Involvement of capsaicin-sensitive nerves in paraquat-induced mortality.
Paraquat (PQ), a broad spectrum herbicide, produces severe lung inflammation and necrosis resulting in pulmonary fibrosis and respiratory failure. Tachykinins are peptides released by sensory C fibers and have the ability of influencing respiratory functions and cellular proliferation. To examine whether the damage caused by PQ involves tachykinins, rats were depleted in their content of tachykinins by systemic treatment with capsaicin prior to PQ exposure. The animal subjected to this treatment showed a 3-fold higher viability compared to those treated with PQ alone (75 vs 27%). Depletion of reduced glutathione (GSH) is associated with oxidative stress produced by reactive oxygen intermediates during PQ metabolism. This is considered to be critical in the pathogenesis of lung damage by PQ. PQ treatment induced a significant depletion of GSH during the first days and a similar effect was also observed in the group of capsaicin-pretreated rats. Four weeks after PQ treatment the levels of GSH were similar to controls in rat pretreated or not with capsaicin plus PQ. This may indicate that the reduced levels of GSH may be associated to the toxicity observed in the acute phase, but not of importance in the final PQ-induced mortality. Neutral endopeptidase (NEP) is an enzyme considered to be critical in controlling the levels of tachykinins. Exposure of crude membrane preparations of rat lung to PQ resulted in a dose-dependent inhibition of NEP activity. Since NEP inactivation may occur in lung following a PQ exposure in vivo, the results indicate that during PQ intoxication a more sustained activity of tachykinins may be present, producing effects such as cell proliferation, fluid extravasation and bronchoconstriction. In conclusion, this finding supports the hypothesis that neuropeptides released from capsaicin-sensitive nerves could be involved in the modulation of PQ-induced lung damage.
Atzori
L
L
Department of Toxicology, University of Cagliari, Italy. latzori@vaxcal.unica.it
Cannas
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B
Dettori
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T
Dore
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M
Montaldo
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C
Ugazio
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Congiu
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D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology; D010269:Paraquat / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D015320:Tachykinins / Q000378:metabolism / Q000502:physiology
D006540:Herbicides; D009479:Neuropeptides; D015320:Tachykinins; D015260:Neprilysin; D005978:Glutathione; D010269:Paraquat; D002211:Capsaicin