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In patients with a progressive interstitial lung disease, 62% of whom had a CT pattern of usual interstitial pneumonia, those who received nintedanib had a lower annual rate of decline in the forced vital capacity than those who received placebo at 52 weeks.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various cellular models. GNS-3595 also prevented transforming growth factor β-induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.

Background Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare. Methods A double bleomycin dose was administered to 18–24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8–12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint. Results Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function. Conclusions Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.

Background Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by a constant incidence rate. Unfortunately, effective pharmacological treatments for this condition are lacking and the identification of novel therapeutic approaches and underlying pathological mechanisms are required. This study investigated the potential of quercetin in alleviating pulmonary fibrosis by promoting autophagy and activation of the SIRT1/AMPK pathway. Methods Mouse models of IPF were divided into four treatment groups: control, bleomycin (BLM), quercetin (Q), and quercetin + EX-527 (Q + E) treatment. Pulmonary fibrosis was induced in the mouse models through intratracheal instillation of BLM. Various indexes were identified through histological staining, Western blotting analysis, enzyme-linked immunosorbent assay, immunohistochemistry, and transmission electron microscopy. Results Quercetin treatment ameliorated the pathology of BLM-induced pulmonary fibrosis of mice by reducing α-smooth muscle actin (α-SMA), collagen I (Col I), and collagen III (Col III) levels, and also improved the level of E-cadherin in lung tissue. Furthermore, Quercetin significantly enhanced LC3II/LC3I levels, decreased P62 expression, and increased the number of autophagosomes in lung tissue. These effects were accompanied by the activation of the SIRT1/AMPK pathway. Treatment with EX-527, an inhibitor for SIRT1, reversed all effects induced by quercetin. Conclusion This study showed that quercetin could alleviate pulmonary fibrosis and improve epithelial-mesenchymal transition by acting on the SIRT1/AMPK signaling pathway, which may be achieved by regulating the level of autophagy.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by excessive extracellular matrix deposition and limited therapeutic options. Conventional preclinical models, such as the bleomycin (BLM)-induced lung fibrosis (BILF) model in immunocompetent mice, fail to replicate the complexity of the human immune environment and are thus unsuitable for evaluating human-specific antibody and cell therapies. To overcome this limitation, we developed two humanized mouse models with functional human immune components: one engrafted with peripheral blood mononuclear cells (PBMCs) and the other with hematopoietic stem cells (HSCs). Pulmonary fibrosis was induced using BLM in both humanized models. In the PBMC-humanized model, human T cells accounted for 79.9% ± 9.7% of CD45 + cells; however, this model was limited by high incidence of graft-versus-host disease (GvHD). In contrast, the HSC-humanized model demonstrated stable multilineage engraftment (T cells: 20.1% ± 28.3%; B cells: 56.8% ± 25.4%), absence of GvHD, and consistent fibrotic pathology. Both models exhibited increased inflammatory infiltration, fibroblast activation, and collagen deposition following BLM induction. Nintedanib treatment significantly ameliorated fibrotic changes in both models. These findings establish the HSC-humanized BILF model as a clinically relevant platform for investigating human immune responses in IPF and for preclinical evaluation of human-targeted therapies.

