Fatty acid metabolism-related genes in bronchoalveolar lavage fluid unveil prognostic and immune infiltration in idiopathic pulmonary fibrosis

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition with an unfavorable prognosis. A recent study has demonstrated that IPF patients exhibit characteristic alterations in the fatty acid metabolism in their lungs, suggesting an association with IPF pathogenesis. Therefore, in this study, we have explored whether the gene signature associated with fatty acid metabolism could be used as a reliable biological marker for predicting the survival of IPF patients.MethodsData on the fatty acid metabolism-related genes (FAMRGs) were extracted from databases like Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, and Reactome pathway. The GSE70866 dataset with information on IPF patients was retrieved from the Gene Expression Omnibus (GEO). Next, the consensus clustering method was used to identify novel molecular subgroups. Gene Set Enrichment Analysis (GSEA) was performed to understand the mechanisms involved. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the level of immune cell infiltration in the identified subgroups based on gene expression signatures of immune cells. Finally, the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression analysis were performed to develop a prognostic risk model.ResultsThe gene expression signature associated with fatty acid metabolism was used to create two subgroups with significantly different prognoses. GSEA reveals that immune-related pathways were significantly altered between the two subgroups, and the two subgroups had different metabolic characteristics. High infiltration of immune cells, mainly activated NK cells, monocytes, and activated mast cells, was observed in the subgroup with a poor prognosis. A risk model based on FAMRGs had an excellent ability to predict the prognosis of IPF. The nomogram constructed using the clinical features and the risk model could accurately predict the prognosis of IPF patients.ConclusionThe fatty acid metabolism-related gene expression signature could be used as a potential biological marker for predicting clinical outcomes and the level of infiltration of immune cells. This could eventually enhance the accuracy of the treatment of IPF patients.

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry

“…In our study, the patients with IPF had significantly higher circulating levels of several lipid species, including multiple long-chain acylcarnitines and ceramides and one sphingomyelin species, compared with the controls. These findings are consistent with data showing dysregulated fatty acid or lipid metabolism in mouse models of IPF [ 16 , 32 ], elevated free fatty acids or dysregulation of fatty acid metabolism-related genes in the lungs of patients with IPF [ 16 , 33 ], and elevated circulating levels of fatty acids in patients with IPF [ 19 , 21 , 34 ]. The pattern of higher levels of NEFA along with higher levels of acylcarnitines and select ceramides in patients with IPF in our study points to enhanced availability of fatty acids, possibly due to lipolysis related to wasting.…”

“…In studies in patients with IPF, negative correlations were observed between levels of select signaling lipids in peripheral blood and lung function [ 34 ], and higher levels of certain triglycerides and phosphatidylcholines were found in the plasma of patients with more rapid progression [ 21 ]. A risk model based on expression of select fatty acid genes in bronchoalveolar lavage fluid predicted outcomes among patients with IPF [ 33 ]. In our study, higher levels of ceramide C18:1/C16:0 was associated with more severe disease.…”

Mendelian Randomization revealed a one-way causal association between increased Isovalerylcarnitine (C5) levels and the risk of idiopathic pulmonary fibrosis

“…identi ed ve fatty acid metabolite-related genes (FAMRG) in bronchoalveolar lavage uid of IPF patients (50). Additionally, Miriana d'Alessandro found differential lipid metabolites in IPF alveolar lavage uid, however, these lipid metabolites do not possess diagnostic value in serum for distinguishing IPF from hypersensitivity pneumonitis (fHP) (51).…”

Codium fragile Suppressed Chronic PM2.5-Exposed Pulmonary Dysfunction via TLR/TGF-β Pathway in BALB/c Mice

“…Furthermore, it has been reported that lung fibrosis is sensitively affected by lipid changes [ 46 ]. Impairments and changes in fatty acid metabolism are associated with the pathogenesis of pulmonary fibrosis, and changes in the profile and metabolome of fatty acids are associated with disease progression and outcome [ 47 ]. The accumulation of triglyceride in the form of lipid droplets in alveolar epithelial cells induces endoplasmic reticulum (ER) stress and induces apoptosis of these cells through the expression of TGF-β1 [ 48 ].…”