Cyclic stretch augments human rhinovirus induced inflammatory responses in airway epithelial cells
Bibliographic record
Abstract
Structural cells of the airways are subject to normal mechanical stretch during respiration [ 1 ]. Mechanical stretch acts as a mechanism of cell activation, and mechanotransduction pathways have been shown to activate pro-inflammatory genes [ 2 ]. Human rhinovirus (HRV) infections are a major cause of asthma exacerbations, and mechanical forces are likely to be more pronounced during asthma exacerbations [ 3 ]. Moreover, smoking is associated with worse clinical outcomes in asthma. Previous studies have shown that HRV infection, cigarette smoke extract (CSE), or mechanical stretch each induce CXCL8 production in bronchial epithelial cells [ 4 – 6 ]. In this study, we sought to determine whether mechanical stretch interacts with HRV infection and CSE to further upregulate airway inflammation. Studies were performed using primary human bronchial epithelial cells (HBEC), the human bronchial epithelial cell line BEAS-2B. Cells were treated with CS (FlexCell FX-4000), HRV-16 or with a combination of CS+HRV-16. Protein and mRNA levels were measured using ELISA (R&D Systems) and real-time RT-PCR (Applied Biosystems). Mechanical stretch and HRV infection each significantly increased CXCL8 release in BEAS-2B and HBE cells compared to static controls (p<0.001). When studied in combination, there was a significant synergistic increase in CXCL8 in BEAS-2B (p<0.001). Ultraviolet (UV) inactivation of HRV attenuated this increase in CXCL8 release. Mechanical stretch and HRV infection each increased CXCL8 mRNA levels compared to static controls, with the combination resulting in further enhanced induction (p<0.01). CSE alone did not significantly increase CXCL8 production in BEAS-2B. However, the combination of CSE+HRV significantly enhanced CXCL8 release compared to medium control (p<0.001) and HRV alone (p<0.05), and this increase was significantly further augmented by mechanical stretch (p<0.001). Mechanical stretching of BEAS-2B and HBE cells increased HRV-induced CXCL8 mRNA and protein levels, confirming that this effect is, at least in part, regulated at the transcriptional level. Moreover, the combination of mechanical stretch and HRV infection, as might occur during asthma exacerbations, resulted in a synergistic enhancement of CXCL8 expression, compared to either stimulus alone. CSE further enhanced HRV-induced and stretch-induced CXCL8 release, and the combination of all three variables potentiated this effect. Since levels of CXCL8 have been linked to increased airway neutrophils and symptom severity, mechanical stretch, if it also enhances CXCL8 production induced during HRV infections in vivo , may contribute to the pathogenesis of airway inflammation in HRV-induced asthma exacerbations.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".