Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy.

Abstract:

:Impaired apoptotic clearance of myofibroblasts can result in the continuous expansion of scar tissue during the persistent injury in the lung. However, the molecular and cellular mechanisms underlying the apoptotic clearance of multiple mesenchymal cells including fibrocytes, fibroblasts and myofibroblasts in severe fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) remain largely unknown. We analyzed the apoptotic pathways activated in mesenchymal cells of IPF and in a mouse model of TGFα-induced pulmonary fibrosis. We found that fibrocytes and myofibroblasts in fibrotic lung lesions have acquired resistance to Fas-induced apoptosis, and an FDA-approved anti-fibrotic agent, nintedanib, effectively induced apoptotic cell death in both. In support, comparative gene expression analyses suggest that apoptosis-linked gene networks similarly dysregulated in both IPF and a mouse model of TGFα-induced pulmonary fibrosis. TGFα mice treated with nintedanib show increased active caspase 3-positive cells in fibrotic lesions and reduced fibroproliferation and collagen production. Further, the long-term nintedanib therapy attenuated fibrocyte accumulation, collagen deposition, and lung function decline during TGFα-induced pulmonary fibrosis. These results highlight the importance of inhibiting survival pathways and other pro-fibrotic processes in the various types of mesenchymal cells and suggest that the TGFα mouse model is relevant for testing of anti-fibrotic drugs either alone or in combination with nintedanib.

journal_name

Front Pharmacol

authors

Kasam RK,Reddy GB,Jegga AG,Madala SK

doi

10.3389/fphar.2019.00532

subject

Has Abstract

pub_date

2019-05-17 00:00:00

pages

532

issn

1663-9812

journal_volume

10

pub_type

杂志文章
  • Roles, Actions, and Therapeutic Potential of Specialized Pro-resolving Lipid Mediators for the Treatment of Inflammation in Cystic Fibrosis.

    abstract::Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produc...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2019.00252

    authors: Recchiuti A,Mattoscio D,Isopi E

    更新日期:2019-04-02 00:00:00

  • Chromatin Regulation by HP1γ Contributes to Survival of 5-Azacytidine-Resistant Cells.

    abstract::Recent investigations of the treatment for hematologic neoplasms have focused on targeting epigenetic regulators. The DNA methyltransferase inhibitor 5-azacytidine (AZA) has produced good results in the treatment of patients with myelodysplastic syndromes. The mechanism underlying its pharmacological activity involves...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.01166

    authors: Imanishi S,Umezu T,Kobayashi C,Ohta T,Ohyashiki K,Ohyashiki JH

    更新日期:2018-10-16 00:00:00

  • A Novel Network Pharmacology Strategy to Decode Mechanism of Lang Chuang Wan in Treating Systemic Lupus Erythematosus.

    abstract::Complex disease is a cascade process which is associated with functional abnormalities in multiple proteins and protein-protein interaction (PPI) networks. One drug one target has not been able to perfectly intervene complex diseases. Increasing evidences show that Chinese herb formula usually treats complex diseases ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.512877

    authors: Gao Y,Wang KX,Wang P,Li X,Chen JJ,Zhou BY,Tian JS,Guan DG,Qin XM,Lu AP

    更新日期:2020-10-02 00:00:00

  • Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape.

    abstract::The Tim-3-galectin-9 secretory pathway is known to protect various types of cancer cells against host immune surveillance. We found that pharmacologically induced mitochondrial dysfunction leads to a reduced galectin-9 expression/exocytosis in human colorectal cancer cells and re-distribution of this protein (the effe...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2019.00342

    authors: Sakhnevych SS,Yasinska IM,Fasler-Kan E,Sumbayev VV

    更新日期:2019-04-05 00:00:00

  • Hupresin Retains Binding Capacity for Butyrylcholinesterase and Acetylcholinesterase after Sanitation with Sodium Hydroxide.

    abstract::Hupresin is a new affinity resin that binds butyrylcholinesterase (BChE) in human plasma and acetylcholinesterase (AChE) solubilized from red blood cells (RBC). Hupresin is available from the CHEMFORASE company. BChE in human plasma binds to Hupresin and is released with 0.1 M trimethylammonium bromide (TMA) with full...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00713

    authors: Onder S,David E,Tacal O,Schopfer LM,Lockridge O

    更新日期:2017-10-10 00:00:00

  • Folliculin Interacts with Rab35 to Regulate EGF-Induced EGFR Degradation.

    abstract::Aims and Hypothesis: This study aims to investigate the mechanism involved in intracellular regulation of EGFR degradation induced by EGF. Methods: Phosphorylation of proteins related to EGFR signaling was examined by western blot analysis. Activation, connection between Rab35 and folliculin (FLCN) were assessed by pu...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00688

    authors: Zheng J,Duan B,Sun S,Cui J,Du J,Zhang Y

    更新日期:2017-09-26 00:00:00

  • CTRP5-Overexpression Attenuated Ischemia-Reperfusion Associated Heart Injuries and Improved Infarction Induced Heart Failure.

    abstract::Aims: C1q/tumor necrosis factor (TNF)-related protein 5 (CTRP5) belongs to the C1q/TNF-α related protein family and regulates glucose, lipid metabolism, and inflammation production. However, the roles of CTRP5 in ischemia/reperfusion (I/R) associated with cardiac injuries and heart failure (HF) needs to be elaborated....

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.603322

    authors: Peng M,Liu Y,Zhang XQ,Xu YW,Zhao YT,Yang HB

    更新日期:2020-12-22 00:00:00

  • β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2.

    abstract::The inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impedes its clinical appl...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.01413

    authors: Cheng H,Ge X,Zhuo S,Gao Y,Zhu B,Zhang J,Shang W,Xu D,Ge W,Shi L

    更新日期:2018-11-30 00:00:00

  • CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist.

    abstract::Synthetic cannabinoid receptor agonists (SCRAs) are the largest class of new psychoactive substances (NPS). New examples are detected constantly, and some are associated with a series of adverse effects, including seizures. CUMYL-4CN-BINACA (1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)indazole-3-carboxamide) is structural...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2019.00595

    authors: Kevin RC,Anderson L,McGregor IS,Boyd R,Manning JJ,Glass M,Connor M,Banister SD

    更新日期:2019-05-29 00:00:00

  • Histone Deacetylase 6 as a Therapeutic Target in B cell-associated Hematological Malignancies.

    abstract::B lymphocytes play a critical role in humoral immunity. Abnormal B cell development and function cause a variety of hematological malignancies such as myeloma, B cell lymphoma, and leukemia. Histone deacetylase 6 (HDAC6) inhibitors alone or in combination with other drugs have shown efficacy in several hematological m...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2020.00971

    authors: Yang J,Li D,Zhou J

    更新日期:2020-06-26 00:00:00

  • Suppression of mICAT in Mouse Small Intestinal Myocytes by General Anaesthetic Ketamine and its Recovery by TRPC4 Agonist (-)-englerin A.

    abstract::A better understanding of the negative impact of general anesthetics on gastrointestinal motility requires thorough knowledge of their molecular targets. In this respect the muscarinic cationic current (mICAT carried mainly via TRPC4 channels) that initiates cholinergic excitation-contraction coupling in the gut is of...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.594882

    authors: Melnyk MI,Dryn DO,Al Kury LT,Dziuba DO,Zholos AV

    更新日期:2020-12-18 00:00:00

  • Analysis of biomarker utility using a PBPK/PD model for carbaryl.

    abstract::There are many types of biomarkers; the two common ones are biomarkers of exposure and biomarkers of effect. The utility of a biomarker for estimating exposures or predicting risks depends on the strength of the correlation between biomarker concentrations and exposure/effects. In the current study, a combined exposur...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2014.00246

    authors: Phillips MB,Yoon M,Young B,Tan YM

    更新日期:2014-11-18 00:00:00

  • Network Pharmacology-Based Approach Uncovers the Mechanism of GuanXinNing Tablet for Treating Thrombus by MAPKs Signal Pathway.

    abstract:Background:GuanXinNing tablet (GXNT), a traditional Chinese patent medicine, has been found to have remarkable antithrombotic effects and can effectively inhibit pro-thrombotic factors in previous studies. However, the mechanism of its antithrombotic effects remains little known. Methods:In this study, we first determ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00652

    authors: Wang ML,Yang QQ,Ying XH,Li YY,Wu YS,Shou QY,Ma QX,Zhu ZW,Chen ML

    更新日期:2020-05-13 00:00:00

  • Semipermeable Cellulose Beads Allow Selective and Continuous Release of Small Extracellular Vesicles (sEV) From Encapsulated Cells.

    abstract::The clinical benefit of therapies using Mesenchymal Stem Cells (MSCs) is attributable to their pleiotropic effect over cells and tissues, mainly through their secretome. This paracrine effect is mediated by secreted growth factors and extracellular vesicles (EV) including small EV (sEV). sEV are extra-cellular, membra...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00679

    authors: Zavala G,Ramos MP,Figueroa-Valdés AI,Cisternas P,Wyneken U,Hernández M,Toa P,Salmons B,Dangerfield J,Gunzburg WH,Khoury M

    更新日期:2020-05-21 00:00:00

  • Layered Double Hydroxide Nanomaterials Encapsulating Angelica gigas Nakai Extract for Potential Anticancer Nanomedicine.

    abstract::We prepared hybrids consisting of Angelica gigas Nakai (AGN) root or flower extract and layered double hydroxide (LDH) for potential anticancer nanomedicine, as decursin species (DS) in AGN are known to have anticancer activity. Dimethylsulfoxide solvent was determined hybridization reaction media, as it has affinity ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00723

    authors: Kim HJ,Lee GJ,Choi AJ,Kim TH,Kim TI,Oh JM

    更新日期:2018-07-09 00:00:00

  • α2- and β2-Adrenoreceptor-Mediated Efficacy of the Atypical Antidepressant Agomelatine Combined With Gabapentin to Suppress Allodynia in Neuropathic Rats With Ligated Infraorbital or Sciatic Nerve.

    abstract::Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves has specific characteristics and responds differently to alleviating drugs at cephalic versus extracephalic level. This is especially true for tricyclic antidepressants currently used for alleviating neuropathic pain in humans...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00587

    authors: M'Dahoma S,Poitevin M,Dabala E,Payan H,Gabriel C,Mocaër E,Bourgoin S,Hamon M

    更新日期:2018-06-07 00:00:00

  • Pulsatilla Decoction Can Treat the Dampness-Heat Diarrhea Rat Model by Regulating Glycerinphospholipid Metabolism Based Lipidomics Approach.

    abstract:Ethnopharmacological Relevance:Diarrhea is a major medical problem in clinical practice. According to the theory of traditional Chinese medicine (TCM), different types of diarrhea should be treated with different TCM formulations based on the targeted medical condition. Dampness-heat diarrhea (DHD) is a serious diarrhe...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00197

    authors: Hua YL,Ma Q,Zhang XS,Jia YQ,Peng XT,Yao WL,Ji P,Hu JJ,Wei YM

    更新日期:2020-03-03 00:00:00

  • Relations between Effects and Structure of Small Bicyclic Molecules on the Complex Model System Saccharomyces cerevisiae.

    abstract::The development of compounds able to modify biological functions largely took advantage of parallel synthesis to generate a broad chemical variance of compounds to be tested for the desired effect(s). The budding yeast Saccharomyces cerevisiae is a model for pharmacological studies since a long time as it represents a...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00170

    authors: Brilli M,Trabocchi A,Weil T,Cavalieri D,Stefanini I

    更新日期:2017-03-30 00:00:00

  • Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity.

    abstract::Selective estrogen receptor modulators (SERMs) are used to treat estrogen receptor (ER)-positive breast cancer and osteoporosis. Interestingly, tamoxifen and newer classes of SERMs also exhibit cytotoxic effects in cancers devoid of ERs, indicating a non-estrogenic mechanism of action. Indicative of a potential ER-ind...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2016.00503

    authors: Franks LN,Ford BM,Prather PL

    更新日期:2016-12-22 00:00:00

  • Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization.

    abstract::Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are pot...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2016.00525

    authors: Rossi A,Caiazzo E,Bilancia R,Riemma MA,Pagano E,Cicala C,Ialenti A,Zjawiony JK,Izzo AA,Capasso R,Roviezzo F

    更新日期:2017-01-13 00:00:00

  • Periplaneta americana Extracts Accelerate Liver Regeneration via a Complex Network of Pathways.

    abstract::Successful recovery from hepatectomy is partially contingent upon the rate of residual liver regeneration. The traditional Chinese medicines known as Periplaneta americana extracts (PAEs) positively influence wound healing by promoting tissue repair. However, the effect of PAEs on liver regeneration is unknown. We use...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.01174

    authors: Zou Y,Zhang M,Zeng D,Ruan Y,Shen L,Mu Z,Zou J,Xie C,Yang Z,Qian Z,Xu R,Li S,Kang Q,Zou H,Zhao S,Liu L,Wang K,Wang X,Zhang X

    更新日期:2020-07-31 00:00:00

  • Efficacy of Pharmacist Based Diabetes Educational Interventions on Clinical Outcomes of Adults With Type 2 Diabetes Mellitus: A Network Meta-Analysis.

    abstract::Background: Comparative efficacy of different pharmacist based interventions on glycemic control of type 2 diabetes patients is unclear. This review aimed to evaluate and compare the efficacy of different pharmacist based interventions on clinical outcomes of type 2 diabetes patients. Methods: A systematic search was ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2018.00339

    authors: Bukhsh A,Khan TM,Lee SWH,Lee LH,Chan KG,Goh BH

    更新日期:2018-04-10 00:00:00

  • Protein kinases as switches for the function of upstream stimulatory factors: implications for tissue injury and cancer.

    abstract::The upstream stimulatory factors (USFs) are regulators of important cellular processes. Both USF1 and USF2 are supposed to have major roles in metabolism, tissue protection and tumor development. However, the knowledge about the mechanisms that control the function of USFs, in particular in tissue protection and cance...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2015.00003

    authors: Horbach T,Götz C,Kietzmann T,Dimova EY

    更新日期:2015-02-18 00:00:00

  • Changes in PGC-1α/SIRT1 Signaling Impact on Mitochondrial Homeostasis in Amyloid-Beta Peptide Toxicity Model.

    abstract::Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AβOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Aβ are not well understood. We studied the effects of Aβ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00709

    authors: Panes JD,Godoy PA,Silva-Grecchi T,Celis MT,Ramirez-Molina O,Gavilan J,Muñoz-Montecino C,Castro PA,Moraga-Cid G,Yévenes GE,Guzmán L,Salisbury JL,Trushina E,Fuentealba J

    更新日期:2020-05-21 00:00:00

  • Glucocorticoid-Induced Leucine Zipper: A Novel Anti-inflammatory Molecule.

    abstract::Glucocorticoids (GCs) are the most commonly used drugs for treatment of autoimmune and inflammatory diseases. Their efficacy is due to their ability to bind cytoplasmic receptors (glucocorticoid receptors, GR) and other cytoplasmic proteins, thus regulating gene expression. Although GCs are potent life-saving drugs, t...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2019.00308

    authors: Bereshchenko O,Migliorati G,Bruscoli S,Riccardi C

    更新日期:2019-03-27 00:00:00

  • ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients.

    abstract::Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan ...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2020.00973

    authors: Riera P,Artigas-Baleri A,Salazar J,Sebio A,Virgili AC,Arranz MJ,Páez D

    更新日期:2020-06-30 00:00:00

  • In Vivo Cannabidiol Treatment Improves Endothelium-Dependent Vasorelaxation in Mesenteric Arteries of Zucker Diabetic Fatty Rats.

    abstract::Background and purpose: We have shown that in vitro treatment with cannabidiol (CBD, 2 h) enhances endothelial function in arteries from Zucker diabetic fatty (ZDF) rats, partly due to a cyclooxygenase (COX)-mediated mechanism. The aim of the present study was to determine whether treatment with CBD in vivo would also...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00248

    authors: Wheal AJ,Jadoon K,Randall MD,O'Sullivan SE

    更新日期:2017-05-18 00:00:00

  • The Bone Extracellular Matrix in Bone Formation and Regeneration.

    abstract::Bone regeneration repairs bone tissue lost due to trauma, fractures, and tumors, or absent due to congenital disorders. The extracellular matrix (ECM) is an intricate dynamic bio-environment with precisely regulated mechanical and biochemical properties. In bone, ECMs are involved in regulating cell adhesion, prolifer...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2020.00757

    authors: Lin X,Patil S,Gao YG,Qian A

    更新日期:2020-05-26 00:00:00

  • Internalized Functional DNA Aptamers as Alternative Cancer Therapies.

    abstract::Despite major advances, cancer remains one of the largest burdens of disease worldwide. One reason behind this is that killing tumor cells without affecting healthy surrounding tissue remains a largely elusive prospect, despite the widespread availability of cytotoxic chemotherapeutic agents. To meet these modern heal...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审

    doi:10.3389/fphar.2020.01115

    authors: Marshall ML,Wagstaff KM

    更新日期:2020-07-24 00:00:00

  • The Effect of Pungent and Tingling Compounds from Piper nigrum L. on Background K+ Currents.

    abstract::Black peppercorns (Piper nigrum L.) elicit a pungent and tingling oral impression. Their pungency is partially explained by the agonist activity of some of their active principles, especially piperine, on TRP channels. However, we recently showed that piperine, as well as other pungent compounds, also possess a marked...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章

    doi:10.3389/fphar.2017.00408

    authors: Beltrán LR,Dawid C,Beltrán M,Levermann J,Titt S,Thomas S,Pürschel V,Satalik M,Gisselmann G,Hofmann T,Hatt H

    更新日期:2017-06-26 00:00:00