scholarly journals The Protective Effect of Naringenin on Airway Remodeling after Mycoplasma Pneumoniae Infection by Inhibiting Autophagy-Mediated Lung Inflammation and Fibrosis

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yan Lin ◽  
Dan Tan ◽  
Qianna Kan ◽  
Zhen Xiao ◽  
Zhiyan Jiang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Effect ◽  
Mycoplasma Pneumoniae ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Airway Remodeling ◽  
Enzyme Linked Immunosorbent Assay ◽  
The Relationship

Our previous study has shown that Chinese medicine, Qingfei Tongluo formula (QTF), has a significantly therapeutic effect to Mycoplasma pneumoniae (MP) pneumonia (MPP). The aim of this study was to investigate the therapeutic effect and mechanism of naringenin (NRG) on MPP which was an important component of QTF. Here, we studied 124 children with or without MPP and compared inflammatory cytokines and fibrinogen-related protein expression with enzyme-linked immunosorbent assay. We also employed a BALB/c mouse model of MPP and divided the mice into three groups: ctrl (normal control mice), MPP (MP-infected mice), and MPP + NRG (MP-infected mice treated with NRG). BEAS-2B cells were used to confirm the relationship between autophagy, inflammation, and fibrosis. The results show proinflammatory cytokines (interleukin- [IL-] 6, IL-1β, and tumor necrosis factor-α), and transforming growth factor beta (TGF-β) expression was significantly increased after MP infection from both clinical and animal experiment. In vivo experimental confirmation showed that NRG treatment decreased MPP-induced lung injury in mice by inhibiting autophagy-mediated inflammatory cytokine expression and pulmonary fibrosis. In vitro experiments confirmed it. These results indicate that NRG treatment suppressed the inflammatory response and pulmonary fibrosis by inhibition of autophagy after MP infection.

Bixin Protects Mice Against Bronchial Asthma Though Modulating PI3K/Akt Pathway

2021 ◽  
Author(s):  
Yingjie Zhu ◽  
Dong Sun ◽  
Han Liu ◽  
Linzi Sun ◽  
Jing Jie ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Airway Remodeling ◽  
Akt Pathway ◽  
Enzyme Linked Immunosorbent Assay ◽  
Natural Food ◽  
Mesenchymal Transition

Abstract Background: Accumulating evidence has implicated the potential of natural compounds in treatment of asthma. Bixin is a natural food coloring isolated from the seeds of Bixa Orellana, which possesses anti-tumor, anti-inflammatory and antioxidative properties. Nevertheless, its therapeutic effect in asthma has not been elucidated. Methods: Acute and chronic asthma models of Balb/c mice were established by ovalbumin (OVA) sensitization. For the establishment of a glucocorticoids (GCs) resistant asthma model, Freund’s Adjuvant (CFA) was injected intraperitoneally with OVA. After Bixin treatment, cells in Bronchoalveolar lavage fluid (BALF) were stained with Diff Quick staining and the levels of cytokines were measured by enzyme linked immunosorbent assay (ELISA). The levels of protein in cells and tissues were determined by immunoblotting and/or immunostaining with specific antibodies. The histological changes were determined by Hematoxylin and eosin (H&E), PAS and MASSON staining. Results: Our present study demonstrated that administration of Bixin suppressed allergic airway inflammation and reversed GCs resistance, as well as alleviated airway remodeling and airway hyperresponsiveness (AHR) in asthmatic mice. In vitro studies showed that Bixin treatment could inhibit the development of epithelial-mesenchymal transition (EMT) mediated by transforming growth factor beta (TGF-β) signaling. Importantly, Bixin antagonized activation of phosphatidylinositol 3‑kinase/protein kinase B (PI3K/Akt) pathway both in vitro and in vivo. Conclusions: Above all, our findings reveal that Bixin functions as a potent antagonist of PI3K/Akt signaling to protect against allergic asthma, highlighting a novel strategy for asthma treatment based on natural products.

scholarly journals Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in In Vitro, In Vivo and Ex Vivo Models of Pulmonary Fibrosis

2022 ◽  
Author(s):  
Farida Ahangari ◽  
Christine Becker ◽  
Daniel G Foster ◽  
Maurizio Chioccioli ◽  
Meghan Nelson ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Recombinant Adenovirus ◽  
Ex Vivo ◽  
Src Kinase ◽  
Lung Fibroblasts

