Therapeutic Target For Pulmonary Fibrosis Research Articles

Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy

Background8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified.MethodsA bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1.ResultsIn BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells.ConclusionOGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Aldehyde Dehydrogenase 2 Deficiency Aggravates Lung Fibrosis through Mitochondrial Dysfunction and Aging in Fibroblasts

Idiopathic pulmonary fibrosis, a fatal interstitial lung disease, is characterized by fibroblast activation and aberrant extracellular matrix accumulation. Effective therapeutic development is limited because of incomplete understanding of the mechanisms by which fibroblasts become aberrantly activated. Here, we show acetaldehyde dehydrogenase 2 (ALDH2) in fibroblasts as a potential therapeutic target for pulmonary fibrosis. A decrease in ALDH2 expression was observed in patients with idiopathic pulmonary fibrosis and bleomycin-treated mice. ALDH2 deficiency spontaneously induces collagen accumulation in the lungs of aged mice. Furthermore, young ALDH2 knockout mice exhibited exacerbated bleomycin-induced pulmonary fibrosis and increased mortality compared with that in control mice. Mechanistic studies revealed that transforming growth factor (TGF)-β1 induction and ALDH2 depletion constitute a positive feedback loop that exacerbates fibroblast activation. TGF-β1 down-regulated ALDH2 through a TGF-β receptor 1/Smad3-dependent mechanism. The subsequent deficiency in ALDH2 resulted in fibroblast dysfunction that manifested as impaired mitochondrial autophagy and senescence, leading to fibroblast activation and extracellular matrix production. ALDH2 overexpression markedly suppressed fibroblast activation, and this effect was abrogated by PTEN-induced putative kinase 1 (PINK1) knockdown, indicating that the profibrotic effects of ALDH2 are PINK1- dependent. Furthermore, Alda-1-induced ALDH2 activation reversed the established pulmonary fibrosis in both young and aged mice. In conclusion, ALDH2 expression inhibits the pathogenesis of pulmonary fibrosis. Strategies to up-regulate or activate ALDH2 expression could be potential therapies for pulmonary fibrosis.

The role and regulation of SIRT1 in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a progressive and fatal lung disease with high incidence and a lack of effective treatment, which is a severe public health problem. PF has caused a huge socio-economic burden, and its pathogenesis has become a research hotspot. SIRT1 is a nicotinamide adenosine dinucleotide (NAD)-dependent sirtuin essential in tumours, Epithelial mesenchymal transition (EMT), and anti-aging. Numerous studies have demonstrated after extensive research that it is crucial in preventing the progression of pulmonary fibrosis. This article reviews the biological roles and mechanisms of SIRT1 in regulating the progression of pulmonary fibrosis in terms of EMT, oxidative stress, inflammation, aging, autophagy, and discusses the potential of SIRT1 as a therapeutic target for pulmonary fibrosis, and provides a new perspective on therapeutic drugs and prognosis prospects.

WSB1, a Hypoxia-Inducible E3 Ligase, Promotes Myofibroblast Accumulation and Attenuates Alveolar Epithelial Regeneration in Mouse Lung Fibrosis

Idiopathic pulmonary fibrosis is a progressive interstitial lung disease for which there is no curative therapy available. Repetitive alveolar epithelial injury repair, myofibroblast accumulation, and excessive collagen deposition are key pathologic features of idiopathic pulmonary fibrosis, eventually leading to cellular hypoxia and respiratory failure. The precise mechanism driving this complex maladaptive process remains inadequately understood. WD repeat and suppressor of cytokine signaling box containing 1 (WSB1) is an E3 ubiquitin ligase, the expression of which is associated strongly with hypoxia, and forms a positive feedback loop with hypoxia-inducible factor 1α (HIF-1α) under anoxic condition. This study explored the expression, cellular distribution, and function of WSB1 in bleomycin (BLM)-induced mouse lung injury and fibrosis. WSB1 expression was highly induced by BLM injury and correlated with the progression of lung fibrosis. Significantly, conditional deletion of Wsb1 in adult mice ameliorated BLM-induced pulmonary fibrosis. Phenotypically, Wsb1-deficient mice showed reduced lipofibroblast to myofibroblast transition, but enhanced alveolar type 2 proliferation and differentiation into alveolar type 1 after BLM injury. Proteomic analysis of mouse lung tissues identified caveolin 2 as a potential downstream target of WSB1, contributing to BLM-induced epithelial injury repair and fibrosis. These findings unravel a vital role for WSB1 induction in lung injury repair, thus highlighting it as a potential therapeutic target for pulmonary fibrosis.

