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Inflammatory response and hypoxia are dominant risk factors for patients with idiopathic pulmonary fibrosis (IPF) in the training cohort. (A) Univariate Cox regression analysis for the prognostic value of various hallmarks. Red, p < 0.05; grey, p > 0.05. (B) Spearman correlation analysis was performed to construct a correlation network for prognosis-related hallmarks. (C) Multivariate Cox regression analyses of clinical factors and the inflammatory response and hypoxia-related signature. (D) Kaplan–Meier survival analysis of the single-sample gene set enrichment analysis (ssGSEA) score of hypoxias for overall survival. (E) Kaplan–Meier survival analysis of the ssGSEA score of inflammatory response for overall survival.
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Currently, the aetiology and pathogenesis of idiopathic pulmonary fibrosis (IPF) are still largely unclear. Moreover, patients with IPF exhibit a considerable difference in clinical presentation, treatment, and prognosis. Optimal biomarkers or models for IPF prognosis are lacking. Therefore, this study quantified the levels of various hallmarks usi...
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... Studies have established a robust method to predict clinical outcomes in IPF patients based on inflammation and hypoxia related gene characteristics. Five genes, including HE4, were identified as inflammation hypoxia-related genes, which can accurately predict the clinical outcome of IPF patients [31]. Hence, we believe that HE4 may play a key [32]. ...
Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease. Identifying biomarkers for early diagnosis is of great clinical importance. The epididymis protein 4 (HE4) is important in the process of inflammation and fibrosis in the epididymis. Its prognostic value in IPF, however, has not been studied. The mRNA and protein levels of HE4 were used to determine the prognostic value in different patient cohorts. In this study, prognostic nomograms were generated based on the results of the cox regression analysis. We identified the HE4 protein level increased in IPF patients, but not the HE4 gene expression. The increased expression of HE4 correlated positively with a poor prognosis for patients with IPF. The HR and 95% CI were 2.62 (1.61–4.24) (p < 0.001) in the training set. We constructed a model based on the risk-score = 0.16222182 * HE4 + 0/0.37580659/1.05003609 (for GAP index 0–3/4–5/6–8) + (− 1.1183375). In both training and validation sets, high-risk patients had poor prognoses (HR: 3.49, 95%CI 2.10–5.80, p = 0.001) and higher likelihood of dying (HR: 6.00, 95%CI 2.04–17.67, p = 0.001). Analyses of calibration curves and decision curves suggest that the method is effective in predicting outcomes. Furthermore, a similar formulation was used in a protein-based model based on HE4 that also showed prognostic value when applied to IPF patients. Accordingly, HE4 is an independent poor prognosis factor, and it has the potential to predict IPF patient survival.
... Network-based methods on the other hand amount to pathway-based gene selection approaches [8] as they consider the strength of interactions and intramodular connectivity between the genes and are therefore known to produce biologically meaningful gene lists. Recent attempts have been made to analyze gene coexpression networks to detect key genes, pathways, and regulatory factors in IPF [9][10][11][12][13][14]. These modules are often strongly enriched for distinct functional categories, phenotypegenotype associations, or cell type markers. ...
Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease characterized by irreversible scarring of the lung parenchyma leading to dyspnea, progressive decline in lung function, and respiratory failure. We analyzed lung transcriptomic data from independent IPF cohorts using weighted gene co-expression network analysis (WGCNA) to identify gene modules based on their preservation status in these cohorts. The consensus gene modules were characterized by leveraging existing clinical and molecular data such as lung function, biological processes, pathways, and lung cell types. From a total of 32 consensus gene modules identified, two modules were found to be significantly correlated with the disease, lung function, and preserved in other IPF datasets. The upregulated gene module was enriched for extracellular matrix, collagen metabolic process, and BMP signaling while the downregulated module consisted of genes associated with tube morphogenesis, blood vessel development, and cell migration. Using a combination of connectivity-based and trait-based significance measures, we identified and prioritized 103 “hub” genes (including 25 secretory candidate biomarkers) by their similarity to known IPF genetic markers. Our validation studies demonstrate the dysregulated expression of CRABP2, a retinol-binding protein, in multiple lung cells of IPF, and its correlation with the decline in lung function.
