Paraquat-induced lung injury: prevention by N-tert-butyl-alpha-phenylnitrone, a free-radical spin-trapping agent

Abstract

The herbicide paraquat causes lung injury that is believed to be oxygen-radical mediated. To further characterize this injury and explore new methods of preventing it, we used the spin-trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) to identify the paraquat radical in lung tissue and to reduce the injury resulting from the subsequent generation of reactive oxygen species. The formation of a paraquat free radical by guinea pig lung was detected under anaerobic conditions by electron paramagnetic resonance spectrometry. Infused (25, 50, or 100 mg/kg) into guinea pig lungs (perfused at constant flow with Krebs solution containing 4% bovine serum albumin and ventilated with 95% O2-5% CO2), paraquat produced dose-dependent increases in peak airway pressure (Paw), mean pulmonary arterial perfusion pressure (Ppa), and wet-to-dry (W/D) lung weight ratio. At 100 mg/kg, paraquat increased Paw by 589.6 +/- 59.8% (mean +/- SE, n = 8) and W/D ratio from 5.33 +/- 0.07 to 6.29 +/- 0.11 (P less than 0.001). Pulmonary vascular leak index increased from 0.40 +/- 0.09 to 1.96 +/- 0.45 (P less than 0.02), without changes in pulmonary microvascular pressure. Perfusate concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha increased, but indomethacin did not reduce the injury. PBN (2.3 mM) markedly attenuated all evidence of lung injury, which was also reduced by catalase, mannitol, ethanol, and vitamin E.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants as Potential Therapeutics for Lung Fibrosis

“…The manganese-containing porphyrin catalytic antioxidant MnTBAP has been shown to have protective effects against paraquat-induced injury both in vitro (55,97) and in vivo (52). In addition, the spin-trap PBN also has protective effects against paraquat-mediated damage (170). The administration of vitamin E has protective effects, and its deficiency potentiates paraquat-induced lung injury and fibrosis in animals (18,187).…”

Vitamin E: Focus on Microcirculation

“…It reduces the microvascular manifestations of sickle cell anemia (95) and of adult respiratory distress syndrome in animals as well as in patients (134). Treatment of animals with vitamin E prevented bleomycininduced pulmonary fibrosis (69), adriamycininduced focal glomerulosclerosis (131), as well as oxygen-(59), ionophore-(134) and paraquatinduced lung toxicity in guinea pigs (116), presumably due to inhibition of endothelial cell damage and microvascular leakage (59,109). In the clinical setting, vitamin E has been found to significantly attenuate retinopathy and intraventricular hemorrhage in oxygen-ventilated babies (110), and to reduce the clinical manifestations of intermittent claudication in elderly human subjects (44,45,121).…”

α-PHENYL-N-tert-BUTYLNITRONE ATTENUATES HYPEROXIA-INDUCED LUNG INJURY BY DOWN-MODULATING INFLAMMATION IN NEONATAL RATS

“…Recent studies have shown that PBN can protect against various injuries of the central nervous system [8,9], delay senescence in pulmonary fibroblasts [10], and reduce paraquat-induced lung injury [11]. Although these protective effects have been attributed primarily to the ability of PBN to scavenge the free radicals that are produced during various organ injuries, PBN also possesses potent anti-inflammatory capabilities in conditions such as endotoxic shock [12,13] and dextran sulfate sodium-induced colitis [14].…”