Endotoxin Triggers Nuclear Factor-κB–dependent Up-regulation of Multiple Proinflammatory Genes in the Diaphragm
Bibliographic record
Abstract
BACKGROUND: Sepsis-induced diaphragmatic force loss and failure are associated with an increased exposure of the muscle to proinflammatory mediators. OBJECTIVES: Our objectives were to test the hypothesis that force-inhibiting mediators may arise in large part from the diaphragm itself and to evaluate the roles of mechanical stress, free radicals, and the nuclear factor (NF)-kappaB transcription factor pathway in endotoxin (LPS)-induced proinflammatory responses of the diaphragm. METHODS: Murine diaphragm and limb muscle cells were exposed to LPS in vitro and in vivo. Proinflammatory gene expression was measured using RNase protection assays (tumor necrosis factor [TNF]-alpha, TNF-alpha receptor p55, interleukin [IL]-1alpha, IL-1beta, IL-6, macrophage inflammatory peptide-2, intercellular adhesion molecule-1, Fas ligand, and inducible nitric oxide synthase) and ELISAs (TNF-alpha, IL-6, and macrophage inflammatory peptide-2). Cyclical muscle cell stretch and free-radical scavengers (N-acetylcysteine and catalase) were used to alter mechanical and oxidative stress levels, respectively. Pharmacologic (pyrrolidinedithiocarbamate) and dominant-negative transfection strategies were used to inhibit the NF-kappaB pathway. RESULTS: In primary diaphragm muscle cell cultures, modulation of mechanical stress levels or free-radical exposure did not alter responses to LPS stimulation. However, pharmacologic blockade of the NF-kappaB pathway and dominant-negative molecular inhibition of IKB kinase-beta strongly suppressed LPS-induced proinflammatory gene expression. In vivo, acute endotoxemia induced significantly greater mRNA and protein levels for proinflammatory mediators in the diaphragm as compared with limb muscle. Basal expression levels of proinflammatory genes were significantly higher in the diaphragm. CONCLUSIONS: Constitutive and LPS-induced proinflammatory gene expression are exaggerated in the diaphragm compared with limb muscles and are critically dependent on the NF-kappaB pathway. We suggest the diaphragm may be relatively predisposed to proinflammatory responses.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".