BACKGROUND: Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs. METHODS AND RESULTS: In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT. CONCLUSIONS: Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.
BACKGROUND:Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs. METHODS AND RESULTS: In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT. CONCLUSIONS: Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.
Authors: Charlie Strange; Robert M Senior; Frank Sciurba; Scott O'Neal; Alison Morris; Stephen R Wisniewski; Russell Bowler; Harry S Hochheiser; Michael J Becich; Yingze Zhang; Joseph K Leader; Barbara A Methé; Naftali Kaminski; Robert A Sandhaus Journal: Ann Am Thorac Soc Date: 2015-10
Authors: Sadaf Sohrab; Daniela N Petrusca; Angelia D Lockett; Kelly S Schweitzer; Natalia I Rush; Yuan Gu; Krzysztof Kamocki; Jana Garrison; Irina Petrache Journal: FASEB J Date: 2009-05-07 Impact factor: 5.191