Tanshinone IIA alleviates bleomycin-induced pulmonary fibrosis by inhibiting Zbtb16

Pulmonary fibrosis is a complex disease that can occur in a variety of clinical settings. The Zinc Finger and BTB Domain Containing 16 (Zbtb16) is a transcription factor and has not been studied in pulmonary fibrosis. Lung tissues from rats which were treated with bleomycin and Tanshinone IIA (Tan IIA) were collected for mRNA sequencing. Zbtb16, a differentially expressed gene, was screened. Using adeno-associated virus to knock down Zbtb16 in rats, it was found that the lung index and the content of hydroxyproline in lung tissue were decreased. HE and Masson staining revealed that pathological symptoms of lung histopathology were relieved after Zbtb16 knockdown. Protein expressions of α-SMA, Collagen I and Fibronectin were significantly decreased after Zbtb16 knockdown in vivo and in vitro. Meanwhile, the protein content of TGF-β1 and the phosphorylation of Smad2/3 were inhibited by Zbtb16 knockdown. Conversely, under the treatment of Tan IIA and TGF-β1, overexpression of Zbtb16 improved cell viability, increased the expression of fibrosis-related proteins, and promoted the phosphorylation of Smad 2/3. All above demonstrates that Zbtb16 inhibition ameliorates pulmonary fibrosis and suppresses the TGF-β/Smad pathway. Furthermore, Zbtb16 mediates the inhibitory process of Tan IIA on pulmonary fibrosis. This study provides a novel candidate therapeutic target for pulmonary fibrosis.

ACSS3 regulates the metabolic homeostasis of epithelial cells and alleviates pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic homeostatic imbalance caused by repetitive injuries of the alveolar epithelium is the potential pathogenesis of IPF. Proteomic analysis identified that Acetyl-CoA synthetase short chain family member 3 (ACSS3) expression was decreased in IPF patients and mice with bleomycin-induced fibrosis. ACSS3 participated in lipid and carbohydrate metabolism. Increased expression of ACSS3 downregulated carnitine palmitoyltransferase 1A (CPT-1A) and resulted in the accumulation of lipid droplets, while enhanced glycolysis which led to an increase in extracellular lactic acid levels in A549 cells. ACSS3 increases the production of succinyl-CoA through propionic acid metabolism, and decreases the generation of acetyl-CoA and ATP in alveolar epithelial cells. Overexpression of Acss3 inhibited the excessive deposition of ECM and attenuated the ground-glass opacity which determined by micro-CT in vivo. In a nutshell, our findings demonstrate that ACSS3 decreased the fatty acid oxidation through CPT1A deficiency and enhanced anaerobic glycolysis, this metabolic reprogramming deactivate the alveolar epithelial cells by lessen mitochondrial fission and fusion, increase of ROS production, suppression of mitophagy, promotion of apoptosis, suggesting that ACSS3 might be potential therapeutic target in pulmonary fibrosis.

A selective CB2R agonist (JWH133) protects against pulmonary fibrosis through inhibiting FAK/ERK/S100A4 signaling pathways

