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Pullamsetti, S.S.* ; Savai, R.* ; Dumitrascu, R.* ; Dahal, B.K.* ; Wilhelm, J.* ; Königshoff, M. ; Zakrzewicz, D.* ; Ghofrani, H.A.* ; Weissmann, N.* ; Eickelberg, O. ; Guenther, A.* ; Leiper, J.* ; Seeger, W.* ; Grimminger, F.* ; Schermuly, R.T.*

The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis.

Sci. Transl. Med. 3:87ra53 (2011)
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Idiopathic pulmonary fibrosis (IPF) is a progressive, dysregulated response to alveolar injury that culminates in compromised lung function from excess extracellular matrix production. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. We examined fibrotic lungs from mice and from patients with IPF and detected increased expression of dimethylarginine dimethylaminohydrolases (DDAHs)--key enzymes that metabolize asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase, to form l-citrulline and dimethylamine. DDAHs are up-regulated in primary alveolar epithelial type II cells from these mice and patients where they are colocalized with inducible nitric oxide synthase. In cultured alveolar epithelial type II cells from bleomycin-induced fibrotic mouse lungs, inhibition of DDAH suppressed proliferation and induced apoptosis in an ADMA-dependent manner. In addition, DDAH inhibition reduced collagen production by fibroblasts in an ADMA-independent but transforming growth factor/SMAD-dependent manner. In mice with bleomycin-induced pulmonary fibrosis, the DDAH inhibitor L-291 reduced collagen deposition and normalized lung function. In bleomycin-induced fibrosis, inducible nitric oxide synthase inhibition decreased fibrosis, but an even stronger reduction was observed after inhibition of DDAH. Thus, DDAH inhibition reduces fibroblast-induced collagen deposition in an ADMA-independent manner and reduces abnormal epithelial proliferation in an ADMA-dependent manner, offering a possible therapeutic avenue for attenuation of pulmonary fibrosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords nitric-oxide synthesis; placebo-controlled trial; asymmetric dimethylarginine; endothelial-cells; wound repair; bleomycin; mechanisms; expression; synthase; pathway
Language english
Publication Year 2011
HGF-reported in Year 2011
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 3, Issue: 87, Pages: , Article Number: 87ra53 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC, USA
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
Research field(s) Lung Research
PSP Element(s) G-501600-001
G-551800-001
PubMed ID 21677199
DOI 10.1126/scitranslmed.3001725
WOS ID WOS:000292981000004
Erfassungsdatum 2011-11-09
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