The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis
Authors: Rajkumar Savai
Norbert Weissmann
Oliver Eickelberg
Bhola Kumar Dahal
Ralph Theo Schermuly
Dariusz Zakrzewicz
Soni Savai Pullamsetti
Andreas Guenther
Hossein Ardeschir Ghofrani
Rio Dumitrascu
James Leiper
Melanie Konigshoff
Friedrich Grimminger
Werner Seeger
Jochen Wilhelm
Journal: Science Translational Medicine (2011)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Idiopathic pulmonary fibrosis; DDAHs; ADMA; nitric oxide synthase; alveolar epithelial type II cells
Affiliations: Max-Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.

Abstract:  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. 

Retracted: No

PubPeer comments:
  Retraction Following publication, concerns were raised about similarities between this article [1] and an article published earlier by the same group in BMC Complementary and Alternative Medicine [2]. The two articles reported experiments addressing the same overall research questions but in different squamous cell carcinoma cell lines of tongue origin (OSC19 [1] and SCC13 [2]). The conclusions are largely overlapping, and there is substantial text overlap between the two articles in the Introduction, Discussion, and Conclusions. The BMC Complementary and Alternative Medicine article was not cited or discussed in the PLOS ONE article, and the two articles were under review during overlapping time periods. In addition, concerns were raised about similarities between figures in the two articles: Fig 1A (FaDu panel) in the PLOS ONE article [1] is identical to Fig 1A (A431 panel) in [2], though these panels reportedly show results from different cell lines. The University of Alabama at Birmingham confirmed that there are no original data available to determine the cell line that was used in either article, and so the conclusion regarding the invasive potential of OSC19 cells versus squamous cell carcinoma cells from other head and neck sites is not supported. Fig 7 in the PLOS ONE article [1] is a modified version of Fig 6 in [2]. The BMC Complementary and Alternative Medicine article was not cited as the foundation of the PLOS ONE Figure. Following a joint investigation by the Birmingham VA Medical Center and the University of Alabama at Birmingham, the institutions requested retraction of this article, as the conclusions could not be supported by available data. In light of the above issues, and in line with the institutionsu2019 recommendation, the PLOS ONE Editors retract this article. The authors did not comment on the retraction decision. 31 Dec 2018: The PLOS ONE Editors (2018) Retraction: Grape Seed Proanthocyanidins Inhibit the Invasiveness of Human HNSCC Cells by Targeting EGFR and Reversing the Epithelial-To-Mesenchymal Transition. PLOS ONE 13(12): e0210346. https: doi.org 10.1371 journal.pone.0210346 View retraction ,