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BMC Pulmonary Medicine Dec 2021Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic... (Comparative Study)
Comparative Study Meta-Analysis
Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis.
BACKGROUND
Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF.
STUDY DESIGN AND METHODS
A search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies.
RESULTS
13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was - 0.305 (SE 0.043) (p < 0.001) and in the non-IPF studies the figures were - 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71.
INTERPRETATION
Anti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy. Trial Registration PROSPERO, registration number CRD42021266046.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antifibrotic Agents; Cause of Death; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pulmonary Fibrosis; Pyridones; Treatment Outcome
PubMed: 34895203
DOI: 10.1186/s12890-021-01783-1 -
Biomedicine & Pharmacotherapy =... Sep 2022Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies...
BACKGROUND
Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies have found that IGU has certain advantages in improving lung function and shows great potential for pulmonary fibrosis therapy. However, the specific mechanism is not clear. This study was designed to observe and investigate the therapeutic effects of IGU on bleomycin-induced pulmonary fibrosis and further investigate its underlying mechanism.
METHODS
A mouse model of pulmonary fibrosis was induced by intratracheal injection of bleomycin (BLM). Model mice were randomly assigned to receive different concentrations of IGU. A TGF-β (T)-induced A549 epithelial-mesenchymal transition (EMT) cell model was utilized to investigate the effects of IGU on EMT in vitro. The NLRP3 inflammasome was activated by the costimulation of LPS+ATP (LA) to evaluate the effects of IGU in vitro.
RESULTS
We found that IGU resulted in favourable therapeutic outcomes by affecting inflammatory infiltration and collagen deposition. Additionally, the markers of the BLM-mediated EMT phenotype and NLRP3-activated phenotype in the lung were also attenuated after IGU administration. In vitro experiments, the results confirmed its anti-EMT and anti-NLRP3 inflammasome activation effects.We then found that the anti-lung fibrosis effect of IGU was accompanied by a decrease in reactive oxygen species (ROS) production.
CONCLUSION
IGU can inhibit the EMT process and NLRP3 inflammasome activation and reduce ROS production to ameliorate pulmonary fibrosis, which may provide new insights into the further application of IGU in interstitial pulmonary fibrosis.
Topics: Animals; Bleomycin; Chromones; Epithelial-Mesenchymal Transition; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Fibrosis; Reactive Oxygen Species; Sulfonamides
PubMed: 36076570
DOI: 10.1016/j.biopha.2022.113460 -
Frontiers in Immunology 2023Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast.... (Review)
Review
Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast. While Pirfenidone and Nintedanib are FDA-approved drugs that can slow down the progression of pulmonary fibrosis, they are unable to reverse the disease. Therefore, there is an urgent demand to develop more efficient therapeutic approaches for pulmonary fibrosis. The intracellular DNA sensor called cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays a crucial role in detecting DNA and generating cGAMP, a second messenger. Subsequently, cGAMP triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases. This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis. Moreover, we discuss the potential therapeutic implications of targeting the cGAS-STING pathway, including the utilization of inhibitors of cGAS and STING.
Topics: Humans; Chromogranin A; DNA; Nucleotidyltransferases; Pulmonary Fibrosis; Second Messenger Systems; Signal Transduction
PubMed: 37965345
DOI: 10.3389/fimmu.2023.1273248 -
EBioMedicine Sep 2023Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous, unpredictable and ultimately lethal chronic lung disease. Over the last decade, two anti-fibrotic agents... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous, unpredictable and ultimately lethal chronic lung disease. Over the last decade, two anti-fibrotic agents have been shown to slow disease progression, however, both drugs are administered uniformly with minimal consideration of disease severity and inter-individual molecular, genetic, and genomic differences. Advances in biological understanding of disease endotyping and the emergence of precision medicine have shown that "a one-size-fits-all approach" to the management of chronic lung diseases is no longer appropriate. While precision medicine approaches have revolutionized the management of other diseases such as lung cancer and asthma, the implementation of precision medicine in IPF clinical practice remains an unmet need despite several reports demonstrating a large number of diagnostic, prognostic and theragnostic biomarker candidates in IPF. This review article aims to summarize our current knowledge of precision medicine in IPF and highlight barriers to translate these research findings into clinical practice.
