title: Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury.
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 anti-nSMase2 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.
authors.affiliation: Genome and Biomedical Sciences Facility, Division of Pulmonary and Critical Care Medicine, University of California Davis, School of Medicine, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Filosto
authors.forename: Sianna
authors.initials: S
authors.lastname: Castillo
authors.forename: Aaron
authors.initials: A
authors.lastname: Danielson
authors.forename: Lisa
authors.initials: L
authors.lastname: Franzi
authors.forename: Elaine
authors.initials: E
authors.lastname: Khan
authors.forename: Nick
authors.initials: N
authors.lastname: Kenyon
authors.forename: Jerold
authors.initials: J
authors.lastname: Last
authors.forename: Kent
authors.initials: K
authors.lastname: Pinkerton
authors.forename: Rubin
authors.initials: R
authors.lastname: Tuder
authors.forename: Tzipora
authors.initials: T
authors.lastname: Goldkorn
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D055370:Lung Injury / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012907:Smoking / Q000009:adverse effects*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C491484:SMPD3 protein, human; C491483:Smpd3 protein, mouse; C107180:Smpd3 protein, rat; D013108:Sphingomyelin Phosphodiesterase
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