Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury.
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.
Filosto
Simone
S
Genome and Biomedical Sciences Facility, Division of Pulmonary and Critical Care Medicine, University of California Davis, School of Medicine, USA.
Castillo
Sianna
S
Danielson
Aaron
A
Franzi
Lisa
L
Khan
Elaine
E
Kenyon
Nick
N
Last
Jerold
J
Pinkerton
Kent
K
Tuder
Rubin
R
Goldkorn
Tzipora
T
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*
D034741:RNA, Small Interfering; C491484:SMPD3 protein, human; C491483:Smpd3 protein, mouse; C107180:Smpd3 protein, rat; D013108:Sphingomyelin Phosphodiesterase
Am J Respir Cell Mol Biol. 2009 Sep;41(3):314-23
19168702
Am J Physiol Regul Integr Comp Physiol. 2006 Jan;290(1):R11-26
16352856
Neuroscience. 2005;130(3):657-66
15590150
Am J Respir Cell Mol Biol. 2000 Apr;22(4):460-8
10745027
Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L44-53
18441093
J Nutr Biochem. 2002 Oct;13(10):625-633
12550075
Nat Med. 2005 May;11(5):491-8
15852018
Exp Cell Res. 2007 Jul 15;313(12):2680-6
17498692
J Biol Chem. 2008 Oct 24;283(43):29447-60
18718906
J Lipid Res. 2009 Jun;50(6):1101-8
19144995
Biochem Biophys Res Commun. 2006 Jun 9;344(3):900-5
16631623
Biochem J. 2006 Jan 15;393(Pt 2):513-21
16201965
Apoptosis. 1998 Oct;3(5):317-34
14646479
Curr Opin Pulm Med. 2005 Mar;11(2):153-9
15699789
Proc Am Thorac Soc. 2006 Nov;3(8):713-7
17065379
J Pharmacol Exp Ther. 2008 Feb;324(2):548-57
18042827
J Neuroimmune Pharmacol. 2007 Jun;2(2):184-93
18040843
J Lipid Res. 2007 Nov;48(11):2443-52
17693623
Am J Physiol Lung Cell Mol Physiol. 2009 Jul;297(1):L125-33
19395669
COPD. 2007 Dec;4(4):347-53
18027162
Nat Med. 2008 Apr;14(4):382-91
18376404
FEBS Lett. 2002 Oct 23;530(1-3):104-8
12387875
Am J Respir Crit Care Med. 2008 Dec 1;178(11):1100-14
18755926
COPD. 2005 Sep;2(3):289-302
17146994
J Biol Chem. 2004 Mar 12;279(11):10677-84
14688267
J Biol Chem. 2002 Jul 19;277(29):25847-50
12011103
Respir Res. 2006 Mar 30;7:53
16571143
Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L1-15
18456796
J Pathol. 2003 Oct;201(2):181-6
14517834
J Biol Chem. 2010 Apr 2;285(14):10213-22
20106976
Hepatology. 2007 Oct;46(4):1166-76
17668873
Toxicology. 2009 Jun 30;261(1-2):33-40
19394401
Nat Genet. 1995 Jul;10(3):288-93
7670466
FASEB J. 1998 Aug;12(11):999-1006
9707172
Respir Res. 2004 Nov 02;5:18
15522115
Basic Clin Pharmacol Toxicol. 2009 Aug;105(2):98-104
19389043
Antioxid Redox Signal. 2005 Jan-Feb;7(1-2):119-28
15650401
J Lipid Res. 2007 Apr;48(4):968-75
17210985
FASEB J. 2008 Oct;22(10):3419-31
18567738
FASEB J. 2005 Oct;19(12):1719-21
16051685
Am J Physiol Lung Cell Mol Physiol. 2003 Jun;284(6):L1082-92
12576296
Proc Natl Acad Sci U S A. 2000 May 23;97(11):5895-900
10823942
Proc Am Thorac Soc. 2006 Aug;3(6):494-8
16921126
Biophys J. 2005 Jan;88(1):348-59
15465865
Toxicol Sci. 2006 Aug;92(2):545-59
16699168
PLoS One. 2009 Oct 08;4(10):e7380
19812684
Nat Med. 2004 Feb;10(2):155-60
14704790
J Cell Sci. 1998 Nov;111 ( Pt 21):3209-20
9763515
Physiol Rev. 2007 Jul;87(3):1047-82
17615396
Am J Respir Cell Mol Biol. 2001 Dec;25(6):676-84
11726392
Carcinogenesis. 2009 Aug;30(8):1398-401
19458036