Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice

Cell Physiol Biochem. 2010;26(4-5):749-60. doi: 10.1159/000322342. Epub 2010 Oct 29.


Background/aims: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Antibiotics, Antineoplastic
  • Bleomycin
  • Lysophospholipids / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NIH 3T3 Cells
  • Pneumonia / chemically induced
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism*
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism


  • Actins
  • Antibiotics, Antineoplastic
  • Lysophospholipids
  • RNA, Small Interfering
  • Bleomycin
  • sphingosine 1-phosphate
  • Sphingomyelin Phosphodiesterase
  • Sphingosine