BackgroundThe combination of the endocannabinoid system (ECS) and the type 2 cannabinoid receptor (CB2R) can activate various signal pathways, leading to distinct pathophysiological roles. This interaction has gained significant attention in recent research on fibrosis diseases. Focal adhesion kinase (FAK) plays a crucial role in regulating signals from growth factor receptors and Integrins. It is also involved in the transformation of fibroblasts into myofibroblasts. This study aims to investigate the impact of the CB2R agonist JWH133 on lung fibrosis and its potential to alleviate pulmonary fibrosis in mice through the FAK pathway.MethodsThe C57 mice were categorized into five groups: control, BLM, BLM + JWH133, BLM + JWH133 + NC, and BLM + JWH133 + FAK groups.JWH133 was administered to mice individually or in conjunction with the FAK vector. After 21 days, pathological changes in mouse lung tissues, inflammatory factor levels, hydroxyproline levels, and collagen contents were evaluated. Moreover, the levels of the FAK/ERK/S100A4 pathway-related proteins were measured.ResultsJWH133 treatment decreased inflammatory factor levels, attenuated pathological changes, and reduced extracellular matrix accumulation in the mouse model of bleomycin-induced pulmonary fibrosis; however, these effects were reversed by FAK. JWH133 attenuated fibrosis by regulating the FAK/ERK/S100A4 pathway.ConclusionsThe results presented in this study show that JWH133 exerts a protective effect against pulmonary fibrosis by inhibiting the FAK/ERK/S100A4 pathway.Therefore, JWH133 holds promise as a potential therapeutic target for pulmonary fibrosis.

Paroxetine protects against bleomycin-induced pulmonary fibrosis by blocking GRK2/Smad3 pathway.

G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. In vitro experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.

Intestinal overgrowth of Candida albicans exacerbates bleomycin-induced pulmonary fibrosis in mice with dysbiosis.

Increasing evidence indicates an interaction between the intestinal microbiota and diseases in distal organs. However, the relationship between pulmonary fibrosis and the intestinal microbiota, especially intestinal fungal microbiota, is poorly understood. Thus, this study aimed to determine the effects of changes in the intestinal fungal microbiota on the pathogenesis of pulmonary fibrosis. Mice with intestinal overgrowth of Candida albicans, which was established by oral administration of antibiotics plus C. albicans, showed accelerated bleomycin-induced pulmonary fibrosis relative to the control mice (i.e. without C. albicans treatment). In addition, the mice with intestinal overgrowth of C. albicans showed enhanced Th17-type immunity, and treatment with IL-17A-neutralizing antibody alleviated pulmonary fibrosis in these mice but not in the control mice. This result indicates that IL-17A is involved in the pathogenesis of C. albicans-exacerbated pulmonary fibrosis. Even before bleomycin treatment, the expression of Rorc, the master regulator of Th17, was already upregulated in the pulmonary lymphocytes of the mice with intestinal overgrowth of C. albicans. Subsequent administration of bleomycin triggered these Th17-skewed lymphocytes to produce IL-17A, which enhanced endothelial-mesenchymal transition. These results suggest that intestinal overgrowth of C. albicans exacerbates pulmonary fibrosis via IL-17A-mediated endothelial-mesenchymal transition. Thus, it might be a potential therapeutic target in pulmonary fibrosis. This study may serve as a basis for using intestinal fungal microbiota as novel therapeutic targets in pulmonary fibrosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The chemokine CCL1 facilitates pulmonary fibrosis by promoting macrophage migration and M2 polarization

Macrophage M2 polarization has been identified in the pathogenesis of pulmonary fibrosis (PF), but the mediators that drive the macrophage M2 program in PF need to be clarified. We showed that the expression of AMFR and CCR8, two known receptors of CCL1, was increased in macrophages from lungs of mice with bleomycin (BLM)-induced PF. Deficiency in either AMFR or CCR8 in macrophages protected mice from BLM-induced PF. In vitro experiments revealed that CCL1 recruited macrophages by binding to its classical receptor CCR8 and drove the macrophage M2 phenotype via its interaction with the recently identified receptor AMFR. Mechanistic studies revealed that the CCL1-AMFR interaction enhanced CREB/C/EBPβ signaling to promote the macrophage M2 program. Together, our findings reveal that CCL1 acts as a mediator of macrophage M2 polarization and could be a therapeutic target in PF.

