Ameliorative Effect of Mepenzolate Bromide against Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-b1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO 2 ). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO 2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-b1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-b1 activities and its stimulatory effect on GST.

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling

“…Consistent with our in vitro findings, administration of the TAT-SH3-2 peptide not only diminished the expression of profibrotic genes ( Figure 7, A-C, Supplemental Figure 7B, and Figure 9, B and C) in the absence of any demonstrable systemic toxicity ( Figure 8 and Supplemental Figure 7A), but stabilized lung function as assessed by peripheral blood oxygenation in a pSMAD3-binding and dose-dependent manner ( Figure 7D and Figure 9A). These results not only provided a physiologic readout consistent with our biochemical and molecular data, but in addition, pulseoximetry has been shown to accurately predict lung pathology in numerous animal models (65)(66)(67)(68). It is currently unclear wheth- Figure 1.…”

Fatty acid synthase is required for profibrotic TGF‐β signaling

“…As shown in Fig. 7, not only were profibrotic mediators, such as collagen, FN, and a-smooth muscle actin, inhibited in a C75-dependent manner, but also, a primary indicator of lung physiology (e.g., peripheral blood oxygenation on room air), which has been shown in various animal models (68)(69)(70) to predict lung function accurately, was similarly improved following FASN inhibition. Moreover, the inhibitory action(s) of C75 occurred independently of cellular toxicity (Supplemental Fig.…”

Functions of Galectin-3 and Its Role in Fibrotic Diseases

“…Pulmonary fibrosis (PF), characterized by excessive ECM deposition, is involved in abnormal inflammatory cell increase, FB proliferation, FB-to-MFb transformation, EMT, procoagulant signaling, and oxidative stress (He et al, 2012;Todd et al, 2012;Wollin et al, 2014). TGF-b has been assigned a clear pathogenic role by its induction of EMT, ECM production, and apoptosis of alveolar epithelial cells (AECs) in PF, whereas inhibiting TGF-b activity reduces PF (Kim et al, 2006;Sureshbabu et al, 2011;Kurotsu et al, 2014;Wollin et al, 2014). Gal-3, involved in TGF-b signaling, has also been investigated in PF ).…”