Alterations in pulmonary mRNA encoding procollagens, fibronectin and transforming growth factor-beta precede bleomycin-induced pulmonary fibrosis in mice.
Female C57Bl/6 mice treated by constant s.c. infusion for 1 week with 100 mg of bleomycin per kg of body weight develop a more pronounced pulmonary fibrosis than BALB/c mice. Within 4 weeks after bleomycin treatment, the pulmonary content of mRNAs encoding fibronectin, alpha 2I procollagen and alpha 1III procollagen was increased. The increases were greater and occurred earlier in C57Bl/6 mice compared to BALB/c mice. Fibronectin mRNA increased 12-fold in C57Bl/6 mice and only 3-fold in BALB/c mice, whereas alpha 1III procollagen mRNA increased 4-fold in C57Bl/6 mice and 2-fold in BALB/c mice. alpha 2I procollagen mRNA was increased only in C57Bl/6 mice (2-fold). The increases were sequential in C57Bl/6 mice: fibronectin mRNA was elevated first, followed by alpha 2I procollagen, then alpha 1III procollagen mRNA. The temporal relationship between these mRNA elevations and extracellular matrix accumulation, and the exaggerated responses in C57Bl/6 mice, suggest that matrix accumulation is a function of the mRNA levels. Transforming growth factor-beta mRNA relative to total polyadenylated RNA was elevated 5-fold in C57Bl/6 mice and depressed 80% in BALB/c mice 1 week after treatment. Early alterations in transforming growth factor-beta mRNA may contribute to murine strain variation in bleomycin-induced pulmonary fibrosis and suggest the involvement of transforming growth factor-beta in this disease.
Hoyt
D G
DG
Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut.
Lazo
J S
JS
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D005260:Female; D005353:Fibronectins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009693:Nucleic Acid Hybridization; D010455:Peptides / Q000235:genetics*; D011347:Procollagen / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects*; D013045:Species Specificity; D015291:Transforming Growth Factors
D005353:Fibronectins; D010455:Peptides; D011347:Procollagen; D012333:RNA, Messenger; D001761:Bleomycin; D015291:Transforming Growth Factors