S77 The G proteins Gαq/11 and Gα12/13 drive unique myofibroblast functions to promote pulmonary fibrosis
Bibliographic record
Abstract
Introduction Idiopathic pulmonary fibrosis (IPF) is relentlessly progressive with a poor prognosis. In IPF, excessive scar tissue replaces normal lung parenchyma following alveolar injury. There is currently no treatment that can reverse fibrosis. Myofibroblasts drive fibrosis through contraction and extracellular matrix (ECM) generation. Increasing ECM stiffness promotes fibroblast-to-myofibroblast differentiation, ECM production, and activation of the profibrotic cytokine transforming growth factor-β (TGFβ). However, the precise mechanisms that drive this feedback loop are uncertain. Signalling by G protein coupled receptors (GPCRs) has been implicated in IPF. Messages from hundreds of GPCRs converges on four Gα subunit families, however the role of these molecules in myofibroblast activity in IPF is unknown. Aim Understand the role of Gαq/11 and Gα12/13 in profibrotic myofibroblast functions. Methods Wild-type (WT), Gnaq-/-;Gna11-/- (Gαq/11-/-), and Gna12-/-;Gna13-/- (Gα12/13-/-) murine embryonic fibroblasts (MEFs) and human lung fibroblasts (HLFs) were stimulated with lysophosphatidic acid (LPA, 50µM). TGFβ signalling was measured using Smad2 phosphorylation. MEFs were cultured on gels of fibrotic (100kPa, 36kPa) and physiological (5kPa) stiffness. Myofibroblast differentiation was assessed using α smooth muscle actin (αSMA) expression. MEFs and HLFs cultured on thin gels were stimulated with GPCR agonists (LPA 30µM, SFLLRN 20µM and TFLLRN 20µM), and time lapse images taken. Gel wrinkling was used to quantify contraction. Results Gαq/11 and Gα12/13 knockdown both reduced LPA-induced TGFβ signalling in MEFs and HLFs compared with controls (p<0.05, n=4). Rho-associated kinase (ROCK) inhibition reduced LPA-induced TGFβ signalling, suggesting that cellular contraction mediates LPA-induced TGFβ activation. HLFs from IPF donors were more contractile than non-diseased HLFs (91 vs 42 wrinkles/image, p=0.02, n=5 per group). MEFs and HLFs lacking Gα12/13 had reduced baseline and GPCR agonist-induced contraction (p<0.05), and Gα12/13-/- MEFs had abnormal cytoskeletal appearances on immunofluorescence. Gαq/11 knockdown did not affect contractility or cytoskeletal appearance. Gαq/11-/- MEFs had reduced αSMA expression when transferred to soft tissue culture conditions (p<0.05, n=4), whereas WT and Gα12/13-/- MEFs did not. Conclusions Myofibroblast activity is enhanced in IPF. Gαq/11 and Gα12/13 both mediate TGFβ signalling, but via different mechanisms, and they drive distinct myofibroblast profibrotic functions. A greater understanding of these processes could identify new treatments for IPF.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 0.003 |
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".