Idiopathic Pulmonary Fibrosis (IPF) is a debilitating and fatal lung disease characterized by the excessive formation of scar tissue and decline of lung function. Despite extensive research, only two FDA-approved drugs exist for IPF, with limited efficacy and relevant side effects. Thus, there is an urgent need for new effective therapies, whose discovery strongly relies on IPF animal models. Despite some limitations, the Bleomycin (BLM)-induced lung fibrosis mouse model is widely used for antifibrotic drug discovery and for investigating disease pathogenesis. The initial acute inflammation triggered by BLM instillation and the spontaneous fibrosis resolution that occurs after 3 weeks are the major drawbacks of this system. In the present study, we applied micro-CT technology to a longer-lasting, triple BLM administration fibrosis mouse model to define the best time-window for Nintedanib (NINT) treatment. Two different treatment regimens were examined, with a daily NINT administration from day 7 to 28 (NINT 7–28), and from day 14 to 28 (NINT 14–28). For the first time, we automatically derived both morphological and functional readouts from longitudinal micro-CT. NINT 14–28 showed significant effects on morphological parameters after just 1 week of treatment, while no modulations of these biomarkers were observed during the preceding 7–14-days period, likely due to persistent inflammation. Micro-CT morphological data evaluated on day 28 were confirmed by lung histology and bronchoalveolar lavage fluid (BALF) cells; Once again, the NINT 7–21 regimen did not provide substantial benefits over the NINT 14–28. Interestingly, both NINT treatments failed to improve micro-CT-derived functional parameters. Altogether, our findings support the need for optimized protocols in preclinical studies to expedite the drug discovery process for antifibrotic agents. This study represents a significant advancement in pulmonary fibrosis animal modeling and antifibrotic treatment understanding, with the potential for improved translatability through the concurrent structural–functional analysis offered by longitudinal micro-CT.

Idiopathic pulmonary fibrosis (IPF) is an interstitial fibrotic lung disease characterized by myofibroblast differentiation and collagen deposition. Excessive activation of fibroblasts in the lungs leads to severe alveolar dysfunction and tissue destruction seen by histological assessment. IPF presents a high mortality rate, limited therapeutic options, and an intense need to develop safe and effective therapeutic drugs. Lysionotin is a flavonoid isolated from herbal extracts with various biological effects such as anti-tuberculosis mycobacteria and anti-inflammatory. Nevertheless, its effect on pulmonary fibrosis is not known. This study aims to investigate the effect of Lysionotin on bleomycin (BLM)-induced pulmonary fibrosis and its mechanism. We used BLM to establish a mouse model of pulmonary fibrosis and injected Lysionotin intraperitoneally on days 15–28 to observe its effect on pulmonary fibrosis. The molecular mechanism of Lysionotin was investigated in vitro using transforming growth factor-β (TGF-β) induced myofibroblasts. Lysionotin attenuates TGF-β-induced myofibroblast differentiation and oxidative stress by promoting nuclear factor erythroid 2–related factor 2 (Nrf2) and its downstream expression of antioxidant genes NAD(P)H quinone dehydrogenase 1 (NQO-1) and heme oxygenase 1 (HO-1) by activating AMP-activated protein kinase (AMPK). Lysionotin exerts anti-pulmonary fibrosis effects by regulating myofibroblast differentiation and reducing oxidative stress through the AMPK/Nrf2 pathway, illustrating the potential significance of Lysionotin in protecting against BLM-induced pulmonary fibrosis.