G protein coupled receptor 41 regulates fibroblast activation in pulmonary fibrosis via Gαi/o and downstream Smad2/3 and ERK1/2 phosphorylation

Pulmonary fibrosis is a progressive and fatal fibrotic lung disease with mysterious pathogenesis and limited effective therapies. G protein-coupled receptors (GPRs) participate in a variety of physiologic functions, and several GPRs have critical fibrosis-promoting or -inhibiting roles in pulmonary fibrosis. Here, we explored the role of GPR41 in the pathobiology of pulmonary fibrosis. We found that GPR41 expression was elevated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-β1 (TGF-β1). Knockout of GPR41 attenuated pulmonary fibrosis in mice, as evidenced by improved lung morphology, decreased lung weight and collagen secretion, and down-regulated α-SMA, collagen type I alpha and fibronectin expression in lungs. Additionally, GPR41 knockout inhibited the differentiation of fibroblasts to myofibroblasts, and decreased myofibroblast migration. By further mechanistic analysis, we demonstrated that GPR41 regulated TGF-β1-induced fibroblast-to-myofibroblast differentiation and Smad2/3 and ERK1/2 phosphorylation via its Gαi/o subunit but not Gβγ subunit. Together, our data indicate that GPR41 is involved in pulmonary fibroblast activation and fibrosis, and GPR41 represents a potential therapeutic target for pulmonary fibrosis.

Deficiency of HtrA3 Attenuates Bleomycin-Induced Pulmonary Fibrosis Via TGF-β1/Smad Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by excessive extracellular matrix deposition. No effective treatments are currently available for IPF. High-temperature requirement A3 (HtrA3) suppresses tumor development by antagonizing transforming growth factor β (TGF-β) signaling; however, little is known about the role of HtrA3 in IPF. This study investigated the role of HtrA3 in IPF and underlying mechanisms. Lung tissues were collected from patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis, and HtrA3 expression was measured in tissue samples. Then, HtrA3 gene knockout mice were treated with BLM to induce pulmonary fibrosis and explore the effects and underlying mechanism of HtrA3 on pulmonary fibrosis. HtrA3 was up-regulated in the lung tissues of patients with IPF and the pulmonary fibrotic mouse model compared to corresponding control groups. HtrA3 knockout decreased pulmonary fibrosis-related protein expression, alleviated the symptoms of pulmonary fibrosis, and inhibited epithelial-mesenchymal transition (EMT) in BLM-induced lung tissue compared with BLM-induced wild-type mice. The TGF-β1/Smad signaling pathway was activated in fibrotic lung tissue, whereas HtrA3 knockout inhibited this pathway. The expression level of HtrA3 is increased in fibrotic lungs. HtrA3 knockout alleviates the symptoms of pulmonary fibrosis probably via the TGF-β1/Smad signaling pathway. Therefore, HtrA3 inhibition is a potential therapeutic target for pulmonary fibrosis.

The Role of Nrf2 in Pulmonary Fibrosis: Molecular Mechanisms and Treatment Approaches.

Pulmonary fibrosis is a chronic, progressive, incurable interstitial lung disease with high mortality after diagnosis and remains a global public health problem. Despite advances and breakthroughs in understanding the pathogenesis of pulmonary fibrosis, there are still no effective methods for the prevention and treatment of pulmonary fibrosis. The existing treatment options are imperfect, expensive, and have considerable limitations in effectiveness and safety. Hence, there is an urgent need to find novel therapeutic targets. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular antioxidative responses, inflammation, and restoration of redox balance. Accumulating reports reveal that Nrf2 activators exhibit potent antifibrosis effects and significantly attenuate pulmonary fibrosis in vivo and in vitro. This review summarizes the current Nrf2-related knowledge about the regulatory mechanism and potential therapies in the process of pulmonary fibrosis. Nrf2 orchestrates the activation of multiple protective genes that target inflammation, oxidative stress, fibroblast–myofibroblast differentiation (FMD), and epithelial–mesenchymal transition (EMT), and the mechanisms involve Nrf2 and its downstream antioxidant, Nrf2/HO−1/NQO1, Nrf2/NOX4, and Nrf2/GSH signaling pathway. We hope to indicate potential for Nrf2 system as a therapeutic target for pulmonary fibrosis.