Topics: Humans; Precision Medicine; Lung Neoplasms; Asthma; Genomics; Idiopathic Pulmonary Fibrosis
PubMed: 37625268
DOI: 10.1016/j.ebiom.2023.104766 -
Life Sciences Feb 2022Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer.... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer. Environmental and genetic predisposition are the two major etiological or risk factors involved in the pathology of the IPF. Among the environmental risk factors, smoking is one of the major causes for the development of IPF. Epigenetic pathways like nucleosomes remodeling, DNA methylation, histone modifications and miRNA mediated genes play a crucial role in development of IPF. Mutations in the genes make the epigenetic factors as important drug targets in IPF. Transcriptional changes due to environmental factors are also involved in the progression of IPF. The mutations in human telomerase reverse transcriptase (hTERT) have shown decreased life expectancy in IPF patients. The TERT-gene is highly expressed in chronic smokers and makes the role of epigenetics evident. Drug like nintedanib acts through vascular endothelial growth factor receptors (VEGFR), while drug pirfenidone acts through transforming growth factor (TGF), which is useful in IPF. Gefitinib, a tyrosine kinase inhibitor of EGFR, is useful as an anti-fibrosis agent in preclinical models. Newer drugs such as Celgene-CC90001 and FibroGen-FG-3019 are currently under investigations acts through the modulating epigenetic mechanisms. Thus, the study on epigenetics opens a wide window for the discovery of newer drugs. This study provides an elementary analysis of multiple regulators of epigenetics and their roles associated with the pathology of IPF. Further, this review also includes epigenetic drugs under development in preclinical and clinical stages.
Topics: DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis
PubMed: 34998839
DOI: 10.1016/j.lfs.2021.120283 -
The Veterinary Clinics of North... Mar 2020Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease (ILD) affecting older West Highland white terriers (WHWTs). According to... (Review)
Review
Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease (ILD) affecting older West Highland white terriers (WHWTs). According to one classification, CIPF is a familial fibrotic ILD in the group of idiopathic interstitial pneumonias. Etiology is unknown but likely arises from interplay between genetic and environmental factors. CIPF shares features with human idiopathic pulmonary fibrosis and human nonspecific interstitial pneumonia. This article describes clinical signs, findings in physical examination, arterial oxygenation, diagnostic imaging, bronchoscopy, bronchoalveolar lavage, histopathology, disease course, and outcome of WHWTs with CIPF; compares canine and human diseases; summarizes biomarker research; and gives an overview of potential treatment.
Topics: Animals; Dog Diseases; Dogs; Idiopathic Pulmonary Fibrosis; Prognosis
PubMed: 31866093
DOI: 10.1016/j.cvsm.2019.11.004 -
Experimental & Molecular Medicine Dec 2020Spermidine is an endogenous biological polyamine that plays various longevity-extending roles and exerts antioxidative, antiaging, and cell growth-promoting effects. We...
Spermidine is an endogenous biological polyamine that plays various longevity-extending roles and exerts antioxidative, antiaging, and cell growth-promoting effects. We previously reported that spermidine levels were significantly reduced in idiopathic pulmonary fibrosis (IPF) of the lung. The present study assessed the potential beneficial effects of spermidine on lung fibrosis and investigated the possible mechanism. Lung fibrosis was established in mice using bleomycin (BLM), and exogenous spermidine was administered daily by intraperitoneal injection (50 mg/kg in phosphate-buffered saline). BLM-induced alveolar epithelial cells showed significant increases in apoptosis and endoplasmic reticulum stress (ERS)-related mediators, and spermidine attenuated BLM-induced apoptosis and activation of the ERS-related pathway. Senescence-associated β-gal staining and decreased expression of p16 and p21 showed that spermidine ameliorated BLM-induced premature cellular senescence. In addition, spermidine enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts and BLM-induced mouse lungs, in which inflammation and collagen deposition were significantly decreased. This beneficial effect was related to the antiapoptotic downregulation of the ERS pathway, antisenescence effects, and autophagy activation. Our findings suggest that spermidine could be a therapeutic agent for IPF treatment.
