Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice.
OBJECTIVE
The sphingomyelin/ceramide signaling pathway is an important component of many cellular processes implicated in the pathogenesis of lung disease. Acid sphingomyelinase (ASM) is a key mediator of this pathway, but its specific role in pulmonary fibrosis has not been previously investigated. Here we used the bleomycin model of pulmonary fibrosis to investigate fibrotic responses in normal and ASM knockout (ASM(-/-)) mice, and in NIH3T3 fibroblasts with and without ASM siRNA treatment.


METHODS
Mice and cells with and without ASM activity were treated with bleomycin, and the effects on lung inflammation, formation of collagen producing myofibroblasts, and apoptosis were assessed.


RESULTS
The development of bleomycin-induced inflammation and fibrosis in wildtype mice correlated with the rapid activation of ASM, and was markedly attenuated in the absence of ASM activity. Along with the elevated ASM activity, there also was an elevation of acid ceramidase (AC) activity, which was sustained for up to 14 days post-bleomycin treatment. Studies in NIH3T3 fibroblasts confirmed these findings, and revealed a direct effect of ASM/AC activation on the formation of myofibroblasts. Cell studies also showed that a downstream effect of bleomycin treatment was the production of sphingosine-1-phosphate.


CONCLUSIONS
These data demonstrate that the sphingomyelin/ceramide signaling pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis, and suggest that inhibition of ASM may potentially slow the fibrotic process in the lung.
Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Rajwinder
R
Dhami
Xingxuan
X
He
Edward H
EH
Schuchman
D000199:Actins / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
D000199:Actins; D000903:Antibiotics, Antineoplastic; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D001761:Bleomycin; C060506:sphingosine 1-phosphate; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine