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(Chest. 2000;117:303S.)
© 2000 American College of Chest Physicians

Quantum Proteolysis by Neutrophils*

Implications for Pulmonary Emphysema in {alpha}1-Antitrypsin Deficiency

Edward J. Campbell, MD; M. A. Campbell, MT(ASCP); S. S. Boukedes, BS and Caroline A. Owen, MD, PhD

* From the Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT.

Correspondence to: Edward J. Campbell, MD, University of Utah School of Medicine, 50 North Medical Dr, Salt Lake City, UT 84132


   Introduction
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 Introduction
References
 
Abbreviation: AAT = {alpha}1-antitrypsin

{alpha}1-Antitrypsin (AAT) deficiency is the most prevalent potentially fatal hereditary disease in white individuals, and is an important risk factor for pulmonary emphysema, especially in cigarette smokers. Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in AAT deficiency. We have found that when millimolar concentrations of leukocyte elastase are released from single azurophil granules of activated neutrophils, they transiently overwhelm local proteinase inhibitors, leading to evanescent quantum bursts of proteolytic activity. Catalysis is quenched when enzyme concentration no longer exceeds that of pericellular inhibitors.1 2 Herein, we tested the possibility that quantum proteolytic events are abnormal in AAT deficiency. We incubated neutrophils on opsonized fluoresceinated fibronectin in serum from individuals with various AAT phenotypes, and then measured and modeled quantum proteolytic events. The mean areas of the events in serum from heterozygotes (Pi MZ and Pi SZ) were 16.1 ± (SEM) 4.0 µm2 and 14.2 ± 3.3 µm2, respectively, which were slightly (but significantly) larger than those in serum from normals (Pi M), which were 9.7 ± 1.2 µm2. In marked contrast, events in serum from AAT-deficient individuals were 97.4 ± 7.8 µm2. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for <20 ms and >80 ms in Pi M and Pi Z individuals, respectively. Thus, quantum proteolytic events are abnormally large and prolonged in AAT deficiency, leading directly to an increased risk of tissue injury in the immediate vicinity of activated neutrophils. These results have potentially important implications for the pathogenesis and prevention of lung disease in AAT deficiency.


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 Introduction
 References
 

  1. Liou, TG, Campbell, EJ (1995) Nonisotropic enzyme–inhibitor interactions: a novel nonoxidative mechanism for quantum proteolysis by human neutrophils. Biochemistry 34,16171-16177[CrossRef][Medline]
  2. Liou, TG, Campbell, EJ (1996) Quantum proteolysis resulting from release of single granules by human neutrophils: a novel, nonoxidative mechanism of extracellular proteolytic activity. J Immunol 157,2624-2631[Abstract]



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