Antisense oligonucleotide inhibition of heat shock protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats.
BACKGROUND
The most common pathologic form of pulmonary fibrosis arises from excessive deposition of extracellular matrix proteins such as collagen. The 47 kDa heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that has been shown to play a major role during the processing and/or secretion of procollagen.


OBJECTIVE
To determine whether inhibition of HSP47 could have beneficial effects in mitigating bleomycin-induced pulmonary fibrosis in rats.


METHODS
All experiments were performed with 250-300 g male Wistar rats. Animals were randomly divided into five experimental groups that were administered: 1) saline alone, 2) bleomycin alone, 3) antisense HSP47 oligonucleotides alone, 4) bleomycin + antisense HSP47 oligonucleotides, and 5) bleomycin + sense control oligonucleotides. We investigated lung histopathology and performed immunoblot and immunohistochemistry analyses.


RESULTS
In rats treated with HSP47 antisense oligonucleotides, pulmonary fibrosis was significantly reduced. In addition, treatment with HSP47 antisense oligonucleotides significantly improved bleomycin-induced morphological changes. Treatment with HSP47 antisense oligonucleotides alone did not produce any significant changes to lung morphology. Immunoblot analyses of lung homogenates confirmed the inhibition of HSP47 protein by antisense oligonucleotides. The bleo + sense group, however, did not exhibit any improvement in lung pathology compared to bleomycin alone groups, and also had no effect on HSP47 expression.


CONCLUSIONS
These findings suggest that HSP47 antisense oligonucleotide inhibition of HSP47 improves bleomycin-induced pulmonary fibrosis pathology in rats.
Hagiwara
Satoshi
S
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Idaigaoka-Hasamamachi-Yufu City-Oita, Japan. saku@med.oita-u.ac.jp
Iwasaka
Hideo
H
Matsumoto
Shigekiyo
S
Noguchi
Takayuki
T
D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D050958:HSP47 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D050958:HSP47 Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D001761:Bleomycin