Toll-like receptors in the pathogenesis of pulmonary fibrosis

Karampitsakos, Theodoros; Woolard, Tony; Bouros, Demosthenes; Τzouvelekis, Αrgyris

doi:10.1016/j.ejphar.2016.06.045

Cited by 61 publications

(41 citation statements)

References 124 publications

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“…Pirfenidone was the first drug to be approved for the treatment of IPF in the European Union in 2011 ( 12 ). Pirfenidone represents an oral pyridine with anti-fibrotic, anti-inflammatory, and anti-oxidant properties in experimental models of lung fibrosis ( 13 – 15 ); yet, its exact mechanism of action is currently unknown ( 16 , 17 ). Importantly, pirfenidone has been clinically evaluated and has shown beneficial effects in patients with IPF in five randomized controlled trials comprising 1,710 patients ( 18 – 20 ).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal “Real-World” Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece

et al. 2017

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BackgroundPirfenidone is an antifibrotic compound able to slow down disease progression in patients with idiopathic pulmonary fibrosis (IPF).ObjectiveTo investigate the safety and efficacy of pirfenidone in patients with IPF in a real-life setting.MethodsThis was a multicenter, retrospective, real-life, observational study for patients with IPF receiving pirfenidone.ResultsWe identified 92 patients with IPF receiving pirfenidone. Eighty patients (70 males and 10 females, mean age ± SD: 68.1 + 7.5, mean %FVC ± SD = 74.9 ± 17.2, mean %DLCO ± SD = 48.1 ± 16.9) were included in the analysis. Skin-related (25%) and gastrointestinal (17.5%) adverse events were the most common and led to drug discontinuation in 22.5% of cases. The majority (87%) of patients experienced side effects during the first 6 months of treatment. At 36 months, changes in %FVC and %DLCO were −9.25 ± 16.34 and −9.26 ± 15.26, respectively. At 6, 12, and 24 months after treatment initiation (n = 80, 60, and 26), 18, 15, and 5 patients (22.5, 25, and 19.2%) experienced significant (>10%) and 11, 3, and 3 patients (13.8, 5, and 11.5%) experienced marginal (5–10%) %FVC improvement; and 13, 6, and 1 patient (16.2, 10, and 3.9%) experienced marginal (−5 to −10%) and 20, 21, and 8 patients (25, 35, and 30.8%) experienced significant decline (<−10%) in %FVCpred. Median survival was 851 days, and 41 patients died during the study period.ConclusionPirfenidone demonstrated an acceptable safety and therapeutic profile in patients with IPF on a longitudinal basis. Prospective observational registries are urgently needed to provide a real-world view of outcomes of pirfenidone in clinical practice.

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Section: Introductionmentioning

confidence: 99%

Longitudinal “Real-World” Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece

et al. 2017

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“…Current evidence suggests that the areas of fibrosis seen in lungs of patients with IPF share many features with normal aging lung, such as genomic instability, telomere attrition, mitochondrial dysfunction, cellular senescence, and immune dysregulation ( 10 , 15 , 16 ). Due to the inefficacy of immunomodulatory and immunosuppressive agents in the past, the role of the immune system in the pathogenesis of IPF remains poorly understood ( 17 – 22 ).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells for the Treatment of Idiopathic Pulmonary Fibrosis

et al. 2018

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Idiopathic pulmonary fibrosis (IPF) is an inexorably progressive lung disease of unknown origin. Prognosis is poor, with limited treatment options available, and the median survival remains just 3–5 years. Despite the use of pirfenidone and nintedanib for the treatment of IPF, curative therapies remain elusive and mortality remains high. Regenerative medicine and the use of cell-based therapies has recently emerged as a potential option for various diseases. Promising results of preclinical studies using mesenchymal stem cells (MSCs) suggest that they may represent a potential therapeutic option for the treatment of chronic lung diseases including IPF. Encouraging results of Phase 1 studies of MSCs various have reduced safety concerns. Nonetheless, there is still a pressing need for exploratory biomarkers and interval end-points in the context of MSCs investigation. This review intends to summarize the current state of knowledge for stem cells in the experimental and clinical setting of IPF, present important safety and efficacy issues, highlight future challenges and address the need for large, multicenter clinical trials coupled with realistic end-points, including biomarkers, to assess treatment efficacy.

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“…Because the respiratory airways are constantly exposed to environmental pathogens and other elements, TLRs play a crucial role in innate immunity to endogenous and exogenous ligands (81). TLR2 and TLR4 have been shown to trigger immune and fibrotic responses in PF (82). TLR4 activation induces the release of profibrotic and proangiogenic chemokines from antifibroblast antibodies stimulated fibroblasts (83).…”

Section: Tlr8: Autoimmunity Fibrosis and Angiogenesismentioning

confidence: 99%

Prominence of IL6, IGF, TLR, and Bioenergetics Pathway Perturbation in Lung Tissues of Scleroderma Patients With Pulmonary Fibrosis

et al. 2020

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Scleroderma-associated pulmonary fibrosis (SSc-PF) and idiopathic pulmonary fibrosis (IPF) are two of many chronic fibroproliferative diseases that are responsible for nearly 45% of all deaths in developed countries. While sharing several pathobiological characteristics, they also have very distinct features. Currently no effective anti-fibrotic treatments exist that can halt the progression of PF or reverse it. Our goal is to uncover potential gene targets for the development of anti-fibrotic therapies efficacious in both diseases, and those specific to SSc-PF, by identifying universal pathways and molecules driving fibrosis in SSc-PF and IPF tissues as well as those unique to SSc-PF. Using DNA microarray data, a meta-analysis of the differentially expressed (DE) genes in SSc-PF and IPF lung tissues (diseased vs. normal) was performed followed by a full systems level analysis of the common and unique transcriptomic signatures obtained. Protein-protein interaction networks were generated to identify hub proteins and explore the data using the centrality principle. Our results suggest that therapeutic strategies targeting IL6 trans-signaling, IGFBP2, IGFL2, and the coagulation cascade may be efficacious in both SSc-PF and IPF. Further, our data suggest that the expression of matrikine-producing collagens is also perturbed in PF. Lastly, an overall perturbation of bioenergetics, specifically between glycolysis and fatty acid metabolism, was uncovered in SSc-PF. Our findings provide insights into potential targets for the development of anti-fibrotic therapies that could be effective in both IPF and SSc-PF.

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Toll-like receptors in the pathogenesis of pulmonary fibrosis

Cited by 61 publications

References 124 publications

Longitudinal “Real-World” Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece

Longitudinal “Real-World” Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece

Mesenchymal Stem Cells for the Treatment of Idiopathic Pulmonary Fibrosis

Prominence of IL6, IGF, TLR, and Bioenergetics Pathway Perturbation in Lung Tissues of Scleroderma Patients With Pulmonary Fibrosis

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