title: Elastase inhibitory activity of airway α1-antitrypsin is protected by treatment with a catalytic antioxidant in a baboon model of severe bronchopulmonary dysplasia.
abstract: Recent studies in animal models of bronchopulmonary dysplasia (BPD) suggest that antioxidant treatments may be beneficial for the disease. However, the mechanisms by which these drugs improve the course of BPD are not completely known. Alpha1-antitrypsin (α1-AT) is one of the major serine protease inhibitors in human plasma that has antielastase and antiapoptotic activities. Both activities of α1-AT are dependent on its reactive site loop (RSL), which is highly susceptible to oxidative inactivation. In this study, we investigated the elastase inhibitory activity of α1-AT in two different baboon models of BPD, the "new BPD" and the "severe BPD" models, and determined the effect of treatment with a catalytic antioxidant, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP), on the elastase inhibitory activity of α1-AT in the severe BPD model. Our results demonstrate the presence of sufficient elastase inhibitory activity of the airway α1-AT in the new but not in the severe BPD model. Treatment of severe BPD group baboons with the catalytic antioxidant MnTE-2-PyP resulted in augmentation of the elastase inhibitory activity of α1-AT. These findings suggest that prevention of the oxidative inactivation of α1-AT may be one of the mechanisms by which antioxidant therapy improves the pulmonary outcomes in animal models of severe BPD.
authors.affiliation: Division of Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Cagatay
authors.initials: C
authors.lastname: Karaaslan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirakawa
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yasumatsu
authors.forename: Ling-Yi L
authors.initials: LY
authors.lastname: Chang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pierce
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Sule
authors.initials: S
authors.lastname: Cataltepe
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy*; D002384:Catalysis; D004195:Disease Models, Animal; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008665:Metalloporphyrins / Q000627:therapeutic use*; D010215:Papio; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D008665:Metalloporphyrins; D000515:alpha 1-Antitrypsin; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; D019272:Leukocyte Elastase