scholarly journals Tartrate-resistant acid phosphatase 5 serves as a viable target against pulmonary fibrosis by modulating β-catenin signaling

2020 ◽  
Author(s):  
Yinan Hu ◽  
Jun Yu ◽  
Qi Wang ◽  
Qing Zhou ◽  
Yanhan Deng ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Diffusing Capacity ◽  
Mechanistic Studies ◽  
Therapeutic Approaches ◽  
Differentiation And Proliferation ◽  
Tgf Β1

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrated that the levels of ACP5 were increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 were noted in the sera of IPF patients with a diffusing capacity of the lungs for carbon monoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protected mice from BLM-induced lung injury and fibrosis and reduced the differentiation and proliferation of fibroblasts. Mechanistic studies revealed that Acp5 was upregulated by TGF-β1 in a TGFβR1/Smad3-dependent manner, after which Acp5 dephosphorylated p-β-catenin at Ser33 and Thr41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promoted the differentiation and proliferation of fibroblast. Notably, the treatment of mice with BLM-induced fibrosis with Acp5 siRNA-loaded liposomes robustly reversed lung fibrosis. Collectively, these data indicate that Acp5 plays an essential role in the initiation and progression of pulmonary fibrosis; therefore, strategies aimed at silencing Acp5 could be novel therapeutic approaches against pulmonary fibrosis in a clinical setting.

scholarly journals Tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis by modulating β-catenin signaling

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yinan Hu ◽  
Qi Wang ◽  
Jun Yu ◽  
Qing Zhou ◽  
Yanhan Deng ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Therapeutic Approaches ◽  
Β Receptor ◽  
And Migration ◽  
Differentiation And Proliferation

AbstractIdiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis.

scholarly journals A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice

2020 ◽  
Author(s):  
Anghesom Ghebremedhin ◽  
Ahmad Bin Salam ◽  
Benjamin Adu-Addai ◽  
Steve Noonan ◽  
Richard Stratton ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Early Stage ◽  
Blood Chemistry ◽  
Dependent Manner ◽  
Similar Reduction ◽  
Clinical Scenarios ◽  
Approved Drugs ◽  
Tgf Β1

AbstractActivated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNFα, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-β1 and α-SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNFα, IL-6, IL-10, INF-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

scholarly journals Anti-fibrosis effect for Hirsutella sinensis mycelium based on inhibition of mTOR p70S6K phosphorylation

2017 ◽  
Vol 23 (7) ◽  
pp. 615-624 ◽  
Author(s):  
Huimin Yue ◽  
Yarong Zhao ◽  
Haining Wang ◽  
Feiya Ma ◽  
Fei Liu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Histopathological Examination ◽  
Smooth Muscle Actin ◽  
A549 Cells ◽  
Mtor Pathway ◽  
Cordyceps Sinensis ◽  
Tgf Β1

Hirsutella sinensis, cultured in vitro, is an attractive substitute for Cordyceps sinensis as health supplement. The aim of this study was to demonstrate whether H. sinensis mycelium (HSM) attenuates murine pulmonary fibrosis induced by bleomycin and to explore the underlying molecular mechanisms. Using lung fibrosis modle induced by intratracheal instillation of bleomycin (BLM; 4 mg/kg), we observed that the administration of HSM reduced HYP, TGF-β1 and the production of several pro-fibrosis cytokines (α-smooth muscle actin, fibronectin and vimentin) in fibrotic mice lung sections. Histopathological examination of lung tissues also demonstrated that HSM improved BLM-induced pathological damage. Concurrently, HSM supplementation markedly reduced the chemotaxis of alveolar macrophages and potently suppressed the expression of inflammatory cytokines. Also, HSM influenced Th1/Th2 and Th17/Treg imbalance and blocked the phosphorylation of mTOR pathway in vivo. Alveolar epithelial A549 cells acquired a mesenchymal phenotype and an increased expression of myofibroblast markers of differentiation (vimentin and fibronectin) after treatment with TGF-β1. HSM suppressed these markers and blocked the phosphorylation of mTOR pathway in vitro. The results provide evidence supporting the use of HSM in the intervention of pulmonary fibrosis and suggest that HSM is a potential therapeutic agent for lung fibrosis.

scholarly journals Lung Fibrosis-associated Surfactant Protein A1 and C Variants Induce Latent Transforming Growth Factor β1 Secretion in Lung Epithelial Cells

2013 ◽  
Vol 288 (38) ◽  
pp. 27159-27171 ◽  
Author(s):  
Meenakshi Maitra ◽  
Moushumi Dey ◽  
Wen-Cheng Yuan ◽  
Peter W. Nathanielsz ◽  
Christine Kim Garcia
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Surfactant Protein ◽  
Transforming Growth Factor Β1 ◽  
Lung Epithelial Cells ◽  
Missense Mutations ◽  
Lung Epithelial ◽  
Tgf Β1

