Leukotriene C4 Synthase Deficiency Causes Spontaneous Emphysema in Female Mice
Bibliographic record
Abstract
Emphysema, an important component of chronic obstructive pulmonary disease (COPD), whereby there is progressive destruction of alveolar tissues, remains poorly understood. Cysteinyl-leukotrienes (cysLTs) and their receptors have been extensively investigated in asthma but not in COPD. Whether cysLTs influence emphysema is unknown. To investigate the influence of the constitutive synthesis of cysLTs on airspace integrity, we assessed lung structure and function in leukotriene C4 synthase-deficient (Ltc4s-/-) mice lacking the pivotal enzyme for cysLT biosynthesis. Mice ranged in age from 5-20 weeks. Emphysema was assessed from the mean linear intercept and pulmonary mechanics. Differential cell counts and iron staining were performed on BAL fluid cells. Emphysema-related gene expression was assessed by qRT-PCR. Oxidative stress and oxygen consumption in alveolar macrophages were evaluated by flow cytometry and Seahorse assay. Ltc4s-/- female mice developed extensive emphysema by 10 weeks of age histologically and by lung function. There was evidence of abnormal alveolar macrophage function comprising a reduction of SOD-2 (superoxide dismutase 2), increase in MMP8 (matrix metalloproteinase 8), an enhanced mitochondrial oxidative stress, and an increase in iron deposition. Treatment with sulforaphane, an activator of the transcription of antioxidant genes, prevented the development of emphysema. We conclude that spontaneous emphysema in female mice deficient in LTC4S is associated with enhanced mitochondrial oxidative stress. These findings indicate a homeostatic role for cysLTs in preserving alveolar structure and provide a novel model to explore mechanisms of emphysema.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".