Abstract 13924: NLRP3 Inflammasome Activation in Macrophages Drives Adverse Right Ventricular Remodeling and Dysfunction
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy that causes right ventricle failure (RVF) and death. This study evaluates the role of the pyrin domain-containing protein 3 (NLRP3) inflammasome activation within RV macrophages in RVF. Hypothesis: In PAH, the NLRP3 inflammasome is activated in macrophages infiltrating the RV and contributes to RVF. Methods: We compared inflammation in monocrotaline (MCT=25; PBS=21) rats, which have decompensated RV hypertrophy (RVH), and pulmonary artery banding (PAB=11; Sham=11) rats, which have compensated RVH. RV function was assessed by echocardiography and right heart catheterization. Macrophages’ abundance and polarization were evaluated by confocal microscopy and flow cytometry. NLRP3 inflammasome activation was assessed by western blot and in vitro strategies. On day 14 post-MCT injection, rats were treated daily with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). We assessed macrophage abundance and NLRP3 activity in PAH-RVF patients (n=12) and controls (n=9). Results: Macrophage abundance was significantly higher in MCT-RV compared to controls (p=0.023 microscopy; 0.004 flow cytometry), but it was insignificant between PAB and sham-RVs. While MCT-RV macrophages were inflammatory, lung macrophages carried an anti-inflammatory phenotype. NLRP3, cleaved caspase1 and IL1β were highest in MCT-RVs (p= 0.021, 0.008, 0.027). The macrophage-NLRP3 pathway was also upregulated in PAH-RVF patients. Cultured MCT monocytes revealed increased NLRP3:ASC interaction upon Nigericin stimulation, which MCC950 inhibited. In vivo , MCC950 reduced NLRP3 activation (p=0.012) and improved RV function. SC-144 significantly reduced RV macrophage count, STAT3 and NLRP3 activation (p= 0.0001, 0.042, 0.05), while improving RV function without regressing pulmonary vascular disease. Conclusion: The concept that PAH-RVF results, in part, from local RV inflammation rather than a passive consequence of elevated afterload is new. Blocking the inflammasome pathway reduces RV-macrophage accumulation and NLRP3 inflammasome activation. It also improves RV function, despite persistent pulmonary vascular remodeling offering a new therapeutic paradigm.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
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".