Pathogenesis of Pulmonary Fibrosis - The Role of Extracellular Heat Shock Protein-90 (HSP90) in Myofibroblast Differentiation and Persistence
Why this work is in the frame
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Bibliographic record
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by extensive extracellular matrix (ECM) deposition. ECM from fibrotic lungs, mainly produced by myofibroblasts, is stiffer than non-fibrotic ECM increasing mechanical stress. The ECM is a major storage compartment for extracellular proteins which affect pulmonary cells’ behavior. HSP90 belongs to the heat shock protein (HSP) family that are involved in various pathologic processes. HSP90 is secreted by cells subjected to stress conditions and promotes matrix metalloproteinase activation, integrin upregulation and epithelial-to-mesenchymal transition; processes involved in fibrogenesis. We hypothesize that eHSP90’s secretion is enhanced in fibrotic conditions and that eHSP90 contributes to the differentiation and persistence of lung myofibroblasts. HSP90 serum level was assessed in IPF patients by ELISA. eHSP90’s release by mechanical stretch was assessed ex vivo in rat fibrotic lung slices. In vitro experiments were performed using recombinant HSP90 and blocking antibodies. We demonstrated that circulating HSP90 is enhanced in IPF patients’ serum and is correlated with IPF severity. HSP90’s secretion was enhanced after mechanical stretch of fibrotic lungs ex vivo and was upregulated in BAL of fibrotic mice in vivo. Recombinant HSP90 induced myofibroblast differentiation indicated by an increase in α-SMA expression, MMP activation and ECM production. We identified that eHSP90 signaled through the membrane receptor LRP-1. HSP90 and LRP-1 inhibition limited myofibroblasts differentiation.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 it