In vivo suppression of immune complex-induced alveolitis by secretory leukoproteinase inhibitor and tissue inhibitor of metalloproteinases 2.
The pulmonary tree is exposed to neutrophil-derived serine proteinases and matrix metalloproteinases in inflammatory lung diseases, but the degree to which these enzymes participate in tissue injury remains undefined, as does the therapeutic utility of antiproteinase-based interventions. To address these issues, an in vivo rat model was examined in which the intrapulmonary deposition of immune complexes initiates a neutrophil-mediated acute alveolitis. In vitro studies demonstrated that rat neutrophils can release neutrophil elastase and cathepsin G as well as a neutrophil progelatinase, which was subsequently activated by either chlorinated oxidants or serine proteinases. Based on structural homologies that exist between rat and human neutrophil proteinases, rat neutrophil elastase and cathepsin G activities could be specifically regulated in vitro by recombinant human secretory leukoproteinase inhibitor, and rat neutrophil gelatinase activity proved sensitive to inhibition by recombinant human tissue inhibitor of metalloproteinases 2. When either of the recombinant antiproteinases were instilled intratracheally, in vivo lung damage as assessed by increased permeability or hemorrhage was significantly reduced. Furthermore, the coadministration of the serine and matrix metalloproteinase inhibitors almost completely prevented pulmonary damage while effecting only a modest decrease in neutrophil influx. These data support a critical role for neutrophil-derived proteinases in acute lung damage in vivo and identify recombinant human secretory leukoproteinase and recombinant human tissue inhibitor of metalloproteinases 2 as potentially efficacious interventions in inflammatory disease states.
Mulligan
M S
MS
Department of Pathology, University of Michigan, Ann Arbor 48109.
Desrochers
P E
PE
Chinnaiyan
A M
AM
Gibbs
D F
DF
Varani
J
J
Johnson
K J
KJ
Weiss
S J
SJ
D000818:Animals; D000936:Antigen-Antibody Complex; D056649:Cathepsin G; D002403:Cathepsins / Q000097:blood; D003571:Cytochalasin B / Q000494:pharmacology; D004792:Enzyme Precursors / Q000097:blood; D018093:Gelatinases / Q000097:blood; D006801:Humans; D019272:Leukocyte Elastase; D008171:Lung Diseases / Q000097:blood / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D008666:Metalloendopeptidases / Q000097:blood; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000097:blood / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011650:Pulmonary Alveoli; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2
D000936:Antigen-Antibody Complex; D004792:Enzyme Precursors; D009363:Neoplasm Proteins; D016877:Oxidants; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase; D013755:Tetradecanoylphorbol Acetate