The cysteine pro-drug Z2196 ((2RS, 4R)-2-methylthiazolidine carboxylic acid) and two drugs with methyl esters attached to Z2196 (Z2197 and Z2199) were evaluated for antifibrotic effects in the hamster bleomycin model of lung fibrosis. Each drug or phosphate-buffered saline (PBS) was given daily (300 mg/kg intraperitoneally) for 2 days before intratracheal instillation of bleomycin (7.5 units/kg) or saline for an additional 13 days. Lung collagen measured as hydroxyproline was significantly increased to 138% of the control groups in the PBS + Bleomycin treated group, but the Z2196 + Bleomycin group was increased to 108% and was not statistically different from controls. Protein content of brochoalveolar lavage supernatant in PBS + Bleomycin treated hamsters was significantly increased to 326% of controls. The protein content of bronchoalveolar lavage supernatant for all cysteine pro-drug + Bleomycin treated hamsters was increased to 160% of PBS + Bleomycin treated hamsters. All the Bleomycin treated hamsters had significantly more cells and more neutrophils recovered in bronchoalveolar lavage than controls. The PBS + Bleomycin treated hamsters had significantly more lymphocytes in bronchoalveolar lavage than all the other treatment groups. The Z2196 +Bleomycin and Z2197 +Bleomycin hamsters had significantly less monocytes in BALF than PBS + Bleomycin hamsters. The lung total sulfhydryl and nonprotein sulfhydryl in PBS + Bleomycin treated hamsters were increased to 210% and 253% of controls, respectively, whereas in Z2196 +Bleomycin hamsters they were increased to 152% and 153% respectively. Histopathology of PBS + Bleomycin hamsters showed a diffuse mixed mononuclear alveolitis, multifocal fibrosis and peribronchiolar fibrosis, whereas Z2196 + Bleomycin hamsters showed notably less alveolitis and fibrosis. These observations were supported by a 60% decrease in the volume of lesion in Z2196 + Bleomycin hamsters compared with PBS + Bleomycin hamsters. None of the cysteine pro-drugs given daily for 15 days and a single dose of saline intratracheally resulted in any mortality or any detectable lung injury or fibrosis. It was concluded that treatment with the cysteine pro-drug Z2196 inhibits most of the rise in non-protein sulfhydryl and collagen and some of the inflammation resulting from bleomycin treatment in hamsters, whereas Z2197 and Z2199 failed to manifest any influence on inflammation and collagen accumulation.
- Lung fibrosis
ASJC Scopus subject areas
- Pathology and Forensic Medicine