GPR87 or nintedanib were added at day 3. GPR87 knockout (GPR87 -/-) or wildtype mice injected with intratracheal bleomycin and sacrificed at day 21. Results: Blocking PI3K halts LPA effects, while GPR87 siRNA knockdown halts PI3K stimulation in iBC. Moreover, GPR87 siRNA knockdown leads to lower collagen content than scrambled RNA (trichrome quantification 5.2 Vs 10.2, P<0.001) in PCLS fibrotic cocktail model, and in IPF PCLS (trichrome quantification 5.1 Vs 7.9, P<0.001). GPR87-/- mice lost less weight, had better lung function tests, and better histology than wildtype mice, and lower collagen content: modified Ashcroft score 2.8 Vs 4.7 P<0.01, hydroxyproline content 0.7 ug Vs 0.9 ug P<0.05, and Col1a1 expression 1.2 Vs 1.9 P<0.05. Conclusion: GPR87 is highly expressed in basal and aberrant basaloid cells in IPF lungs and mediates profibrotic effects based on in-vivo, ex-vivo and in-vitro models, suggesting that it should be studied as a potential epithelial specific therapeutic target in pulmonary fibrosis. Legends: A: Enriched pathways involved in GPR87 downstream signaling in iBC. B: qPCR after PI3K stimulation or inhibition in iBC, concomitantly with GPR87 knockdown or LPA treatment. C-D: scRNAseq of normal PCLS after fibrotic cocktail, day 0-5. E-F: histology and trichrome quantification in normal PCLS with fibrotic cocktail, or IPF PCLS, after GPR87 knockdown. G-N: GPR87 knockout or wildtype mice injected with bleomycin or saline: G: weight change, H: pressure volume curves, I: static compliance, J: Col1a1 expression, K: hydroxyproline content, L-M: H&E and Trichrome staining, N: Ashcroft Score
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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 | 0.000 | 0.000 |
| 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".