scholarly journals Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-216882
Author(s):  
Amit Kumar ◽  
Evan Elko ◽  
Sierra R Bruno ◽  
Zoe F Mark ◽  
Nicolas Chamberlain ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Therapeutic Potential ◽  
Lung Parenchyma ◽  
Secretory Protein ◽  
Club Cell ◽  
Club Cells ◽  
Research Consortium ◽  
Related Proteins

BackgroundThe role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.ObjectivesTo examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis.MethodsRole of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice.ResultsPDIA3 and club cell secretory protein (SCGB1A1) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of Pdia3, specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice.ConclusionsOur study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.

Beclin 1, LC3, and p62 expression in paraquat-induced pulmonary fibrosis

2019 ◽  
Vol 38 (7) ◽  
pp. 794-802 ◽  
Author(s):  
G Xu ◽  
X Wang ◽  
H Yu ◽  
C Wang ◽  
Y Liu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Light Chain ◽  
Lung Fibrosis ◽  
Beclin 1 ◽  
Related Protein ◽  
Protein Expressions ◽  
Hematoxylin And Eosin ◽  
Hematoxylin And Eosin Staining ◽  
Related Proteins

Paraquat (PQ) is a highly toxic herbicide to humans. Pulmonary fibrosis is one of the most typical features of PQ poisoning, which develops from several days to weeks after ingestion. However, the mechanism of fibrosis is still unclear. In this study, we aimed to determine expressions of autophagy-related markers Beclin 1, microtubule-associated protein light chain 3 (LC3), and p62 in PQ-poisoned lungs and to explore the role of autophagy in pulmonary fibrosis induced by PQ. We detected markers of lung fibrosis and expressions of autophagy-related protein in the specimens from eight fatal cases of PQ poisoning by hematoxylin and eosin staining, Masson’s trichrome staining, and immunohistochemistry. Based on the staining results of lung fibrosis, these cases were divided into two groups, fibrosis and non-fibrosis groups. The correlation between autophagy protein expressions and pulmonary fibrosis was examined. The results demonstrated that the autophagy-related proteins were significantly expressed in fibrosis group compared with the non-fibrosis group. There was a significantly positive correlation between these protein expressions and severity of lung fibrosis. In conclusion, autophagy dysfunction may be involved in lung fibrogenesis caused by PQ poisoning. This may be a promising clue for understanding the molecular mechanism underlying PQ-induced lung fibrosis and provide evidence for treating fibrosis by regulating the level of autophagy.

scholarly journals PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea Doni ◽  
Alberto Mantovani ◽  
Barbara Bottazzi ◽  
Remo Castro Russo
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Tissue Repair ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Life Quality ◽  
Unknown Origin ◽  
Protective Role

PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient’s life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF.

scholarly journals Club cell-specific role of programmed cell death 5 in pulmonary fibrosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Soo-Yeon Park ◽  
Jung Yeon Hong ◽  
Soo Yeon Lee ◽  
Seung-Hyun Lee ◽  
Mi Jeong Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Pulmonary Fibrosis ◽  
Programmed Cell Death ◽  
Transcriptional Activation ◽  
Lung Fibrosis ◽  
Specific Role ◽  
Matricellular Protein ◽  
Club Cell ◽  
Programmed Cell Death 5

AbstractIdiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.

scholarly journals LncRNA SNHG16 promotes pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Panpan Liu ◽  
Lei Zhao ◽  
Yuxia Gu ◽  
Meilan Zhang ◽  
Hongchang Gao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interstitial Lung Diseases ◽  
Luciferase Reporter ◽  
Qrt Pcr ◽  
Rna Immunoprecipitation ◽  
And Migration

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung diseases with a poor prognosis. Long non-coding RNAs (lncRNAs) have been reported to be involved in IPF in several studies. However, the role of lncRNA SNHG16 in IPF is largely unknown. Methods Firstly, experimental pulmonary fibrosis model was established by using bleomycin (BML). Histology and Western blotting assays were used to determine the different stages of fibrosis and expression of several fibrosis biomarkers. The expression of SNHG16 was detected by quantitative real-time polymerase chain reaction (qRT‐PCR). EdU staining and wound-healing assay were utilized to analyze proliferation and migration of lung fibroblast cells. Molecular mechanism of SNHG16 was explored by bioinformatics, dual-luciferase reporter assay, RNA immunoprecipitation assay (RIP), and qRT-PCR. Results The expression of SNHG16 was significantly up-regulated in bleomycin-(BLM) induced lung fibrosis and transforming growth factor-β (TGF-β)-induced fibroblast. Knockdown of SNHG16 could attenuate fibrogenesis. Mechanistically, SNHG16 was able to bind and regulate the expression of miR-455-3p. Moreover, SNHG16 also regulated the expression of Notch2 by targeting miR-455-3p. Finally, SNHG16 could promote fibrogenesis by regulating the expression of Notch2. Conclusion Taken together, our study demonstrated that SNHG16 promoted pulmonary fibrosis by targeting miR-455-3p to regulate the Notch2 pathway. These findings might provide a novel insight into pathologic process of lung fibrosis and may provide prevention strategies in the future.

scholarly journals HDAC8 inhibition ameliorates pulmonary fibrosis

2019 ◽  
Vol 316 (1) ◽  
pp. L175-L186 ◽  
Author(s):  
Shigeki Saito ◽  
Yan Zhuang ◽  
Takayoshi Suzuki ◽  
Yosuke Ota ◽  
Marjorie E. Bateman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Smooth Muscle Actin ◽  
Lung Fibroblasts ◽  
Peroxisome Proliferator ◽  
Collagen Gels ◽  
Cell Contractility

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease, and fibroblast-myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase-8 (HDAC8) has been shown to associate with α-smooth muscle actin (α-SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been reported. This study investigated the role of HDAC8 in pulmonary fibrosis with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as transforming growth factor (TGF)β1-treated normal human lung fibroblasts (NHLFs). Immunoprecipitation experiments revealed that HDAC8 was associated with α-SMA in TGFβ1-treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8-selective inhibitor) repressed TGFβ1-induced fibroblast contraction and α-SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGFβ1-induced expression of profibrotic molecules such as fibronectin and increased expression of antifibrotic molecules such as peroxisome proliferator-activated receptor-γ (PPARγ). Chromatin immunoprecipitation quantitative PCR using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGFβ1-induced loss of H3K27ac at the PPARγ gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as expression of type 1 collagen and fibronectin in bleomycin-treated mouse lungs. These data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases.

