Cationic Proteins Inhibit L-Arginine Uptake in Rat Alveolar Macrophages and Tracheal Epithelial Cells . Implications for Nitric Oxide Synthesis

Eosinophil-derived cationic proteins play an essential role in the pathogenesis of bronchial asthma. We tested whether cationic proteins interfere with the cationic amino-acid transport in alveolar macrophages (AMPhi) and tracheal epithelial cells, and whether L-arginine-dependent pathways were affe...

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Published in:	American journal of respiratory cell and molecular biology Vol. 21; no. 2; pp. 155 - 162
Main Authors:	Hammermann, Rainer, Hirschmann, Joachim, Hey, Claudia, Mossner, Jutta, Folkerts, Gert, Nijkamp, Frans P, Wessler, Ignaz, Racke, Kurt
Format:	Journal Article
Language:	English
Published:	United States Am Thoracic Soc 01-08-1999 American Thoracic Society
Subjects:	Animals Arginase - pharmacology Arginine - pharmacokinetics Blood Proteins - pharmacology Citrulline - pharmacology Dose-Response Relationship, Drug Eosinophil Granule Proteins Epithelial Cells - metabolism Female Fibrinolytic Agents - pharmacology Gene Expression Heparin - pharmacology Lipopolysaccharides - pharmacology Lung - metabolism Lysine - metabolism Macrophages, Alveolar - metabolism Male Nitric Oxide - biosynthesis Nitrites - metabolism Rats Rats, Sprague-Dawley Ribonucleases Time Factors Trachea - metabolism
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Summary:	Eosinophil-derived cationic proteins play an essential role in the pathogenesis of bronchial asthma. We tested whether cationic proteins interfere with the cationic amino-acid transport in alveolar macrophages (AMPhi) and tracheal epithelial cells, and whether L-arginine-dependent pathways were affected. The effect of cationic polypeptides on cellular uptake of [(3)H]-L-arginine, nitrite accumulation, and the turnover of [(3)H]-L-arginine by nitric oxide (NO) synthase and arginase (formation of [(3)H]-L-citrulline and [(3)H]-L-ornithine, respectively) were studied. Poly-L-arginine reduced [(3)H]-L-arginine uptake in rat AMPhi and tracheal epithelial cells in a concentration-dependent manner (at 300 microgram/ml by 70%). Poly-L-lysine, protamine, and major basic protein (each up to 300 microgram/ml) tested in rat AMPhi inhibited [(3)H]-L-arginine uptake by 35 to 50%. During 6 h incubation in amino acid-free Krebs solution, rat AMPhi, precultured in the absence or presence of LPS (1 microgram/ml), accumulated 1.4 and 3.5 nmol/10(6) cells nitrite, respectively. Addition of 100 microM L-arginine increased nitrite accumulation by 70 and 400% in control and lipopolysaccharide-treated AMPhi, respectively. Nitrite accumulation in the presence of L-arginine was reduced by poly-L-arginine and poly-L-lysine (100 and 300 microgram/ml) by 60 to 85% and 20 to 30%, respectively. Poly-L-arginine, but not poly-L-lysine, inhibited nitrite accumulation already in the absence of extracellular L-arginine. Poly-L-arginine (300 microgram/ml) inhibited [(3)H]-L-citrulline formation by AMPhi stronger than that of [(3)H]-L-ornithine. We conclude that cationic proteins can inhibit cellular transport of L-arginine and this can limit NO synthesis. Poly-L-arginine inhibits L-arginine uptake more effectively than other cationic proteins and exerts additional direct inhibitory effects on NO synthesis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1044-1549 1535-4989
DOI:	10.1165/ajrcmb.21.2.3574