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two FDA approved anti-fibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor, originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. We investigated the anti-fibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: (i) in vitro in normal human lung fibroblasts (NHLFs); (ii) in vivo in bleomycin and recombinant adenovirus transforming growth factor-beta (Ad-TGF-β) murine models of pulmonary fibrosis; and (iii) ex vivo in precision cut lung slices from these mouse models. In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone.

scholarly journals Kasugamycin is a novel chitinase 1 inhibitor with strong antifibrotic effects on pulmonary fibrosis

2021 ◽  
Author(s):  
Jae-Hyun Lee ◽  
Chang-Min Lee ◽  
Mun-Ock Kim ◽  
Jin Wook Park ◽  
Suchitra Kamle ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Glycosyl Hydrolase ◽  
Aminoglycoside Antibiotic ◽  
Therapeutic Drug ◽  
Antifibrotic Effect

Rationale: Pulmonary fibrosis is a devastating lung disease with few therapeutic options. Chitinase 1 (CHIT1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through regulation of Transforming Growth Factor (TGF)-β signaling and effector function. Therefore, CHIT1 is a potential therapeutic target of pulmonary fibrosis. Objectives: This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Methods: Extensive screening of small molecule libraries identified the aminoglycoside antibiotic Kasugamycin as a potent CHIT1 inhibitor. Measurements and Main Results: Elevated levels of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In vivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, Kasugamycin showed impressive anti-fibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that Kasugamycin inhibits fibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation. Null mutation of transforming growth factor beta associated protein 1 (TGFBRAP1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of Kasugamycin in in vivo lungs and in vitro fibroblasts responses. Kasugamycin inhibits physical association between CHIT1 and TGFBRAP1 with decreased levels of SMAD4 association, suggesting that antifibrotic effect of Kasugamycin is mediated through regulation of TGFBRAP1, at least in part. Conclusions: These studies demonstrate that Kasugamycin is a novel CHIT1 inhibitor with strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Xin She ◽  
Qing Yang Yu ◽  
Xiao Xiao Tang
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Strategy ◽  
Future Directions ◽  
Regulation Mechanisms ◽  
Underlying Mechanisms ◽  
Multiple Cells ◽  
The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

scholarly journals Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia.

1991 ◽  
Vol 173 (5) ◽  
pp. 1121-1132 ◽  
Author(s):  
R A Fava ◽  
N J Olsen ◽  
A E Postlethwaite ◽  
K N Broadley ◽  
J M Davidson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Synovial Tissue ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Biologically Active ◽  
Tgf Beta ◽  
Histological Techniques ◽  
Growth Factor Beta

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.

scholarly journals An In Vitro Model for Assessing Corneal Keratocyte Spreading and Migration on Aligned Fibrillar Collagen

2018 ◽  
Vol 9 (4) ◽  
pp. 54 ◽  
Author(s):  
Pouriska Kivanany ◽  
Kyle Grose ◽  
Nihan Yonet-Tanyeri ◽  
Sujal Manohar ◽  
Yukta Sunkara ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cell Movement ◽  
Time Lapse ◽  
Collagen Fibrils ◽  
Fibrillar Collagen ◽  
Freeze Injury

Background: Corneal stromal cells (keratocytes) are responsible for developing and maintaining normal corneal structure and transparency, and for repairing the tissue after injury. Corneal keratocytes reside between highly aligned collagen lamellae in vivo. In addition to growth factors and other soluble biochemical factors, feedback from the extracellular matrix (ECM) itself has been shown to modulate corneal keratocyte behavior. Methods: In this study, we fabricate aligned collagen substrates using a microfluidics approach and assess their impact on corneal keratocyte morphology, cytoskeletal organization, and patterning after stimulation with platelet derived growth factor (PDGF) or transforming growth factor beta 1 (TGFβ). We also use time-lapse imaging to visualize the dynamic interactions between cells and fibrillar collagen during wound repopulation following an in vitro freeze injury. Results: Significant co-alignment between keratocytes and aligned collagen fibrils was detected, and the degree of cell/ECM co-alignment further increased in the presence of PDGF or TGFβ. Freeze injury produced an area of cell death without disrupting the collagen. High magnification, time-lapse differential interference contrast (DIC) imaging allowed cell movement and subcellular interactions with the underlying collagen fibrils to be directly visualized. Conclusions: With continued development, this experimental model could be an important tool for accessing how the integration of multiple biophysical and biochemical signals regulate corneal keratocyte differentiation.

