Idiopathic Pulmonary Fibrosis Genetic Risk Factors, Function, and Mechanisms? The Concepts Are Starting to Gel.
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ABSTRACT:
SUBMITTER: Bonham CA
PROVIDER: S-EPMC9746834 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
Publications
Idiopathic Pulmonary Fibrosis Genetic Risk Factors, Function, and Mechanisms? The Concepts Are Starting to Gel.
Bonham Catherine A CA Noth Imre I
American journal of respiratory and critical care medicine 20221101 10
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Project description:Idiopathic pulmonary fibrosis is an etiologically complex interstitial lung disease characterized by progressive scarring of the lungs with a subsequent decline in lung function. While much of the pathogenesis of IPF still remains unclear, it is now understood that genetic variation accounts for at least one-third of the risk of developing the disease. The single-most validated and most significant risk factor, genetic or otherwise, is a gain-of-function promoter variant in the MUC5B gene. While the functional impact of these IPF risk variants at the cellular and tissue levels are areas of active investigation, there is a growing body of evidence that these genetic variants may influence disease pathogenesis through modulation of innate immune processes.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic 'reaction' patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in T(H)1/T(H)2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.
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Project description:The prevalence of abnormal acid gastroesophageal reflux (GER) is higher in patients with idiopathic pulmonary fibrosis (IPF) than in matched control subjects. Several studies demonstrated that more than one-third of patients with IPF have abnormal esophageal acid exposures. In addition, many of these studies indicate that the majority of patients with IPF have silent reflux with no symptoms of GER. Findings of abnormal reflux persist in a large proportion of patients with IPF placed on antacid therapy such as proton pump inhibitors (PPIs). This seemingly paradoxical observation suggests that either patients with IPF are somehow resistant to PPI-based intervention or PPIs are inherently unable to suppress acid GER. By contrast, patients with IPF who undergo Nissen fundoplication surgery are effectively relieved from the complications of GER, and retrospective studies suggest improved lung function. Retrospective, anecdotal data suggest a beneficial role of PPIs in IPF including stabilization of lung function, reduction in episodes of acute exacerbation, and enhanced longevity. The recent evidence-based guidelines for treatment of IPF approved conditional recommendation of PPIs for all patients with IPF regardless of their GER status. Recently, we have reported that PPIs possess antiinflammatory and antifibrotic activities by directly suppressing proinflammatory cytokines, profibrotic proteins, and proliferation of lung fibroblasts. Our study provides an alternative explanation for the beneficial effect of PPIs in IPF. In this Perspective, we reviewed emerging progress on antifibrotic effect of PPIs using IPF as a disease model. In addition, we summarized surgical and pharmacological interventions for GER and their downstream effect on lung physiology.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.
| S-EPMC8142468 | biostudies-literature
Project description:Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis.
| S-EPMC4849867 | biostudies-literature
Project description:The discovery of shared genetic associations, with sometimes different directions of effect, has implications for drug target discovery for idiopathic pulmonary fibrosis and systemic hypertension https://bit.ly/45IqbRv.
| S-EPMC10641590 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a complex, heterogeneous genetic disorder that is associated with rare and common sequence variants in many genes (MUC5B, SFTPC, SFTPA2, RTEL1, TERT, and hTR), 11 novel loci, and multiple emerging epigenetic and transcriptional profiles. In the past 5 years, we have found that: 1) genetic risk variants play major and similar roles in the development of both familial and sporadic fibrotic idiopathic interstitial pneumonia, accounting for up to 35% of the risk of idiopathic interstitial pneumonia (a disease that was previously thought to be idiopathic); 2) a promoter variant in MUC5B rs35705950 is the strongest risk factor for the development of IIP and IPF; however, rs35705950 has a low penetrance; and 3) IPF is a complex genetic disease with 11 independent loci contributing to the development of this disease, pronounced changes in DNA methylation, and transcriptional subtypes. In aggregate, these findings suggest that IPF is a heterogeneous disease and that genetic and molecular subtypes of IPF will provide essential clues to disease pathogenesis, prognosis, treatment, and survival, all of which remain major problems in understanding and treating patients with IPF. Although the basic biological mechanisms involved in IPF are emerging, the disease is heterogeneous pathologically and the final common pathways of fibrogenesis are not well understood. These observations lead us to postulate that the etiology and severity/extent of this complex condition will best be understood through an integrated approach that accounts for inherited factors, epigenetic marks, and dynamic changes in the transcriptome.
| S-EPMC5216513 | biostudies-literature
Project description:Background: Idiopathic pulmonary fibrosis (IPF) leads to excessive fibrous tissue in the lungs, increasing the risk of lung cancer (LC) due to heightened fibroblast activity. Advances in nucleotide point mutation studies offer insights into fibrosis-to-cancer transitions. Methods: A two-sample Mendelian randomization (TSMR) approach was used to explore the causal relationship between IPF and LC. A weighted gene co-expression network analysis (WGCNA) identified shared gene modules related to immunogenic cell death (ICD) from transcriptomic datasets. Machine learning selected key genes, and a multi-layer perceptron (MLP) model was developed for IPF prediction and diagnosis. SMR and PheWAS were used to assess the expression of key genes concerning IPF risk. The impact of core genes on immune cells in the IPF microenvironment was explored, and in vivo experiments were conducted to examine the progression from IPF to LC. Results: The TSMR approach indicated a genetic predisposition for IPF progressing to LC. The predictive model, which includes eight ICD key genes, demonstrated a strong predictive capability (AUC = 0.839). The SMR analysis revealed that the elevated expression of MS4A4A was associated with an increased risk of IPF (OR = 1.275, 95% CI: 1.029-1.579; p = 0.026). The PheWAS did not identify any significant traits linked to MS4A4A expression. The rs9265808 locus in MS4A4A was identified as a susceptibility site for the progression of IPF to LC, with mutations potentially reprogramming lung neutrophils and increasing the LC risk. In vivo studies suggested MS4A4A as a promising therapeutic target. Conclusions: A causal link between IPF and LC was established, an effective prediction model was developed, and MS4A4A was highlighted as a therapeutic target to prevent IPF from progressing to LC.
| S-EPMC11504276 | biostudies-literature
Project description:Rationale: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonia. Some miRNAs may be associated with IPF and may affect the occurrence and development of IPF in various pathways. Many miRNAs and genes that may be involved in the development of IPF have been discovered using chip and high throughput technologies. Methods: We analyzed one miRNA and four mRNA databases. We identified hub genes and pathways related to IPF using GO, KEGG enrichment analysis, gene set variation analysis (GSVA), PPI network construction, and hub gene analysis. A comprehensive analysis of differentially expressed miRNAs (DEMs), predicted miRNA target genes, and differentially expressed genes (DEGs) led to the creation of a miRNA-mRNA regulatory network in IPF. Results: We found 203 DEGs and 165 DEMs that were associated with IPF. The findings of enrichment analyses showed that these DEGs were mainly involved in antimicrobial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptide, extracellular matrix organization, cell killing, and organ or tissue specific immune response. The VEGFA, CDH5, and WNT3A genes overlapped between hub genes and the miRNA-mRNA regulatory network. The miRNAs including miR-199b-5p, miR-140-5p, miR-199a-5p, miR-125A-5p, and miR-107 that we predicted would regulate the VEGFA, CDH5, and WNT3A genes, which were also associated with IPF or other fibrosis-related diseases. GSVA indicated that metabolic processes of UTP and IMP, immune response, regulation of Th2 cell cytokine production, and positive regulation of NK cell-mediated immunity are associated with the pathogenesis and treatment of IPF. These pathways also interact with VEGFA, CDH5, and WNT3A. Conclusion: These findings provide a new research direction for the diagnosis and treatment of IPF.
| S-EPMC8436110 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2⁻4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterations of growth factors expression, oxidative stress, and large genetic and epigenetic variations that can predispose the patient to develop IPF and LC. The current approved IPF therapies, pirfenidone and nintedanib, are also active in LC. In fact, nintedanib is approved as a second line treatment in NSCLC, and pirfenidone has shown anti-neoplastic effects in preclinical studies. In this review, we focus on the current knowledge on the mechanisms implicated in the development of LC in patients with IPF as well as in current IPF and LC-IPF candidate therapies based on novel molecular advances.
| S-EPMC6387034 | biostudies-literature