The Apelin-APJ axis alleviates LPS-induced pulmonary fibrosis and endothelial mesenchymal transformation in mice by promoting Angiotensin-Converting Enzyme 2

Fibrotic alterations resulting from abnormal tissue repair after lung injury are responsible for the high mortality observed after acute respiratory distress syndrome. Therefore, the prevention and treatment of pulmonary fibrosis has been widely concerned. The Apelin-APJ axis plays an important role in the prevention and treatment of respiratory diseases and organ fibrosis. However, its underlying mechanism remains to be further studied. The aim of this study was to investigate whether the anti-pulmonary fibrosis effect of apelin-APJ axis is related to the activation of angiotensin-converting Enzyme 2 (ACE2). Here, we found that exogenous activation of the Apelin-APJ axis alleviates lipopolysaccharide (LPS)-induced pulmonary fibrosis in mice. In vitro studies revealed that Apelin-13 inhibited LPS-induced endothelial mesenchymal transition in lung microvascular endothelial cells, whereas [Ala13]-Apelin-13 (Apelin-APJ axis inhibitor) accelerated LPS-induced endothelial interstitial transformation in lung microvascular endothelial cells. Notably, angiotensin-converting enzyme 2 (ACE2) inhibitor blocks the beneficial effect of the Apelin-APJ axis activation on LPS-induced pulmonary fibrosis. This finding suggests that the Apelin-APJ axis inhibits pulmonary fibrosis by activating ACE2. Simultaneously, accumulating evidence suggests that ubiquitination may contribute to pulmonary fibrosis. Our study found that LPS increased the ubiquitination of ACE2 protein, whereas Apelin-13 inhibited it. In conclusion, exogenous activation of the Apelin-APJ axis improves LPS-induced pulmonary fibrosis in mice and may be a viable therapeutic target for pulmonary fibrosis.

Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis.

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-β (transforming growth factor-β) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In invivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-β-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in invivo lungs and invitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

LncRNA DACH1 protects against pulmonary fibrosis by binding to SRSF1 to suppress CTNNB1 accumulation

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unknown etiology and limited therapeutic options. Activation of fibroblasts is a prominent feature of pulmonary fibrosis. Here we report that lncRNA DACH1 (dachshund homolog 1) is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis. LncDACH1 knockout mice develop spontaneous pulmonary fibrosis, whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation, collagen deposition and differentiation of mouse lung fibroblasts. Similarly, forced expression of LncDACH1 not only prevented bleomycin (BLM)-induced lung fibrosis, but also reversed established lung fibrosis in a BLM model. Mechanistically, LncDACH1 binding to the serine/arginine-rich splicing factor 1 (SRSF1) protein decreases its activity and inhibits the accumulation of Ctnnb1. Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts. Furthermore, loss of LncDACH1 promoted proliferation, differentiation, and extracellular matrix (ECM) deposition in mouse lung fibroblasts, whereas such effects were abolished by silencing of Ctnnb1. In addition, a conserved fragment of LncDACH1 alleviated hyperproliferation, ECM deposition and differentiation of MRC-5 cells driven by TGF-β1. Collectively, LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation, suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.

Wnt8b regulates myofibroblast differentiation of lung-resident mesenchymal stem cells via the activation of Wnt/β-catenin signaling in pulmonary fibrogenesis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease that is characterized by enhanced changes in stem cell differentiation and fibroblast proliferation. Lung resident mesenchymal stem cells (LR-MSCs) are important regulators of pathophysiological processes including tissue repair and inflammation, and evidence suggests that this cell population also plays an essential role in fibrosis. Our previous study demonstrated that Wnt/β-catenin signaling is aberrantly activated in the lungs of bleomycin-treated mice and induces myofibroblast differentiation of LR-MSCs. However, the underlying correlation between LR-MSCs and the Wnt/β-catenin signaling remains poorly understood. We found that Wnt8b was highly expressed by LR-MSCs undergoing myofibroblast differentiation. In vitro, Wnt8b promoted LR-MSCs differentiate into myofibroblasts via activating Wnt/β-catenin signaling. Moreover, siRNA-mediated inhibition of Wnt8b prevented Transforming growth factor (TGF)-β1-induced myofibroblast differentiation of LR-MSCs in vitro and ameliorated pulmonary fibrotic lesions. Our study identified Wnt proteins and Wnt/β-catenin signaling in pulmonary fibrosis in vitro and in vivo, and highlighted Wnt8b as a potential therapeutic target in pulmonary fibrosis. Moreover, these finding might provide a new perspective in the development of treatment strategies for IPF.

