Document Detail

Functional role and species-specific contribution of arginases in pulmonary fibrosis.
MedLine Citation:
PMID:  17934065     Owner:  NLM     Status:  MEDLINE    
Lung fibrosis is characterized by increased deposition of ECM, especially collagens, and enhanced proliferation of fibroblasts. l-arginine is a key precursor of nitric oxide, asymmetric dimethylarginine, and proline, an amino acid enriched in collagen. We hypothesized that l-arginine metabolism is altered in pulmonary fibrosis, ultimately affecting collagen synthesis. Expression analysis of key enzymes in the arginine pathway, protein arginine methyltransferases (Prmt), arginine transporters, and arginases by quantitative (q) RT-PCR and Western blot revealed significant upregulation of arginase-1 and -2, but not Prmt or arginine transporters, during bleomycin-induced pulmonary fibrosis in mice. HPLC revealed a concomitant, time-dependent decrease in pulmonary l-arginine levels. Arginase-1 and -2 mRNA and protein expression was increased in primary fibroblasts isolated from bleomycin-treated mice, compared with controls, and assessed by qRT-PCR and Western blot analysis. TGF-beta1, a key profibrotic mediator, induced arginase-1 and -2 mRNA expression in primary and NIH/3T3 fibroblasts. Treatment of fibroblasts with the arginase inhibitor, NG-hydroxy-l-arginine, attenuated TGF-beta1-stimulated collagen deposition, but not collagen mRNA expression or Smad signaling, in fibroblasts. In human lungs derived from patients with idiopathic pulmonary fibrosis, arginase activity was unchanged, but arginase-1 expression significantly decreased when compared with donor lungs. Our results thus demonstrate that arginase-1 is expressed and functionally important for collagen deposition in lung fibroblasts. TGF-beta1-induced upregulation of arginase-1 suggests an interplay between profibrotic agents and l-arginine metabolism during the course of lung fibrosis in the mouse, whereas species-specific regulatory mechanisms may account for the differences observed in mouse and human.
Kamila Kitowska; Dariusz Zakrzewicz; Melanie Königshoff; Izabella Chrobak; Friedrich Grimminger; Werner Seeger; Patrick Bulau; Oliver Eickelberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-12
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  294     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-16     Completed Date:  2008-04-10     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L34-45     Citation Subset:  IM    
Department of Medicine II, Univ. of Giessen School of Medicine, Aulweg 123, D-35392 Giessen, Germany.
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MeSH Terms
3T3 Cells
Arginase / genetics,  metabolism*
Bleomycin / therapeutic use
DNA Primers
Lung / enzymology,  pathology
Middle Aged
Protein-Arginine N-Methyltransferases / genetics,  metabolism
Pulmonary Fibrosis / drug therapy,  enzymology*,  pathology
RNA / genetics,  isolation & purification
Reference Values
Reverse Transcriptase Polymerase Chain Reaction
Reg. No./Substance:
0/DNA Primers; 11056-06-7/Bleomycin; 63231-63-0/RNA; EC 2.1.1.-/Protein-Arginine N-Methyltransferases; EC

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