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.

scholarly journals Inhibition of lncRNA PFRL prevents pulmonary fibrosis by disrupting the miR-26a/smad2 loop

2018 ◽  
Vol 315 (4) ◽  
pp. L563-L575 ◽  
Author(s):  
Hua Jiang ◽  
Yingzhun Chen ◽  
Tong Yu ◽  
Xiaoguang Zhao ◽  
Huitong Shan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Feedback Loop ◽  
Transforming Growth Factor ◽  
Molecular Study ◽  
Pulmonary Fibroblasts ◽  
Proliferation And Differentiation ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with increasing mortality and poor prognosis. The current understanding of the role of long noncoding RNAs (lncRNAs) in IPF remains limited. In the present study, we identified a lncRNA NONMMUT022554, designated pulmonary fibrosis-regulatory lncRNA (PFRL), with unknown functions and found that its levels were increased in fibrotic lung tissues of mice and pulmonary fibroblasts exposed to transforming growth factor (TGF)-β1. Furthermore, we found that enforced expression of PFRL induced fibroblast activation and collagen deposition, which could be mitigated by the overexpression of microRNA (miR)-26a. By contrast, the inhibition of PFRL could markedly alleviate the TGF-β1-induced upregulation of fibrotic markers and attenuate fibroblast proliferation and differentiation by regulating miR-26a. Meanwhile, our study confirmed that PFRL inhibited the expression and activity of miR-26a, which has been identified as an antifibrotic miRNA in our previous study. Interestingly, our molecular study further confirmed that Smad2 transcriptionally inhibits the expression of miR-26a and that the miR-26a/Smad2 feedback loop mediates the profibrotic effects of PFRL in lung fibrosis. More importantly, knockdown of PFRL ablated bleomycin-induced pulmonary fibrosis in vivo. Taken together, our findings indicate that lncRNA PFRL contributes to the progression of lung fibrosis by modulating the reciprocal repression between miR-26a and Smad2 and that this lncRNA may be a therapeutic target for IPF.

scholarly journals Osthole Attenuates Bleomycin-Induced Pulmonary Fibrosis by Modulating NADPH Oxidase 4-Derived Oxidative Stress in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Lijun Fang ◽  
Wei Wang ◽  
Jiazheng Chen ◽  
Anju Zuo ◽  
Hongmei Gao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Fibrosis ◽  
Lung Fibroblasts ◽  
Ros Generation ◽  
Dependent Manner ◽  
Active Constituent ◽  
Concentration Dependent Manner ◽  
Nadph Oxidase 4 ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the extensive accumulation of myofibroblasts and collagens. However, the exact mechanism that underlies this condition is unclear. Growing evidence suggests that NADPH oxidases (NOXs), especially NOX4-derived oxidative stress, play an important role in the development of lung fibrosis. Bleomycin (BLM) is a tumor chemotherapeutic agent, which has been widely employed to establish IPF animal models. Osthole (OST) is an active constituent of the fruit of Cnidium ninidium. Here, we used an in vivo mouse model and found that OST suppressed BLM-induced body weight loss, lung injury, pulmonary index increase, fibroblast differentiation, and pulmonary fibrosis. OST also significantly downregulated BLM-induced NOX4 expression and oxidative stress in the lungs. In vitro, OST could inhibit TGF-β1-induced Smad3 phosphorylation, differentiation, proliferation, collagen synthesis, NOX4 expression, and ROS generation in human lung fibroblasts in a concentration-dependent manner. Moreover, NOX4 overexpression could prevent the above effects of OST. We came to the conclusion that OST could significantly attenuate BLM-induced pulmonary fibrosis in mice, via the mechanism that involved downregulating TGF-β1/NOX4-mediated oxidative stress in lung fibroblasts.

scholarly journals Interpreting Immunoregulation in Lung Fibrosis: A New Branch of the Immune Model

2021 ◽  
Vol 12 ◽  
Author(s):  
François Huaux
Keyword(s):  
Animal Models ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Inflammatory Cytokine ◽  
Matrix Protein ◽  
Alternative Mechanism ◽  
Protein Deposition ◽  
Fibrotic Disorders ◽  
Regulatory Lymphocytes ◽  
Tgf Β1

