Hematopoietic and Lung Platelet Biogenesis as a Prognostic Indicator in Idiopathic Pulmonary Fibrosis.
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ABSTRACT:
SUBMITTER: Saito S
PROVIDER: S-EPMC9704823 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Hematopoietic and Lung Platelet Biogenesis as a Prognostic Indicator in Idiopathic Pulmonary Fibrosis.
Saito Shigeki S Chung Cheng Han H CHH Jacob Alex A Nuradin Nebil N Meyer Amy E AE Yang Haoran H Kolls Jay K JK Thannickal Victor J VJ Lasky Joseph A JA Saito Toshie T Liu Yao-Zhong YZ
American journal of respiratory and critical care medicine 20221101 9
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Project description:BackgroundGiven the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another.Research questionDo IPF endotypes exist and are they associated with outcome?Study design and methodsUsing a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples.ResultsOne hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes.InterpretationGene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.
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Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by abnormal fibroblast accumulation in the lung leading to extracellular matrix deposition and remodeling that compromise lung function. However, the mechanisms of interstitial invasion and remodeling by lung fibroblasts remain poorly understood. The invadosomes, initially described in cancer cells, consist of actin-based adhesive structures that coordinate with numerous other proteins to form a membrane protrusion capable of degrading the extracellular matrix to promote their invasive phenotype. In this regard, we hypothesized that invadosome formation may be increased in lung fibroblasts from patients with IPF. Public RNAseq datasets from control and IPF lung tissues were used to identify differentially expressed genes associated with invadosomes. Lung fibroblasts isolated from bleomycin-exposed mice and IPF patients were seeded with and without the two approved drugs for treating IPF, nintedanib or pirfenidone on fluorescent gelatin-coated coverslips for invadosome assays. Several matrix and invadosome-associated genes were increased in IPF tissues and in IPF fibroblastic foci. Invadosome formation was significantly increased in lung fibroblasts isolated from bleomycin-exposed mice and IPF patients. The degree of lung fibrosis found in IPF tissues correlated strongly with invadosome production by neighboring cells. Nintedanib suppressed IPF and PDGF-activated lung fibroblast invadosome formation, an event associated with inhibition of the PDGFR/PI3K/Akt pathway and TKS5 expression. Fibroblasts derived from IPF lung tissues express a pro-invadosomal phenotype, which correlates with the severity of fibrosis and is responsive to antifibrotic treatment.
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2015-12-04 | E-GEOD-75647 | biostudies-arrayexpress
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Project description:BackgroundDysregulation of lipid metabolism is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the association between the blood lipid profiles and the prognosis of IPF is not well defined. We aimed to identify the impacts of lipid profiles on prognosis in patients with IPF.MethodsClinical data of 371 patients with IPF (145 and 226 in the derivation and validation cohorts, respectively), including serum lipid profiles (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I [Apo A-I], and apolipoprotein B), were retrospectively collected. The association with mortality was analyzed using the Cox proportional hazard model.ResultsIn the derivation cohort, the mean age was 67.5 years, 86.2% were men, and 30.3% died during the follow-up (median: 18.0 months). Non-survivors showed lower lung function and greater gender-age-physiology scores than survivors. Among the serum lipid profiles, the levels of triglyceride and Apo A-I were significantly lower in non-survivors than in survivors. In the multivariate Cox analysis, low Apo A-I levels (< 140 mg/dL) were independently associated with the risk of mortality (hazard ratio 3.910, 95% confidence interval 1.170-13.069; P = 0.027), when adjusted for smoking history, body mass index, GAP score, and antifibrotic agent use. In both derivation and validation cohorts, patients with low Apo A-I levels (< 140 mg/dL) had worse survival (median survival: [derivation] 34.0 months vs. not reached, P = 0.003; [validation] 40.0 vs. 53.0 months, P = 0.027) than those with high Apo A-I levels in the Kaplan-Meier survival analysis.ConclusionsOur results indicate that low serum Apo A-1 levels are an independent predictor of mortality in patients with IPF, suggesting the utility of serum Apo A-I as a prognostic biomarker in IPF.
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