Fibrosis is a pathological condition characterized by the excessive deposition of extracellular matrix components in tissues and organs, leading to progressive architectural remodelling and contributing to the development of various diseases. Osteopontin (OPN), a highly phosphorylated glycoprotein, has been increasingly recognized for its involvement in the progression of tissue fibrosis. This review provides a comprehensive overview of the genetic and protein structure of OPN and focuses on our current understanding of the role of OPN in the development of fibrosis in the lungs and other tissues. Additionally, special attention is given to the potential of OPN as a biomarker and a novel therapeutic target in the treatment of fibrosis.
La fibrose pulmonaire idiopathique (FPI) est une maladie chronique, évolutive et mortelle d'origine inconnue. En France, elle figure parmi les pathologies interstitielles (PI) les plus fréquentes et touche 4400 nouvelles personnes chaque année. La FPI est caractérisée par des mécanismes de cicatrisation dérégulés qui induisent l'accumulation de grandes quantités de collagène dans le tissu pulmonaire et provoquent une désorganisation de l'architecture alvéolaire. Elle se manifeste par une détérioration progressive de la fonction respiratoire, conduisant en quelques années à une insuffisance respiratoire chronique puis au décès. Le taux de survie de la fibrose pulmonaire idiopathique est inférieur à celui de nombreux cancers avec une survie médiane de 2 à 5 ans à partir du diagnostic. Cette pathologie, dont le principal facteur de risque outre les facteurs génétiques et environnementaux (cigarette, pollution, etc.) reste l’âge, se manifeste rarement avant 60 ans. Malgré les avancées thérapeutiques récentes réalisées dans le domaine de la fibrose, la FPI reste une maladie incurable et létale. La prise en charge tardive des patients, la complexité du diagnostic et le manque de solutions thérapeutiques et diagnostiques précoces sont autant de points qui expliquent la mortalité associée à cette pathologie. Aujourd’hui, il reste crucial de continuer à identifier les acteurs cellulaires et moléculaires du développement de la FPI afin, d’une part, de développer de nouveaux traitements inhibiteurs et d’autre part, de mettre au point de nouveaux outils diagnostiques plus précoces. Dans ce contexte, l’étude du rôle des protéines de choc thermique HSPB5 et HSP90 dans la FPI ainsi que des marqueurs de l’hypoxie pourraient apporter de nouvelles solutions thérapeutiques et diagnostiques. L'imagerie de la FPI est en pratiquelimitée à la tomodensitométrie à haute résolution (HRCT). Cet examen reste souvent insuffisant pour un diagnostic définitif de la maladie et a un impact limité sur la décision thérapeutique et la prise en charge des patients. L'hypoxie pulmonaire est une caractéristique importante de la FPI, mais son rôle sur la progression de la maladie reste méconnu. Ainsi à l’aide d’un modèle préclinique de fibrose pulmonaire induite par la bléomycine nous avons déterminé in vivo que l’imagerie de l'hypoxie au 18FFMISOpouvait constituer un biomarqueur prédictif de la progression de la maladie et de l'efficacité des traitements par rapport à un autre marqueur utilisé en clinique le 18F-FDG. Nous avons également montré in vivo dans notre modèle murin que l’administration d’un inhibiteur (le NCI-41356) de HSPB5, une protéine de choc thermique de bas poids moléculaire connue pour être impliquée dans le développement de la fibrose, permet de réduire la fibrose en modulant l’expression de plusieurs facteurs pro-fibrotiques dont le TGF-Beta;. De plus, nous avons montré qu’inhiber la protéine HSP90, surexprimée à la fois au niveau circulant et au sein des tissus fibrotiques des patients atteints de FPI, présente un potentiel intérêt théranostique.En conclusion, ce travail de thèse a permis de caractériser un potentiel traceur radiopharmaceutique précoce et prédictif de l’évolution de la fibrose pulmonaire ainsi que le rôle anti-fibrotique d’un inhibiteur chimique de la voie canonique du TGF-Beta;. Par ailleurs nous espérons que nos résultats concernant la protéine HSP90 pourraient permettre d’envisager l’utilisation théranostique d’anticorps recombinant dirigés contre HSP90 dans le contexte de la FPI.
