Involvement of the NO-cGMP-K<sub>ATP</sub> channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis
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Bibliographic record
Abstract
Mesenteric lymphatic vessels actively transport lymph, immune cells, fat, and other macromolecules from the intestine via a rhythmical contraction-relaxation process called lymphatic pumping. We have previously demonstrated that mesenteric lymphatic pumping was compromised in the guinea pig model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis, corroborating clinical and experimental observations of a dilated and/or obstructed phenotype of these vessels in inflammatory bowel disease. Many mediators released during the inflammatory process have been shown to alter lymphatic contractile activity. Among them, nitric oxide (NO), an inflammatory mediator abundantly released during intestinal inflammation, decreases the frequency of lymphatic contractions through activation of ATP-sensitive potassium (K(ATP)) channels. The objective of this study was to investigate the role of NO and K(ATP) channels in the lymphatic dysfunction observed in the guinea pig model of TNBS-induced ileitis. Using quantitative real-time PCR, we demonstrated that expression of Kir6.1, SUR2B, and inducible NO synthase (iNOS) mRNAs was significantly upregulated in TNBS-treated animals. Pharmacological studies performed on isolated, luminally perfused mesenteric lymphatic vessels showed that the K(ATP) channels blocker glibenclamide, the selective iNOS inhibitor 1400W, and the guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) significantly improved lymphatic pumping in quiescent lymphatic vessels from TNBS-treated animals. Membrane potential measurement with intracellular microelectrodes revealed that vessels from TNBS-treated animals were hyperpolarized compared with their sham counterpart and that the hyperpolarization was significantly attenuated in the presence of glibenclamide and ODQ. Our findings suggest that NO and K(ATP) play a major role in the lymphatic contractile dysfunction that occurred as a consequence of the intestinal inflammation caused by TNBS.
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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 | 0.001 |
| 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