Immunostimulation is recognized as an important contribution in lung fibrosis in some animal models and patient subsets. With this review, we illustrate an additional scenario covering the possible implication of immunoregulation during fibrogenesis. Available animal and human data indicate that pulmonary fibrosis also includes diverse and discrete immunoregulating populations comprising regulatory lymphocytes (T and B regs) and myeloid cells (immunosuppressive macrophages and myeloid-derived suppressive cells; MDSC). They are initially recruited to limit the establishment of deleterious inflammation but participate in the development of lung fibrosis by producing immunoregulatory mediators (mainly TGF-β1 and IL-10) that directly or indirectly stimulate fibroblasts and matrix protein deposition. The existence of this silent immunoregulatory environment sustains an alternative mechanism of fibrosis that explains why in some conditions neither pro-inflammatory cytokine deficiency nor steroid and immunosuppressive therapies limit lung fibrosis. Therefore, the persistent presence of immunoregulation is an important parameter to consider for refining therapeutical strategies in lung fibrotic disorders under non-immunostimulatory conditions.

scholarly journals Activated mTORC1-SIRT6 Mediates Myofibroblast Differentiation and Idiopathic Pulmonary Fibrosis

2021 ◽  
Author(s):  
Ji Zhang ◽  
Yi Hu ◽  
Huiping Huang ◽  
Qun Liu ◽  
Yang Du ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Signalling Pathway ◽  
Lung Fibroblasts ◽  
Myofibroblast Differentiation ◽  
Dependent Manner ◽  
Mtor Signaling Pathway ◽  
Mtorc1 Pathway ◽  
Tgf Β1

Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is characterised by accumulation of myofibroblasts and deposition of extracellular matrix proteins. Fibroblast-to-myofibroblast transdifferentiation and myofibroblast hyperproliferation plays a major role in pulmonary fibrosis. Moreover, mTOR signaling pathway and SIRT6 play a critical role in pulmonary fibrosis. However, the mechanisms whether SIRT6 affect the myofibroblasts differentiation during IPF remain unclear.MethodWe investigated myofibroblast differentiation using a bleomycin-induced mouse pulmonary fibrosis model and TGF-b1 induced human fetal lung fibroblasts (MRC5) in vitro. We used both SIRT6 siRNA and rapamycin to study the role of SIRT6 and mTOR signaling pathway in the normal human lung fibroblasts and the myofibroblasts from human IPF lungs.ResultsOur data show that high level of SIRT6 was detected in IPF samples, and SIRT6 was significantly upregulated by TGF-β1 in a time and concentration-dependent manner. SIRT6 expression and activation of mTORC1 signalling pathway were upregulated in fibrotic lung tissues and primary lung fibroblasts isolated from patients with IPF and bleomycin-challenged mice. Furthermore, rapamycin treatment inhibited mTORC1 pathway activity and SIRT6 protein expression. SIRT6 SiRNA failed to mediate the activity of mTORC1 pathway and autophagy induction. However, SIRT6 knockdown could promote TGF-b1 induced pro-fibrotic cytokines.ConclusionActivated mTORC1 signalling pathway regulated SIRT6 overexpression. Deficiency of SIRT6 mediated myofibroblasts differentiation through induced pro-fibrotic cytokines production in the present of TGF-β1. The study indicated that manipulations of SIRT6 expression may provide a new therapeutic strategy to prevent and reverse the progression of pulmonary fibrosis.

Connective-Tissue Growth Factor (CTGF/CCN2) Contributes to TGF-β1-Induced Lung Fibrosis

2020 ◽  
Author(s):  
Toyoshi Yanagihara ◽  
Sy Giin Chong ◽  
Mahsa Gholiof ◽  
Kenneth E. Lipson ◽  
Quan Zhou ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Connective Tissue ◽  
Pulmonary Fibrosis ◽  
Connective Tissue Growth Factor ◽  
Lung Fibrosis ◽  
Adenovirus Vector ◽  
Tissue Growth ◽  
Inhibitory Antibody ◽  
Tgf Β1

AbstractIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and extracellular matrix in the lung. Connective-tissue growth factor (CTGF) is known to exacerbate pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we show the upregulation of CTGF from a rat lung fibrosis model induced by adenovirus vector encoding active TGF-β1 (AdTGF-β1), and also in patients with IPF. The expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on days 7 or 14 as well as endothelial cells sorted from fibrotic lungs on day 14 or 28 respectively. These findings suggest the role of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-β increases pro-fibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-β in inducing pulmonary fibrosis. Also, fibrotic extracellular matrix upregulated the expression of CTGF, as compared to normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for the treatment of pulmonary fibrosis.

scholarly journals NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis

2020 ◽  
pp. 1901949
Author(s):  
Ruy Andrade Louzada ◽  
Raphaël Corre ◽  
Rabii Ameziane El Hassani ◽  
Lydia Meziani ◽  
Madeleine Jaillet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Nadph Oxidase ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Epithelial Surface ◽  
Tgf Β1

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF-β1)/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species (ROS) through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular H2O2-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis.Our in vivo data (IPF patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1+/- and DUOX1-/-) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be also well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H2O2 promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation.These findings highlight a role for DUOX1-derived H2O2 in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.

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