Stimulated pulmonary cell hyperplasia underlies resistance to alpha-naphthylthiourea

The rodenticide alpha-naphthylthiourea (ANTU) causes pulmonary edema and pl eural effusion that leads to death via pulmonary insufficiency. Rats become resistant to the lethal effect of ANTU if they are first exposed to a smal l, nonlethal dose of ANTU. Young rats are also resistant to ANTU. The mecha nism by which rats develop resistance by a prior, small dose exposure has y et to be determined. Growth factor induced-pulmonary hyperplasia has been d emonstrated to attenuate ANTU-induced lung leak. We hypothesized that a sma ll dose of ANTU protects against a large dose through pulmonary cell hyperp lasia induced by the protective dose. Furthermore, we hypothesized that thi s hyperplasia is associated with altered transcription of growth factors. M ale Sprague-Dawley rats (175-225 g) were treated with a low dose of ANTU (5 mg ANTU/kg; ANTU(L)) 24 h before challenge with a 100% lethal dose of ANTU (70 mg ANTU/kg; ANTU(H)) resulting in 100% protection against the lethal e ffect of ANTU(H). ANTU(L) protection against ANTU(H) lasted for 5 days, slo wly phased out, all being lost by day 20. Injury was assessed by estimating pulmonary vascular permeability and through histopathological examination. ANTU(H) alone resulted in an increase in pulmonary edema leading to animal death. However, injury was prevented if the rats were first treated with A NTU(L). There was a stimulation of pulmonary cell hyperplasia in the lungs of ANTU(L) treated rats as measured by [H-3]-thymidine and bromodeoxyuridin e incorporation. Treatment with the antimitotic agent colchicine abolished ANTU(L)-induced resistance to ANTU(H). ANTU resistant rats were also resist ant to the lethal effect of paraquat. Paraquat is not taken up by pneumocyt es if they are undergoing hyperplasia. ANTU(L) administration resulted in a n up regulation of gene transcription for keratinocyte growth factor, trans forming growth factor-beta, keratinocyte growth factor receptor and epiderm al growth factor receptor as determined through reverse transcription-polym erase chain reaction. A significant increase in transforming growth factor- alpha was not observed. These findings collectively suggest that ANTU(L)-in duced pulmonary cell hyperplasia underlies resistance to ANTU(H). Furthermo re. the stimulation of hyperplasia may be due to altered growth factor and growth factor receptor expressions. (C) 2000 Elsevier Science ireland Ltd. All rights reserved.