Introduction of antisense oligonucleotides to heat shock protein 47 prevents pulmonary fibrosis in lipopolysaccharide-induced pneumopathy of the rat

Acute respiratory distress syndrome (ARDS) confers high morbidity, and in part due to pulmonary fibrosis. The 47-kDa heat shock protein 47 (HSP 47) is a collagen-specific molecular chaperone that has been shown to play a major role in the processing and secretion of procollagen. We examined the effect of antisense oligonucleotides against HSP 47 in Wistar rats with lipopolysaccharide (LPS)-induced pulmonary fibrosis. These rats expressed heat shock protein (HSP) 47 and collagen in response to LPS. The distribution of HSP 47 was similar to that of collagen, and all control rats displayed pulmonary fibrosis after intratracheal administration of 20 mg/kg LPS alone. Antisense oligonucleotides (100 nmol/kg dissolved in saline) were administered with the LPS among experimental subjects. Subsequent immunoblot analysis confirmed the inhibition of HSP 47 by the administration of antisense oligonucleotides. The oligonucleotides significantly improved pulmonary fibrosis among those rats administered LPS, but the oligonucletides themselves did not produce any significant changes in the behavior or histology of the lungs among control rats. These findings suggest that HSP 47 antisense oligonucleotides improve lung fibrosis among rats with LPS-induced pneumopathy.