The role of miR-29 in pulmonary fibrosis

2015 ◽  
Vol 93 (2) ◽  
pp. 109-118 ◽  
Author(s):  
Leah Cushing ◽  
Pingping Kuang ◽  
Jining Lü
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Pathological Condition ◽  
Lung Parenchyma ◽  
Interstitial Lung Diseases ◽  
Toxic Substances ◽  
Chronic Infections ◽  
Mesenchymal Transition

Pulmonary fibrosis is a pathological condition in which lungs become scarred due to the excess extracellular matrix (ECM) deposition and structural alterations in the interstitium of lung parenchyma. Many patients with interstitial lung diseases (ILDs) caused by long-term exposure to toxic substances, chronic infections, or autoimmune responses develop fibrosis. Etiologies for many ILDs are unknown, such as idiopathic pulmonary fibrosis (IPF), a devastating, relentless form of pulmonary fibrosis with a median survival of 2–3 years. Despite several decades of research, factors that initiate and sustain the fibrotic response in lungs remain unclear and there is no effective treatment to block progression of fibrosis. Here we summarize recent findings on the antifibrotic activity of miR-29, a small noncoding regulatory RNA, in the pathogenesis of fibrosis by regulating ECM production and deposition, and epithelial–mesenchymal transition (EMT). We also describe interactions of miR-29 with multiple profibrotic and inflammatory pathways. Finally, we review the antifibrotic activity of miR-29 in animal models of fibrosis and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis.

scholarly journals Prostaglandin E2 protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction

2011 ◽  
Vol 301 (5) ◽  
pp. L645-L655 ◽  
Author(s):  
Ryan T. Dackor ◽  
Jennifer Cheng ◽  
James W. Voltz ◽  
Jeffrey W. Card ◽  
Catherine D. Ferguson ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Effect ◽  
Lung Fibrosis ◽  
Prostaglandin E ◽  
Therapeutic Effects ◽  
Inflammatory Factor ◽  
Cellular Infiltration ◽  
Static Compliance ◽  
Lung Dysfunction

Prostaglandin E2 (PGE2) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE2 acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE2 in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE2 on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10–12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE2 (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE2- and iloprost-treated animals compared with vehicle-treated controls ( P < 0.05). When administered 7 days before bleomycin challenge, PGE2 also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE2 had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE2 prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge.

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.

Circular RNA HECTD1 Mitigates Ulcerative Colitis by Promoting Enterocyte Autophagy Via miR-182-5p/HuR Axis

2021 ◽  
Author(s):  
Yan Xu ◽  
Yuxi Tian ◽  
Fujun Li ◽  
Ying Wang ◽  
Junwen Yang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Regulatory Mechanism ◽  
Therapeutic Potential ◽  
Circular Rna ◽  
Unknown Etiology ◽  
Mucosal Tissues ◽  
Related Proteins

Abstract Objective Ulcerative colitis (UC) is a chronic colitis with unknown etiology. Circular RNA (circRNA) has shown regulatory effect in many diseases, but the role of circRNA in UC is barely known. This study uncovers the function and regulatory mechanism of circRNA HECTD1 (circHECTD1) in UC. Methods Colonic mucosal tissues of 60 patients with active UC and 30 healthy controls were collected for H&E staining. Lipopolysaccharide (LPS) and dextran sulfate sodium (DSS) were used to induce inflammation and UC in Caco-2 cells and C57BL/6 mice where modification of circHECTD1, miR-182–5p and/or human antigen R (HuR) took place. The Caco-2 cells and the colon tissues of DSS-treated mice were collected for analysis of the expression levels of inflammatory cytokines, NLRP3 inflammasome, and autophagy-related proteins. The interactions among circHECTD1, miR-182–5p, and HuR were verified. Results The colonic mucosal tissues of UC patients showed impaired autophagy and decreased expressions of circHECTD1 and HuR. Overexpression of circHECTD1 or HuR or inhibition of miR-182–5p suppressed inflammation and promoted autophagy of LPS-induced Caco-2 cells. The expression of HuR was promoted by circHECTD1 via miR-182–5p in Caco-2 cells. Overexpression of circHECTD1 reduced colonic injuries and inflammation by promoting autophagy in DSS-treated mice. Conclusion Overexpression of circHECTD1 alleviates UC by promoting HuR-dependent autophagy via miR-182–5p. This study highlights the therapeutic potential of circHECTD1 for UC and adds to the knowledge of circRNA in the pathogenesis of UC.

scholarly journals Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

2005 ◽  
Vol 201 (6) ◽  
pp. 925-935 ◽  
Author(s):  
Amir Abdollahi ◽  
Minglun Li ◽  
Gong Ping ◽  
Christian Plathow ◽  
Sophie Domhan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Kinase Inhibitors ◽  
Platelet Derived Growth Factor ◽  
Growth Factor Signaling ◽  
Pdgf Receptor ◽  
Pdgf Signaling ◽  
Radiation Induced

Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.

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