Topics: Animals; Autophagy; Biomarkers; Bleomycin; Cell Death; Cellular Senescence; Cytokines; Disease Models, Animal; Endoplasmic Reticulum Stress; Fibroblasts; Inflammation Mediators; Mice; Protective Agents; Pulmonary Fibrosis; Spermidine
PubMed: 33318630
DOI: 10.1038/s12276-020-00545-z -
Small (Weinheim An Der Bergstrasse,... Jul 2023Pulmonary fibrosis, a sequela of lung injury resulting from severe infection such as severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) infection, is a kind...
Pulmonary fibrosis, a sequela of lung injury resulting from severe infection such as severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) infection, is a kind of life-threatening lung disease with limited therapeutic options. Herein, inhalable liposomes encapsulating metformin, a first-line antidiabetic drug that has been reported to effectively reverse pulmonary fibrosis by modulating multiple metabolic pathways, and nintedanib, a well-known antifibrotic drug that has been widely used in the clinic, are developed for pulmonary fibrosis treatment. The composition of liposomes made of neutral, cationic or anionic lipids, and poly(ethylene glycol) (PEG) is optimized by evaluating their retention in the lung after inhalation. Neutral liposomes with suitable PEG shielding are found to be ideal delivery carriers for metformin and nintedanib with significantly prolonged retention in the lung. Moreover, repeated noninvasive aerosol inhalation delivery of metformin and nintedanib loaded liposomes can effectively diminish the development of fibrosis and improve pulmonary function in bleomycin-induced pulmonary fibrosis by promoting myofibroblast deactivation and apoptosis, inhibiting transforming growth factor 1 (TGFβ1) action, suppressing collagen formation, and inducing lipogenic differentiation. Therefore, this work presents a versatile platform with promising clinical translation potential for the noninvasive inhalation delivery of drugs for respiratory disease treatment.
Topics: Humans; Pulmonary Fibrosis; Liposomes; COVID-19; SARS-CoV-2; Lung; Fibrosis; Metformin
PubMed: 37058092
DOI: 10.1002/smll.202300545 -
Science Immunology Dec 2022Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to...
Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs. Here, we define a critical role of epiregulin-EGFR signaling between dendritic cells and fibroblasts to maintain elevated ECM production and accumulation in fibrotic tissue. We found that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon and that DC3-derived epiregulin activates EGFR on fibroblasts, driving a positive feedback loop through NOTCH signaling. In mouse models of skin and lung fibrosis, epiregulin was essential for persistence of fibrosis in both tissues, which could be abrogated by epiregulin genetic deficiency or a neutralizing antibody. Therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a previously unexplored biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and represents a promising antifibrotic target.
Topics: Mice; Animals; Pulmonary Fibrosis; Ligands; Skin; Fibrosis; Dendritic Cells
PubMed: 36490328
DOI: 10.1126/sciimmunol.abq6691 -
JCI Insight Nov 2022Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an...
Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that TGF-β1-mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts. Thus, intravenous administration of UHRF1 siRNA-loaded liposomes significantly protected mice against experimental pulmonary fibrosis. Accordingly, our data suggest that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.
Topics: Mice; Animals; CCAAT-Enhancer-Binding Proteins; Pulmonary Fibrosis; RNA, Small Interfering; Ubiquitin-Protein Ligases; Fibroblasts
PubMed: 36166308
DOI: 10.1172/jci.insight.162831