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Alveolar Macrophages from Normal Subjects Lack the NOS-Related System y⁺ for Arginine Transport

Department of Experimental Medicine, Section of General and Clinical Pathology, and Department of Clinical Sciences, Section of Respiratory Diseases, University of Parma, Parma, Italy

Correspondence and requests for reprints should be addressed to Bianca Maria Rotoli, Ph.D., Sezione di Patologia Generale e Clinica, Dipartimento di Medicina Sperimentale, Università di Parma, Via Volturno, 39, 43100 Parma, Italy. E-mail: biancamaria.rotoli{at}unipr.it

Systems y⁺ and y⁺L represent the main routes for arginine transport in mammalian cells. While system y⁺ activity is needed for the stimulated NO production in rodent alveolar macrophages (AM), no information is yet available about arginine transport in human AM. We study here arginine influx and genes for arginine transporters in AM from bronchoalveolar lavage of normal subjects. These cells express the y⁺-related genes SLC7A1/CAT1 and SLC7A2/CAT2B, as well as the y⁺L genes SLC7A7/y+LAT1 and SLC7A6/y+LAT2. However, compared with human endothelial cells, AM express much less SLC7A2 mRNA and higher levels of SLC7A7 mRNA. Granulocyte macrophage colony-stimulating factor or IFN- do not change the expression of any transporter gene, while lipopolysaccharide induces SLC7A2/CAT2B. Under all the conditions tested, leucine inhibits most of the arginine transport in the presence of Na⁺ and N-ethylmaleimide, an inhibitor of system y⁺, is completely ineffective, indicating that system y⁺L operates most of the arginine influx. Comparable results are obtained in AM from patients with interstitial lung disease, such as Nonspecific Interstitial Pneumonia (NSIP), although these cells have a higher SLC7A1 and a lower SLC7A7 expression than AM from normal subjects. It is concluded that AM from normal subjects or patients with NSIP lack a functional transport system y⁺, a situation that may limit arginine availability for NO synthesis. Moreover, since mutations of SLC7A7/y+LAT1 cause Lysinuric Protein Intolerance, a disease often associated with AM impairment and alveolar proteinosis, the high SLC7A7 expression observed in human AM suggests that y+LAT1 activity is important for the function of these cells.

Key Words: alveolar proteinosis • Lysinuric Protein Intolerance • NO • system y⁺ • system y⁺L

CLINICAL RELEVANCE Alveolar macrophages do not transport Arg through the nitric oxide synthase–related CAT transporters but, rather, through y+LAT1 and 2. Since y+LAT1 mutations underlie some cases of alveolar proteinosis, these data suggest that y+LAT1 activity is required for alveolar macrophage function.