DNA microarray analysis of pulmonary fibrosis three months after exposure to paraquat in rats.
Although paraquat (PQ) is known to induce pulmonary fibrosis, how it does so is not entirely clear. To elucidate the mechanisms involved, the profile of gene expression in the lung at three months after exposure to PQ (7 mg/kg, s.c., daily for eight administrations) was investigated in rats using a DNA microarray. Changes in gene expression that were considered to reflect damage to the lung, a change in the balance of electrolytes and fluid, and alveolar remodeling were observed. The products of these genes were: CSF-1 receptor, which is a receptor of inflammatory cytokines that activates monocyte/macrophages; TGF-beta type II receptor, which is a receptor of TGF-betas involved in wound healing and fibrosis; a subunit of Na+/K(+)-ATPase, an amiloride-sensitive cation channel, and a subunit of the potassium channel, all of which regulate the alveolar fluid balance and play a role in clearing lung edema; the adenosine A2a receptor, which has a protective function in the lung and interacts with dopamine D1 and D2 receptors to regulate the function of amiloride-sensitive cation channels; cofilin, which is involved in the depolymerization and cleavage of actin filaments; LIM motif-containing protein kinase 1, which negatively regulates the activity of cofilin; SHPS-1, which regulates the integrin-mediated reorganization of the cytoskeleton; and sodium channel beta 2, which is involved in cell adhesion and migration. These results indicate that PQ-induced pulmonary fibrosis does not merely terminate as cicatrices three months after the discontinuation of PQ treatment, but that dynamic functional change continues in the lung.
Satomi
Yoshihide
Y
Pharmacology & Safety Research Department, Pharmaceutical Development Research Laboratories, Teijin Pharma Ltd., Hino, Tokyo, Japan. y.satomi@teijin.co.jp
Tsuchiya
Wakana
W
Miura
Daishiro
D
Kasahara
Yoshinori
Y
Akahori
Fumiaki
F
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D020869:Gene Expression Profiling; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects
D015222:Sodium Channels; D003094:Collagen; D010269:Paraquat