The Role of Dimethylarginine Dimethylaminohydrolase in Idiopathic Pulmonary Fibrosis

Inhibition of dimethylarginine dimethylaminohydrolase enzyme in lung attenuates two hallmarks of pulmonary fibrosis, excess cells and excess collagen, thereby offering a therapeutic approach. Matter of Life and Breath For many, fresh air can be rejuvenating, but for patients with idiopathic pulmonary fibrosis (IPF), it can be life saving. This progressive, debilitating, and sometimes fatal disease steals breath from its victims by strangling the lungs with a buildup of excess fibrous connective tissue (scarring). No effective treatments exist to correct this poorly understood process of fibrosis in overdrive. Pullamsetti et al. now identify a critical enzyme, dimethylarginine dimethylaminohydrolase (DDAH), which is overly active in IPF patients’ lungs and in mice with an IPF-like lung injury. Inhibition of enzyme activity attenuates many features of the disease, suggesting a new potential therapy. The authors noted that there were especially large amounts of DDAH in cells from the lungs of IPF patients and a mouse model of IPF in which lung tissue is scarred by treatment with the antibiotic bleomycin. This enzyme breaks down an endogenous inhibitor of inducible nitric oxide synthase (iNOS) so that when DDAH increases, iNOS activity increases, giving rise to products that can contribute to fibrosis. Inhibition of DDAH in epithelial cells from the lung alveoli of IPF patients or bleomycin-treated mice prevented two hallmarks of IPF: epithelial cell overproliferation and collagen production. A third hallmark, enhanced collagen synthesis, did not depend on iNOS and instead seemed to be mediated by transforming growth factor–β (TGFβ)/SMAD. The authors extended this work by using a drug called L-291 to inhibit DDAH in bleomycin-treated mice, which were then protected from lung fibrosis. The improper activation of fibrosis, or scarring, in IPF is in part a result of stimulation by cytokines such as TGFβ and interleukin-6, although the full extent of the control pathways remains unclear. As shown by these new results, NO, the gaseous product of iNOS, contributes to epithelial cell proliferation and TGFβ signaling to collagen manufacture. These pathways are not likely to represent the whole story of this complex disease, but the results from this study do indicate that iNOS signaling and other events downstream from DDAH are critical for the development of lung fibrosis. Keeping these players under tight control with new therapeutic agents may provide a breath of fresh air for patients with IPF. 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.