Important role of p38 MAP kinase/NF-κB signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype
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Bibliographic record
Abstract
Septic plasma can convert murine cardiac myocytes to a proinflammatory phenotype. These myocytes 1) have increased nuclear levels of nuclear factor-kappaB (NF-kappaB), 2) release CXC chemokines, and 3) promote polymorphonuclear neutrophil (PMN) transendothelial migration. The purpose of the present study was to evaluate the role of the mitogen-activated protein (MAP) kinases [p38 MAP kinase, extracellular signal-regulated kinase (ERK) 1/2, and c-Jun NH(2)-terminal kinase (JNK)] as upstream intracellular signaling components involved in this phenomenon. Feces-induced peritonitis (FIP) was employed as a model of sepsis. In vitro, cardiac myocytes were treated with plasma (20%) obtained 6 h after either sham (saline) or FIP procedures. Myocyte supernatants were used for 1) detection of the CXC chemokines (enzyme-linked immunosorbent assay) and 2) assessment of their ability to promote PMN transendothelial migration. In vivo, myocardial PMN accumulation was assessed by measuring myeloperoxidase (MPO) activity and function (dF/dt and heart work). Treatment of cardiac myocytes with septic plasma activated p38 MAP kinase and ERK1/2, but not JNK. Blockade approaches (inhibitors or small-interference RNA) indicated that only p38 MAP kinase played a role in the conversion of the myocytes to a proinflammatory phenotype. Time course studies indicated that phosphorylation of p38 MAP kinase preceded the phosphorylation of NF-kappaB p65. Inhibition of p38 MAP kinase (SB-202190) blocked both NF-kappaB p65 phosphorylation and NF-kappaB nuclear translocation. Confirmatory studies in vivo indicated that FIP resulted in an increase in myocardial MPO activity and dysfunction, events reversed by the inhibitor of p38 MAP kinase. Collectively, these data indicate that the cardiomyocyte p38 MAP kinase/NF-kappaB signaling pathway plays an important role in the sepsis-induced conversion of myocytes to a proinflammatory phenotype.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 it