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Protective effect of mepacrine on hypoxia-reoxygenation-induced acute lung injury in rats
1Department of Medicine, Tri-Service General Hospital, Taiwan, Republic of China.
Abstract:
Mepacrine, a cell membrane stabilizer and inhibitor of phospholipase A2 (PLA2), exerts a protective effect on ischemia-reperfusion injury in heart; however, its effect in lungs has not been examined. This study aimed to determine whether mepacrine pretreatment attenuates ischemia-reperfusion lung injury simulated by hypoxia reoxygenation and to identify possible mechanisms for such protection. Acute lung injury was induced in Sprague-Dawley rats by ventilation with 5% CO2-95% N2 and 5% CO2-95% air. Pretreatment with 0.06 mM mepacrine significantly attenuated the acute lung injury. Capillary filtration coefficient, lung weight gain, and protein concentration of lung lavage fluid were significantly lower in mepacrine-treated rats than in rats exposed to hypoxia reoxygenation alone. Steroid dexamethasone, another potential PLA2 inhibitor, had almost no protective effect. Mepacrine but not dexamethasone caused dose-dependent attenuation of the increase in leukocyte chemiluminescence produced by exposure to phorbol myristate acetate. Mepacrine also dose-dependently inhibited production of tumor necrosis factor-alpha (TNF-alpha) by human monocytes; dexamethasone was much less effective in decreasing TNF-alpha production. We conclude that mepacrine but not dexamethasone can significantly attenuate a hypoxia-reoxygenation-induced injury of the lung. This protective effect of mepacrine may not be the result of its inhibition of PLA2 but rather of its downregulation of oxygen radical production by circulating or resident leukocytes or its attenuation of TNF-alpha production by macrophages.
Insights
Mepacrine pretreatment significantly reduces lung injury from hypoxia and reoxygenation. This protective effect may stem from reduced oxygen radical production and tumor necrosis factor-alpha (TNF-alpha) levels, not phospholipase A2 (PLA2) inhibition.
Area of Science:
- Pulmonary medicine
- Cellular and molecular biology
- Pharmacology
Background:
- Ischemia-reperfusion injury (IRI) affects organs including the heart, but its impact on lungs is less understood.
- Mepacrine, a known cell membrane stabilizer and phospholipase A2 (PLA2) inhibitor, shows cardiac protection.
- The protective mechanisms of mepacrine in lung IRI remain to be elucidated.
Purpose of the Study:
- To investigate the efficacy of mepacrine in attenuating hypoxia-reoxygenation-induced lung injury in rats.
- To explore the potential mechanisms underlying mepacrine's protective effects in the lungs.
Main Methods:
- Acute lung injury was induced in Sprague-Dawley rats via hypoxia (5% CO2-95% N2) and reoxygenation (5% CO2-95% air).
- Rats were pretreated with mepacrine (0.06 mM) or dexamethasone.
- Measurements included capillary filtration coefficient, lung weight gain, lung lavage fluid protein concentration, leukocyte chemiluminescence, and tumor necrosis factor-alpha (TNF-alpha) production.
Main Results:
- Mepacrine pretreatment significantly attenuated lung injury, evidenced by reduced capillary filtration coefficient, lung weight gain, and lavage fluid protein.
- Dexamethasone, another PLA2 inhibitor, showed minimal protective effect.
- Mepacrine dose-dependently inhibited leukocyte chemiluminescence and TNF-alpha production, while dexamethasone was less effective.
Conclusions:
- Mepacrine effectively attenuates hypoxia-reoxygenation-induced lung injury in rats.
- The protective mechanism of mepacrine may involve downregulation of oxygen radical production and TNF-alpha synthesis, rather than PLA2 inhibition.
- Mepacrine offers a potential therapeutic strategy for lung IRI.