Neutral sphingomyelinase 2: A novel target in cigarette smoke-induced apoptosis and lung injury

Simone Filosto, Sianna Castillo, Aaron Danielson, Lisa Franzi, Elaine Khan, Nicholas Kenyon, Jerold A Last, Kent E Pinkerton, Rubin Tuder, Tzipora Goldkorn

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Chronic obstructive pulmonary disease (COPD) is caused by exposure to cigarette smoke (CS). One mechanism of CS-induced lung injury is aberrant generation of ceramide, which leads to elevated apoptosis of epithelial and endothelial cells in the alveolar spaces. Recently, we discovered that CS-induced ceramide generation and apoptosis in pulmonary cells is governed by neutral sphingomyelinase (nSMase) 2. In the current experiments, we expanded our studies to investigate whether nSMase2 governs ceramide generation and apoptosis in vivo using rodent and human models of CS-induced lung injury. We found that exposure of mice or rats to CS leads to colocalizing elevations of ceramide levels and terminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling-positive cells in lung tissues. These increases are nSMase2 dependent, and are abrogated by treatment with N-acetyl cysteine or antinSMase2 small interfering RNA (siRNA). We further showed that mice that are heterozygous for nSMase2 demonstrate significant decrease in ceramide generation after CS exposure, whereas acidic sphingomyelinase (aSMase) knockout mice maintain wild-type ceramide levels, confirming our previous findings (in human airway epithelial cells) that only nSMase2, and not aSMase, is activated by CS exposure. Lastly, we found that lung tissues from patients with emphysema(smokers) display significantly higher levels of nSMase2 expression compared with lung tissues from healthy control subjects. Taken together, these data establish the central in vivo role of nSMase2 in ceramide generation, aberrant apoptosis, and lung injury under CS exposure, underscoring its promise as a novel target for the prevention of CS-induced airspace destruction.

Original languageEnglish (US)
Pages (from-to)350-360
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume44
Issue number3
DOIs
StatePublished - Mar 1 2011

Keywords

  • Apoptosis
  • Ceramide
  • Chronic obstructive pulmonary disease
  • Mouse model
  • Neutral sphingomyelinase2

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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