The Interactions Between Interferon-γ and Leukotriene D4 Signaling and Its Impact on Proliferative and Contractile Responses of Airway Smooth Muscle Cells
Bibliographic record
Abstract
Rationale: Airway smooth muscle (ASM) tone contributes to airway hyperresponsiveness (AHR) and airflow limitation in asthma. Alterations in the airway smooth muscle cell (ASMC) characteristics associated with asthma, including hyperplasia and increased velocity of contraction, have been described. Interferon- (IFN-) is a signature T helper 1 effector cytokine that is upregulated in the airway in severe asthma. It is suggested to promote AHR and steroid-resistance. However, its potential impact on ASM function is largely unknown. Cysteinyl leukotrienes (CysLTs) are important inflammatory mediators in asthma. They are potent contractile agonists and have been shown to also induce ASMC proliferation. IFN- is reported to upregulate the expression of cysteinyl leukotriene receptor 1 (CysLTR1) in ASMCs. We hypothesized that priming ASMCs with IFN- would augment CysLT-mediated contractile and proliferative responses via the upregulation of CysLTR1. In current study, we explored the potential of the described interactions between IFN- and CysLT signaling in ASMCs. Methods: Human ASMC cultures were derived from transplant-grade lungs without any history of asthma. The contractility of the ASMCs was assessed with a collagen contraction assay, in which cells incorporated in collagen gels were treated with 1000 U/mL IFN- for 24 hours followed by challenges with 1 M leukotriene D 4 (LTD4), one of the CysLTs, or 100 M histamine. The gel area reduction 30 minutes following the challenge was recorded. ASMC proliferation, represented by DNA synthesis, was assessed by bromodeoxyuridine (BrdU) assay. Serum-starved control and IFN--primed ASMCs were treated with LTD4, 24-hour BrdU incorporation was assessed by flow cytometry. The effect of IFN- on CysLTR1 expression was assessed by Western blot and quantitative real-time PCR. Results: IFN- priming resulted in a two-fold increase in baseline ASMC contraction relative to control. The contractile effects exerted by IFN- priming and histamine were additive. LTD4 did not induce additional ASMC contraction in either control or IFN- primed conditions. The percentage of BrdU+ ASMCs was significantly elevated among IFN- primed cells. LTD4 did not affect the percentages of BrdU+ cells among either control or IFN- primed ASMCs. LTD4 induced prominent contraction in human ASM tissues, confirming that LTD4 activity was intact. IFN- had no effect on the CysLTR1 protein or transcript levels in ASMC. Conclusion: Cultured ASMCs lacks response to LTD4. IFN- priming increases ASMC contractility and initiates DNA synthesis but does not upregulate CysLTR1 or appear to interact with LTD4 signaling.
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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) | 0.001 | 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".