Stimulated pulmonary cell hyperplasia underlies resistance to α-naphthylthiourea

The rodenticide α -naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion that leads to death via pulmonary insufficiency. Rats become resistant to the lethal effect of ANTU if they are first exposed to a small, nonlethal dose of ANTU. Young rats are also resistant to ANTU. The mechanism by which rats develop resistance by a prior, small dose exposure has yet to be determined. Growth factor induced-pulmonary hyperplasia has been demonstrated to attenuate ANTU-induced lung leak. We hypothesized that a small dose of ANTU protects against a large dose through pulmonary cell hyperplasia induced by the protective dose. Furthermore, we hypothesized that this hyperplasia is associated with altered transcription of growth factors. Male 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 effect of ANTU H. ANTU L protection against ANTU H lasted for 5 days, slowly 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 ANTU L. There was a stimulation of pulmonary cell hyperplasia in the lungs of ANTU L treated rats as measured by [ 3 H]-thymidine and bromodeoxyuridine incorporation. Treatment with the antimitotic agent colchicine abolished ANTU L -induced resistance to ANTU H. ANTU resistant rats were also resistant to the lethal effect of paraquat. Paraquat is not taken up by pneumocytes if they are undergoing hyperplasia. ANTU L administration resulted in an up regulation of gene transcription for keratinocyte growth factor, transforming growth factor-beta, keratinocyte growth factor receptor and epidermal growth factor receptor as determined through reverse transcription-polymerase chain reaction. A significant increase in transforming growth factor-alpha was not observed. These findings collectively suggest that ANTU L -induced pulmonary cell hyperplasia underlies resistance to ANTU H. Furthermore, the stimulation of hyperplasia may be due to altered growth factor and growth factor receptor expressions.