Novel and extensive aspects of paraquat-induced pulmonary fibrogenesis: comparative and time-course microarray analyses in fibrogenic and non-fibrogenic rats.
Although paraquat (PQ) is widely known to induce pulmonary fibrosis, the molecular mechanisms are poorly understood. Therefore, to bring a new dimension to the elucidation of the mechanisms, we conducted microarray experiments to investigate the expression profiles of 1,090 genes in the lungs during the progressive phase of PQ-induced pulmonary fibrosis in rats. After several s.c. injections of PQ, rats were divided into a fibrogenic group and a non-fibrogenic group. Time-course gene expression analysis of the fibrogenic group showed altered gene regulation throughout the experimental period. The expression levels of many cell membrane channel, transporter, and receptor genes were substantially altered. These genes were classified into two categories: polyamine transporter- and electrolyte/fluid balance-related genes. Moreover, comparative analysis of the fibrogenic and the non-fibrogenic group revealed 36 genes with significantly different patterns of expression, including the pro-apoptotic gene Bad. This indicates that Bad is a key factor in apoptosis and that apoptosis provides a major turning point in PQ-induced pulmonary fibrosis. Notably, subtypes of transforming growth factor (TGF)-beta genes that are considered to play a pivotal role in fibrogenesis showed no differences in expression between the two groups, though TGF-beta3 was markedly induced in both groups. These results provide novel and extensive insights into the molecular mechanisms that lead to pulmonary fibrosis after exposure to PQ.
Satomi
Yoshihide
Y
Pharmacology & Safety Research Department, Pharmaceutical Development Research Laboratories, Teijin Pharma Ltd., Japan. y.satomi@teijin.co.jp
Sakaguchi
Kazuko
K
Kasahara
Yoshinori
Y
Akahori
Fumiaki
F
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001835:Body Weight; D016000:Cluster Analysis; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010269:Paraquat; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015291:Transforming Growth Factors / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
C494821:Bad protein, rat; D051025:bcl-Associated Death Protein; D015291:Transforming Growth Factors; D003094:Collagen; D010269:Paraquat; D006909:Hydroxyproline