title: SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in α1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema.
authors.affiliation: Theodor Kocher Institute, Univ. of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland. charaf.benarafa@tki.unibe.ch.
authors.forename: Tiziana P
authors.initials: TP
authors.lastname: Cremona
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Tschanz
authors.forename: Christophe
authors.initials: C
authors.lastname: von Garnier
authors.forename: Charaf
authors.initials: C
authors.lastname: Benarafa
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D015843:Serpins / Q000172:deficiency / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects
chemical_list: C522950:Serpinb1a protein, mouse; D015843:Serpins; D012906:Smoke
keywords: animal model; cigarette smoke; serpin