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Low-dose intramuscular polymyxin B improves survival of septic rats
T Mayumi1, J Takezawa, H Takahashi
1Department of Emergency Medicine, Nagoya University School of Medicine, Japan. mtoshi@med.nagoya-u.ac.jp
Unlabelled:
Polymyxin B (PLB) is a cationic antibiotic that also stoichiometrically neutralizes the lipid A moiety of endotoxin. We examined effects of a small dose of PLB on the mortality of rats with cecal ligation and puncture, on LPS-stimulated nitric oxide (NO) production, and on tumor necrosis factor alpha (TNF alpha) production by isolated rat Kupffer cells.
Materials And Methods:
In vivo studies: Cecal ligation and puncture (CLP) was performed under anesthesia in 28 rats. One hour after CLP, either 600 U/kg of PLB or saline was administered intramuscularly every 6 h (PLB group: n = 12; control group: n = 16). Plasma endotoxin was measured at 3 and 24 h after the CLP by the Endospecy test. This was compared with survival.
In Vitro Studies:
Kupffer cells were isolated from the normal rat liver. The cells were incubated with LPS or LPS + PLB. After 24 h, NO and TNF alpha content were measured using the Griess and ELISA methods, respectively.
Results:
Low dose PLB significantly decreased the endotoxin levels at both 3 and 24 h (5.5 +/- 2.1 pg/mL vs. 32.8 +/- 3.6 at 3 h; 26.1 +/- 6.1 vs. 49.1 +/- 5.6 at 24 h (p < .05) after CLP. PLB significantly improved survival of CLP rats (68.8% in the control group vs. 100% in the PLB treated group on 3 days after CLP, p < .001). PLB also attenuated NO and TNF alpha production from the Kupffer cells.
Conclusion:
Intramuscular PLB administered in low doses may improve the mortality of sepsis.
Insights
Low-dose Polymyxin B (PLB) significantly reduced endotoxin levels and improved survival in rats with sepsis. This antibiotic also decreased nitric oxide and TNF alpha production in immune cells.
Area of Science:
- Pharmacology
- Immunology
- Critical Care Medicine
Background:
- Polymyxin B (PLB) is a cationic antibiotic known to neutralize endotoxin's lipid A moiety.
- Sepsis, a life-threatening condition, is often associated with high levels of endotoxin.
- Investigating therapeutic strategies to mitigate sepsis-induced inflammation and mortality is crucial.
Purpose of the Study:
- To evaluate the efficacy of low-dose Polymyxin B (PLB) in reducing mortality in a rat model of sepsis.
- To assess the impact of PLB on endotoxin levels in vivo.
- To determine PLB's effect on nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) production by Kupffer cells.
Main Methods:
- A cecal ligation and puncture (CLP) model was used to induce sepsis in rats.
- Rats received intramuscular PLB or saline, and plasma endotoxin levels were measured.
- Isolated rat Kupffer cells were stimulated with lipopolysaccharide (LPS) with or without PLB to measure NO and TNF alpha production.
Main Results:
- Low-dose PLB significantly reduced plasma endotoxin levels at 3 and 24 hours post-CLP.
- PLB administration markedly improved survival rates in CLP rats compared to controls (100% vs. 68.8%).
- PLB significantly attenuated LPS-stimulated nitric oxide and TNF alpha production in Kupffer cells.
Conclusions:
- Intramuscular administration of low-dose Polymyxin B demonstrates significant therapeutic potential in sepsis.
- PLB effectively reduces endotoxin burden and inflammatory mediator production, leading to improved survival.
- Low-dose PLB may represent a viable adjunctive therapy for managing sepsis.