title: The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis.
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.
authors.affiliation: Max-Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Rio
authors.initials: R
authors.lastname: Dumitrascu
authors.forename: Bhola Kumar
authors.initials: BK
authors.lastname: Dahal
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Melanie
authors.initials: M
authors.lastname: Konigshoff
authors.forename: Dariusz
authors.initials: D
authors.lastname: Zakrzewicz
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation
chemical_list: D000903:Antibiotics, Antineoplastic; D007527:Isoenzymes; D001761:Bleomycin; C018524:N,N-dimethylarginine; D003094:Collagen; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D000581:Amidohydrolases; C059999:dimethylargininase