scholarly journals Di-Tyrosine Crosslinking and NOX4 Expression as Oxidative Pathological Markers in the Lungs of Patients with Idiopathic Pulmonary Fibrosis

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1833
Author(s):  
Sanja Blaskovic ◽  
Yves Donati ◽  
Isabelle Ruchonnet-Metrailler ◽  
Tamara Seredenina ◽  
Karl-Heinz Krause ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Post Translational Modification ◽  
Pulmonary Tissue ◽  
Nadph Oxidase 4

Idiopathic pulmonary fibrosis (IPF) is a noninflammatory progressive lung disease. Oxidative damage is a hallmark of IPF, but the sources and consequences of oxidant generation in the lungs are unclear. In this study, we addressed the link between the H2O2-generating enzyme NADPH oxidase 4 (NOX4) and di-tyrosine (DT), an oxidative post-translational modification in IPF lungs. We performed immunohistochemical staining for DT and NOX4 in pulmonary tissue from patients with IPF and controls using validated antibodies. In the healthy lung, DT showed little or no staining and NOX4 was mostly present in normal vascular endothelium. On the other hand, both markers were detected in several cell types in the IPF patients, including vascular smooth muscle cells and epithelium (bronchial cells and epithelial cells type II). The link between NOX4 and DT was addressed in human fibroblasts deficient for NOX4 activity (mutation in the CYBA gene). Induction of NOX4 by Transforming growth factor beta 1 (TGFβ1) in fibroblasts led to moderate DT staining after the addition of a heme-containing peroxidase in control cells but not in the fibroblasts deficient for NOX4 activity. Our data indicate that DT is a histological marker of IPF and that NOX4 can generate a sufficient amount of H2O2 for DT formation in vitro.

scholarly journals LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 260 ◽  
Author(s):  
Qing Zhang ◽  
Xiaonan Hou ◽  
Bradley Evans ◽  
Jamison VanBlaricom ◽  
Saravut Weroha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Ascites Formation ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

scholarly journals Characterization of a new monoclonal antibody (PG-M3) directed against the aminoterminal portion of the PML gene product: immunocytochemical evidence for high expression of PML proteins on activated macrophages, endothelial cells, and epithelia

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1871-1880 ◽  
Author(s):  
L Flenghi ◽  
M Fagioli ◽  
L Tomassoni ◽  
S Pileri ◽  
M Gambacorta ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Retinoic Acid Receptor ◽  
Chromosomal Translocation ◽  
Peptide Sequence ◽  
Nuclear Staining

PG-M3 is a new monoclonal antibody (MoAb) specifically directed against a peptide sequence located in the aminoterminal region of the human PML protein. PML gene fuses with the retinoic acid receptor alpha (RAR alpha) gene during the t(15; 17) chromosomal translocation of acute promyelocytic leukemia (APL). The epitope recognized by PG-M3 is species-specific and fixative-resistant and is shared by most PML isoforms and PML/RAR alpha fusion proteins. PML is consistently located within the nucleus, although a minority of cells (about 20%), both in vitro and in vivo, show positivity for PML also in the cytoplasm. The nuclear staining pattern of PG-M3 varies from speckled (cells other than APL) to micropunctate (APL cells). Although two physiologically expressed PML isoforms are detectable by immunocytochemistry only or predominantly in the cytoplasm of transfected cells, the cytoplasmic localization of PML is a property also shared by the PML isoforms that predominantly localize to the nuclei. Immunohistologic analysis of normal human tissues with the PG-M3 MoAb showed variable PML expression, with the highest levels of the protein in postmitotic, differentiated cell types, such as endothelial cells, epithelia, and tissue macrophages, especially activated ones. In keeping with this in vivo finding, PML appears strongly upregulated in the U937 promonocyte cell line after exposure to agents that induce monocyte/macrophage activation (interferon gamma) or maturation (vitamin D3 and transforming growth factor beta 1).

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