A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema.
BACKGROUND
There is growing evidence that alveolar cell apoptosis plays an important role in emphysema pathogenesis, a chronic inflammatory lung disease characterized by alveolar destruction. The association of alpha1-antitrypsin deficiency with the development of emphysema has supported the concept that protease/antiprotease imbalance mediates cigarette smoke-induced emphysema.


OBJECTIVE
We propose that, in addition to its antielastolytic effects, alpha1-antitrypsin may have broader biological effects in the lung, preventing emphysema through inhibition of alveolar cells apoptosis. METHODS, MEASUREMENTS, AND MAIN RESULTS: Transduction of human alpha1-antitrypsin via replication-deficient adeno-associated virus attenuated airspace enlargement and emphysema caused by inhibition of vascular endothelial growth factor (VEGF) receptors with SU5416 in mice, a model of apoptosis-dependent emphysema lacking neutrophilic inflammation. The overexpressed human serine protease inhibitor accumulated in lung cells and suppressed caspase-3 activation and oxidative stress in lungs treated with the VEGF blocker or with VEGF receptor-1 and -2 antibodies. Similar results were obtained in SU5416-treated rats given human alpha1-antitrypsin intravenously.


CONCLUSIONS
Our findings suggest that inhibition of structural alveolar cell apoptosis by alpha1-antitrypsin represents a novel protective mechanism of the serpin against emphysema. Further elucidation of this mechanism may extend the therapeutic options for emphysema caused by reduced level or loss of function of alpha1-antitrypsin.
Petrache
Irina
I
Division of Pulmonary and Critical Care, Department of Medicine, John Hopkins University School of Medicine, Baltimore, Maryland, USA. ipetrach@iupui.edu
Fijalkowska
Iwona
I
Zhen
Lijie
L
Medler
Terry R
TR
Brown
Emile
E
Cruz
Pedro
P
Choe
Kang-Hyeon
KH
Taraseviciene-Stewart
Laimute
L
Scerbavicius
Robertas
R
Shapiro
Lee
L
Zhang
Bing
B
Song
Sihong
S
Hicklin
Dan
D
Voelkel
Norbert F
NF
Flotte
Terence
T
Tuder
Rubin M
RM
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000166:cytology; D011656:Pulmonary Emphysema / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D014361:Trypsin Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000515:alpha 1-Antitrypsin / Q000494:pharmacology* / Q000627:therapeutic use
D014361:Trypsin Inhibitors; D000515:alpha 1-Antitrypsin; D040262:Receptors, Vascular Endothelial Growth Factor