An antisense oligonucleotide to HSP47 inhibits paraquat-induced pulmonary fibrosis in rats.
The most common cause of death from poisoning by the widely used, but highly toxic herbicide paraquat is respiratory failure from pulmonary fibrosis, which develops through pathological overproduction of extracellular matrix proteins such as the collagens. Heat shock protein (HSP47) is a collagen-specific molecular chaperone that assists in the posttranslational modifications of procollagens during collagen biosynthesis. We investigated whether treatment with an HSP47-antisense oligonucleotide would inhibit paraquat-induced pulmonary fibrosis in Wistar rats. Rats randomized into three groups (control, paraquat, and paraquat+antisense). Paraquat (20 mg/kg/day) (n=16) or a saline control (n=10) was administered to groups of Wistar rats. Intratracheal administration of the antisense oligonucleotide (100 nmol/kg in saline) was performed after the initial paraquat treatment (n=16). Treatment with paraquat alone induced pulmonary fibrosis in the entire group, while treatment with the antisense oligonucleotide alone did not produce any substantial change in lung histology. Administration of antisense oligonucleotides produced a substantial reduction in paraquat-induced pulmonary fibrosis. An immunoblot analysis confirmed that the HSP47-antisense oligonucleotide inhibited HSP47 production. These findings indicate that the HSP47-antisense oligonucleotide inhibited paraquat-induced pulmonary fibrosis and pneumopathy in rats.
Hagiwara
Satoshi
S
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita 879-5593, Japan. saku@med.oita-u.ac.jp
Iwasaka
Hideo
H
Matsumoto
Shigekiyo
S
Noguchi
Takayuki
T
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D050958:HSP47 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006540:Herbicides / Q000633:toxicity*; D006909:Hydroxyproline / Q000032:analysis; D007124:Immunoenzyme Techniques; D007442:Intubation, Intratracheal; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010269:Paraquat / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar
D000933:Antifibrinolytic Agents; D050958:HSP47 Heat-Shock Proteins; D006540:Herbicides; D016376:Oligonucleotides, Antisense; D010269:Paraquat; D006909:Hydroxyproline