Cigarette Smoke Causes Small Airway Remodeling by Direct Growth Factor Induction and Release
Bibliographic record
Abstract
Small airway remodeling (SAR) is one of the anatomic causes of airflow obstruction in patients with chronic obstructive pulmonary disease.The pathogenesis of SAR is poorly understood, but there are two general theories: (1 ) SAR is caused by smokeinduced inflammatory cells that damage the airway and evoke a repair process and (2 ) SAR is caused by direct induction of growth factors by cigarette smoke.To investigate this process, we briefly exposed rat tracheal explants, a model system free of exogenous inflammatory cells, to whole cigarette smoke, and then maintained the explants in organ culture for varying periods.With explants cultured in air, smoke induced up-regulation of both transforming growth factor (TGF)- 1 and procollagen gene expression at 24 h after initial exposure.Increased procollagen gene expression was prevented in a dose-response fashion by the TGF- antagonist fetuin, indicating that TGF- was driving fibrosis.Collected supernatant from explants exposed to smoke and cultured in fluid medium showed increased release of TGF- 1, and this was abolished by the oxidant scavenger tetramethylthiourea.Gene expression of connective tissue growth factor (CTGF) was sharply increased 2 h after smoke exposure.Using pure recombinant proteins, smoke-conditioned medium oxidized TGF- latency-associated peptide and also caused release of active TGF- 1 from latent TGF- 1 .We conclude that cigarette smoke directly induces release of preformed TGF- 1 by oxidizing the latency-associated peptide in rat tracheal explants, and that release must be extremely rapid, since gene expression of CTGF, the downstream fibrogenic driver of TGF- effects on collagen synthesis, is elevated very shortly after smoke exposure.Although tracheal explants are only an approximate model of small airways, these findings suggest that smoke-induced SAR may reflect direct induction of growth factor release and signaling and does not require smoke-evoked inflammatory cells.
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How this classification was reachedexpand
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".