The uncontrolled fibrosis of lung tissue can lead to premature death in patients suffering from idiopathic pulmonary fibrosis (IPF), and it complicates the course of chronic obstructive pulmonary disease (COPD) and emphysema. It is also a risk factor for developing lung cancer. Antifibrotic drugs, such as nantedanib and pirfenidone, are able to slow down the progression of pulmonary fibrosis, but more effective treatment is still needed to reverse it. Studies on the pathogenesis of tissue fibrosis have demonstrated that integrins play a crucial role affecting the development of pulmonary fibrosis, for example, by activating transforming growth factor-β (TGF-β). Taking the above into consideration, targeting specific integrins could offer promising opportunities for managing fibroplastic changes in lung tissue. Integrins are a type of transmembrane molecule that mediate interactions between cells and extracellular matrix (ECM) molecules. This review discusses the role of integrins in the pathogeneses of respiratory diseases and carcinogenesis, as well as presents promising approaches to the drug therapy of pulmonary fibrosis of various etiologies based on integrin inhibition.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive form of interstitial lung disease (ILD) characterized by significant extracellular matrix deposition, alveolar damage, and tissue remodeling. Antagonists against the G-protein coupled receptor, lysophosphatidic acid receptor 1 (LPAR1) have shown efficacy in lung fibrosis preclinically and clinically. Here, we profile PIPE-791, a small molecule, orally bioavailable LPAR1 receptor antagonist, and show its effectiveness in several lung fibrosis-related contexts. Methods In vitro, we used human lung fibroblasts and precision cut lung slices (PCLS) derived from donors with pulmonary fibrosis to test PIPE-791 efficacy in reducing markers of fibrosis. In vivo, we used bleomycin-induced lung fibrosis models to demonstrate PIPE-791 efficacy. Results In vitro PIPE-791 reduced LPA-induced collagen expression (IC 50 1.1 nM) in human lung fibroblasts. We also show that LPAR1 is elevated in IPF lung tissue and that PIPE-791 significantly reduced several markers of lung fibrosis in PCLS as measured by gene expression and secreted biomarkers. Using in vivo receptor occupancy, we found that PIPE-791 has long association kinetics resulting in a 20-fold increase in potency when dosed 3 versus 24 h prior to radioligand administration. At 3 mg/kg, PIPE-791 was effective in significantly reducing markers of fibrosis and collagen expression in mouse bleomycin models. Conclusions We show that PIPE-791 effectively reduces fibrosis and fibrotic markers in vitro and in vivo and that it has slow association and dissociation kinetics. Taken together, our data support clinical testing of PIPE-791 in the context of fibrotic conditions such as IPF.

Background Injury-repair responses typically induce tissue or organ scarring. Generally, cAMP-mobilizing agents inhibit the activation of fibroblasts and deposition of extracellular matrix. Some but not all cAMP-mobilizing agents inhibit fibrosis. Evidence suggests that inhaled treprostinil, a prostacyclin (IP) analog, increases intracellular cAMP levels [cAMP] I , and slows the decline in pulmonary function in patients with idiopathic pulmonary fibrosis (IPF). However, the molecular mechanisms by which cAMP-mobilizing agents, including treprostinil, alter the expression of matrix proteins in human lung fibroblasts (HLF) remain unclear. Unlike other G αs -coupled receptors, we posit that the antifibrotic properties of treprostinil are driven by cAMP-mobilizing-dependent and -independent responses mediated by the IP receptor activation. Methods As a model of lung fibrosis, primary HLF derived from non-IPF and IPF donors were stimulated with TGF-β; collagen 1A1 and plasminogen activator inhibitor-1 (PAI) expression were then measured in the presence and absence of cAMP mobilizing agents. The necessity of receptor activation for inhibiting TGF-β-induced markers of fibrosis was determined by using soluble receptor inhibitors and decreasing receptor expression with siRNA. Results Treprostinil decreased TGF-β-induced extracellular matrix production by HLF, and the magnitude of the inhibition was greater than that of other cAMP-mobilizing GPCR agonists despite these agents comparably increasing cAMP levels. There was no difference in the sensitivity and magnitude of the treprostinil inhibition in HLF derived from non-fibrosis and lung fibrosis donors. Treprostinil inhibition of TGF-β-induced collagen 1A1and PAI-1 was mediated through the activation of the IP receptor. The activation of the EP2 receptor, in part, inhibited TGF-β-induced collagen 1A1 expression by treprostinil or prostaglandin E2. β2 agonists had little effect on TGF-β-induced expression of collagen 1A1 and PAI-1. The inhibitory effects of treprostinil on TGF-β-induced collagen 1A1 expression required G αs activation, while G αs only partially mediated treprostinil inhibition of PAI-1. Conclusion The anti-fibrotic properties of treprostinil are primarily mediated by the IP receptor, acting through both G αs -dependent and -independent pathways. Understanding the differential effects of cAMP-mobilizing pathways on HLF fibrotic signatures can provide insight into developing novel targets to manage IPF.