Asbestos-induced injury to cultured human pulmonary epithelial-like cells: role of neutrophil elastase.
The mechanisms responsible for asbestos-induced pulmonary epithelial cell cytotoxicity, especially oxidant-independent mechanisms, are not established. We determined whether human polymorphonuclear leukocyte (PMN) proteases contribute to asbestos-induced damage to human pulmonary epithelial-like cells (PECs) assessed using an in vitro chromium-51 release assay. Serine antiproteases, phenylmethylsulfonyl fluoride and alpha 1-antitrypsin, each ameliorated PEC injury induced by amosite asbestos and PMNs. A role for a specific proteinase, human neutrophil elastase (HNE), is supported by the facts that (1) asbestos increased HNE release assessed by an enzyme-linked immunosorbent assay technique (1.7 +/- 0.5 vs. 2.8 +/- 0.5 micrograms/ml; P < .025), (2) purified HNE or porcine pancreatic elastase (PPE) each alone caused PEC detachment, (3) asbestos plus either HNE or PPE caused PEC lysis similar to that mediated by asbestos and PMNs, and (4) cationic agents released from PMNs were unlikely to be involved because polyanions did not ameliorate injury resulting from asbestos and PMNs. Compared to elastase, cathepsin G caused less PEC detachment and negligible augmentation in asbestos-induced PEC lysis. Asbestos increased the association of 125I-labeled elastase with PECs nearly 50-fold compared with PPE alone (14.4% vs. 0.3%, respectively; P < .01) and nearly 10-fold compared with another particle, opsonized zymosan. We conclude that PMN-derived proteases, especially elastase, may contribute to asbestos-induced lung damage by augmenting pulmonary epithelial cell injury.
Kamp
D W
DW
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611.
Dunne
M
M
Dykewicz
M S
MS
Sbalchiero
J S
JS
Weitzman
S A
SA
Dunn
M M
MM
D001194:Asbestos / Q000633:toxicity*; D001195:Asbestosis / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D004347:Drug Interactions; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D019272:Leukocyte Elastase; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000502:physiology; D013268:Stimulation, Chemical
D011480:Protease Inhibitors; D001194:Asbestos; D012697:Serine Endopeptidases; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase