scholarly journals The Role of PPARs in Lung Fibrosis

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-10 ◽  
Author(s):  
Heather F. Lakatos ◽  
Thomas H. Thatcher ◽  
R. Matthew Kottmann ◽  
Tatiana M. Garcia ◽  
Richard P. Phipps ◽  
...  
Keyword(s):  
Wound Healing ◽  
Animal Models ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Cardiac Fibrosis ◽  
Rapid Development ◽  
Critical Role ◽  
Normal Lung ◽  
Peroxisome Proliferator ◽  
Ongoing Research

Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARαagonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARαagonist significantly inhibited the fibrotic response, while PPARαknockout mice developed more serious fibrosis. PPARβ/δappears to play a critical role in regulating the transition from inflammation to wound healing. PPARβ/δagonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARγagonists. PPARγligands oppose the profibrotic effect of TGF-β, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARγligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARαand PPARγagonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.

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 Itaconate controls the severity of pulmonary fibrosis

2020 ◽  
Vol 5 (52) ◽  
pp. eabc1884 ◽  
Author(s):  
Patricia P. Ogger ◽  
Gesa J. Albers ◽  
Richard J. Hewitt ◽  
Brendan J. O’Sullivan ◽  
Joseph E. Powell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Therapeutic Strategy ◽  
Lung Fibroblasts ◽  
Disease Phenotype ◽  
Wild Type

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1−/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1−/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

A Comprehensive Review on Preclinical Diabetic Models

2020 ◽  
Vol 16 (2) ◽  
pp. 104-116
Author(s):  
Anshul Shakya ◽  
Sushil Kumar Chaudary ◽  
Debapriya Garabadu ◽  
Hans Raj Bhat ◽  
Bibhuti Bhusan Kakoti ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Ongoing Research ◽  
Chronic Hyperglycemia ◽  
Limited Effectiveness

Background: Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. Introduction: Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. Methods: The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. Results: A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. Conclusion: This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.

scholarly journals miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions

2017 ◽  
Vol 312 (3) ◽  
pp. L415-L424 ◽  
Author(s):  
Huachun Cui ◽  
Jing Ge ◽  
Na Xie ◽  
Sami Banerjee ◽  
Yong Zhou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Aged Population ◽  
Age Related ◽  
Micro Rnas ◽  
Lung Epithelial

Idiopathic pulmonary fibrosis is a well-known age-related disease. However, much less recognized has been the aging associated pathogenesis of this disorder. As we and others previously showed that dysregulation of micro-RNAs (miRNAs) was an important mechanism involved in pulmonary fibrosis, the role of these molecules in this pathology in the aged population has not been investigated (Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lü J. Am J Respir Cell Mol Biol 45: 287–294, 2011; Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E. J Exp Med 207: 1589–1597, 2010; Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, Richards T, Selman M, Watkins SC, Pardo A, Ben-Yehudah A, Bouros D, Eickelberg O, Ray P, Benos PV, Kaminski N. Am J Respir Crit Care Med 182: 220–229, 2010). In this study, by using a lung fibrosis model established in old mice, we found that ablation of miR-34a protected aged animals from developing experimental lung fibrosis. miR-34a was upregulated in lung epithelial cells, but not in lung fibroblasts of aged mice, and miR-34a expression was further increased in epithelial cells of the fibrotic lungs of these old animals. We found that miR-34a induced dysfunctions in alveolar epithelial cells (AECs), as evidenced by increased cellular senescence and apoptosis and mitochondrial aberrations. More importantly, these abnormalities were attenuated in AECs of the fibrotic lungs of aged miR-34a−/− mice. We found that miR-34a targeted Sirt1, a master anti-aging regulator, and two key cell cycle modulators, E2F3 and cyclin E2, in lung epithelial cells, and the repression of these targets was relieved in miR-34a-deficient AECs. In summary, our data suggest that elevated AEC miR-34a plays a critical role in the pathogenesis of pulmonary fibrosis in the aged population. Our study also indicates miR-34a to be a more precise miRNA target for treating this disease that overwhelmingly affects people of advanced age.

Surfactant alterations and lung fibrosis in a murine model of amiodarone-induced pulmonary fibrosis

Pneumologie ◽  
2008 ◽  
Vol 62 (S 2) ◽  
Author(s):  
P Mahavadi ◽  
L Schwertner ◽  
T Morky ◽  
I Henneke ◽  
M Korfei ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Murine Model ◽  
Lung Fibrosis

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 Zebrafish Models of Autosomal Recessive Ataxias

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 836
Author(s):  
Ana Quelle-Regaldie ◽  
Daniel Sobrido-Cameán ◽  
Antón Barreiro-Iglesias ◽  
María Jesús Sobrido ◽  
Laura Sánchez
Keyword(s):  
Animal Models ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
System Development ◽  
Rapid Development ◽  
Nervous System Development ◽  
Central Nervous System Development ◽  
Cellular Processes ◽  
Recessive Disorders

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

scholarly journals [18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach

2021 ◽  
Author(s):  
Julie Tanguy ◽  
Françoise Goirand ◽  
Alexanne Bouchard ◽  
Jame Frenay ◽  
Mathieu Moreau ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Disease Progression ◽  
Lung Fibrosis ◽  
Ct Imaging ◽  
Significant Feature ◽  
Preclinical Model ◽  
Lung Density ◽  
Intratracheal Administration ◽  
Therapy Efficacy ◽  
Pet Ct

Abstract Purpose Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG. Methods Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. Results We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. Conclusion [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.

scholarly journals Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
D. J. Leeming ◽  
F. Genovese ◽  
J. M. B. Sand ◽  
D. G. K. Rasmussen ◽  
C. Christiansen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Extracellular Matrix ◽  
Wound Healing ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Interstitial Lung Diseases ◽  
Lessons Learned ◽  
Lung Function Decline ◽  
Tissue Remodelling

AbstractPulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor’s consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.

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