Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity.
Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Furthermore, oxidation and nitration of MnSOD were identified in the asthmatic airway, correlating with physiological parameters of asthma severity. These findings link oxidative and nitrative stress to loss of SOD activity and downstream events that typify asthma, including apoptosis and shedding of the airway epithelium and hyperresponsiveness.
Comhair
Suzy A A
SA
Department of Pathobiology, The Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Xu
Weiling
W
Ghosh
Sudakshina
S
Thunnissen
Frederik B J M
FB
Almasan
Alexandru
A
Calhoun
William J
WJ
Janocha
Allison J
AJ
Zheng
Lemin
L
Hazen
Stanley L
SL
Erzurum
Serpil C
SC
D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001249:Asthma / Q000201:enzymology* / Q000473:pathology; D015152:Blotting, Northern; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D001999:Bronchoscopy; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D004247:DNA / Q000737:chemistry; D015180:Electrophoresis, Gel, Two-Dimensional; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D000975:Antioxidants; D019394:Ki-67 Antigen; D034741:RNA, Small Interfering; D004247:DNA; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D009584:Nitrogen; D010100:Oxygen
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