Quantum proteolysis by neutrophils: implications for pulmonary emphysema in alpha 1-antitrypsin deficiency.
Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in alpha 1-antitrypsin (AAT) deficiency. Millimolar concentrations of leukocyte elastase, when released from single azurophil granules of activated neutrophils, lead to evanescent quantum bursts of proteolytic activity before catalysis is quenched by pericellular inhibitors. 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 heterozygous individuals (Pi MZ and Pi SZ) were slightly, but significantly, larger than those in serum from normal patients (Pi M). In marked contrast, mean areas of events in serum from AAT-deficient individuals were 10-fold larger than those in serum from normal patients. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for less than 20 milliseconds and for more than 80 milliseconds 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.
Campbell
E J
EJ
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City 84132, USA. edward.campbell@hsc.utah.edu
Campbell
M A
MA
Boukedes
S S
SS
Owen
C A
CA
D003594:Cytoplasmic Granules / Q000201:enzymology; D010450:Endopeptidases / Q000097:blood*; D006801:Humans; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000494:pharmacology; D007525:Isoelectric Focusing; D008954:Models, Biological; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010641:Phenotype; D011656:Pulmonary Emphysema / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D011789:Quantum Theory; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000201:enzymology*
D018836:Inflammation Mediators; D000515:alpha 1-Antitrypsin; D010450:Endopeptidases