Serum autotaxin levels in chronic disease and acute exacerbation of fibrosing interstitial lung disease.

BackgroundAutotaxin (ATX) is an ecto-enzyme that catalyses the hydrolysis of lysophospholipids to the lipid mediator lysophosphatidic acid (LPA). LPA/ATX signalling has emerged as a new therapeutic target for pulmonary fibrosis; however, the serum levels and dynamics of ATX during the clinical course of fibrosing interstitial lung disease (ILD) remain unknown. This study sought to examine the serum ATX levels in fibrosing ILD in the chronic phase and in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). We aimed to elucidate the association between serum ATX level and clinical characteristics including disease progression and prognosis.MethodsIn total, 119 patients with fibrosing ILD and 38 healthy volunteers as controls were enrolled in the study and their serum ATX activity was analysed. We also included six male patients with AE-IPF in order to analyse the changes in serum ATX at the onset of AE-IPF.ResultsPatients with fibrosing ILD showed significantly higher serum ATX levels compared with healthy controls in both sexes. Per cent change in forced vital capacity after 1 year correlated with serum ATX levels in female patients. High serum ATX levels (>0.721 mg· L−1) were associated with worse outcome in survival curve and multivariate analysis of male patients. Serum ATX activity decreased after the onset of AE-IPF.ConclusionSerum ATX levels were significantly higher in patients with fibrosing ILD compared with healthy controls, and this was associated with disease progression and outcome. This suggests the potential of serum ATX as a promising biomarker for the treatment of fibrosing ILD.

Complement protein C1q activates lung fibroblasts and exacerbates silica-induced pulmonary fibrosis in mice

Pulmonary fibrosis is a progressive fibrotic disease with a poor prognosis and has suboptimal therapeutic options. The complement protein, C1q, which has various functions, such as promoting phagocytosis and signal transduction, has been shown to exacerbate several fibrosis-related diseases such as myofibrosis. In this study, we examined the role and cellular targets of C1q in pulmonary fibrosis. Silica-induced pulmonary fibrotic C1q-deficient mice showed improvement in fibrosis, and intratracheal administration of C1q to normal mice led to the induction of fibrotic changes. Single-cell RNA sequencing analysis revealed the early activation of fibroblasts and type 2 alveolar epithelial cells after intratracheal administration of C1q, and treatment of primary lung fibroblasts with C1q induced the expression of profibrotic genes. Thus, the inhibition of C1q may be regarded as a therapeutic target for pulmonary fibrosis.

ASK1 Regulates Bleomycin-induced Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is an abnormal remodeling of cellular composition and extracellular matrix that results in histological and functional alterations in the lungs. Apoptosis signal-regulating kinase-1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase family that is activated by oxidative stress and promotes inflammation and apoptosis. Here we show that bleomycin-induced PF is reduced in Ask1 knockout mice (Ask1-/-) compared with wild-type (WT) mice, with improved survival and histological and functional parameters restored to basal levels. In WT mice, bleomycin caused activation of ASK1, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) in lung tissue, as well as changes in redox indicators (thioredoxin and heme-oxygenase-1), collagen content, and epithelial-mesenchymal transition markers (EMTs). These changes were largely restored toward untreated WT control levels in bleomycin-treated Ask1-/- mice. We further investigated whether treatment of WT mice with an ASK1 inhibitor, selonsertib (GS-4997), during the fibrotic phase would attenuate the development of PF. We found that pharmacological inhibition of ASK1 reduced activation of ASK1, p38, and ERK1/2 and promoted the restoration of redox and EMT indicators, as well as improvements in histological parameters. Our results suggest that ASK1 plays a central role in the development of bleomycin-induced PF in mice via p38 and ERK1/2 signaling. Together, these data indicate a possible therapeutic target for PF that involves an ASK1/p38/ERK1/2 axis.