title: Disruption of the murine alpha1-antitrypsin/PI2 gene.
abstract: Alpha-1-antitrypsin (alpha1-AT) is a member of the serine protease inhibitor family regulating numerous proteolytic processes. The genetic disorder, alpha1-AT deficiency, is well known as a cause of hereditary pulmonary emphysema and liver cirrhosis. To create an animal model of human alpha1-AT deficiency, we disrupted the major murine isoform PI2, which is similar to human alpha1-AT and is one of 7 alpha1-AT isoforms found in the mouse. The ability of the serum to inhibit the activities of human leukocyte elastase (HLE) and human chymotrypsin (CYT) was significantly lower in heterozygous mice (alpha1-AT/PI2 -/+) than wild-type (alpha1-AT/PI2 +/+) mice (73.2% vs. 100% for HLE and 67.8% vs.100% for CYT, respectively; P<0.05). The distribution of genotypes among F(2) progeny was not in accordance with Mendelian distribution (P<0.01), as the percentages of wild-type, heterozygotes and homozygotes were 47.8%, 37.3% and 14.9%, respectively. Thus, it is likely that impairment of the protease inhibitor had a critical effect on fetus development. The alpha1-AT/PI2 deficient mouse will be a useful animal model for elucidating the function of alpha1-AT in fetal development, studying the mechanisms of chronic inflammatory disease and evaluating therapeutic candidates for the treatment of inflammatory disease.
authors.affiliation: Central Pharmaceutical Research Institute, Pharmaceutical Frontier Research Laboratory, Japan Tobacco Inc., Yokohama, Kanagawa, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kushi
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Akiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Noguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Edamura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasai
mesh_terms: D000818:Animals; D002908:Chronic Disease; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development; D007249:Inflammation / Q000209:etiology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011506:Proteins; D015843:Serpins; D000515:alpha 1-Antitrypsin / Q000502:physiology; D019896:alpha 1-Antitrypsin Deficiency
chemical_list: D011506:Proteins; D015843:Serpins; D000515:alpha 1-Antitrypsin; C075177:SERPINB1 protein, human; D002918:Chymotrypsin; D019272:Leukocyte Elastase