Disturbance of serum lipid metabolites and potential biomarkers in the Bleomycin model of pulmonary fibrosis in young mice

Abstract

Background Altered metabolic pathways have recently been considered as potential drivers of idiopathic pulmonary fibrosis (IPF) for the study of drug therapeutic targets. However, our understanding of the metabolite profile during IPF formation is lacking. Methods To comprehensively characterize the metabolic disorders of IPF, a mouse IPF model was constructed by intratracheal injection of bleomycin into C57BL/6J male mice, and lung tissues from IPF mice at 7 days, 14 days, and controls were analyzed by pathology, immunohistochemistry, and Western Blots. Meanwhile, serum metabolite detections were conducted in IPF mice using LC–ESI–MS/MS, KEGG metabolic pathway analysis was applied to the differential metabolites, and biomarkers were screened using machine learning algorithms. Results We analyzed the levels of 1465 metabolites and found that more than one-third of the metabolites were altered during IPF formation. There were 504 and 565 metabolites that differed between M7 and M14 and controls, respectively, while 201 differential metabolites were found between M7 and M14. In IPF mouse sera, about 80% of differential metabolite expression was downregulated. Lipids accounted for more than 80% of the differential metabolite species with down-regulated expression. The KEGG pathway enrichment analysis of differential metabolites was mainly enriched to pathways such as the metabolism of glycerolipids and glycerophospholipids. Eight metabolites were screened by a machine learning random forest model, and receiver operating characteristic curves (ROC) assessed them as ideal diagnostic tools. Conclusions In conclusion, we have identified disturbances in serum lipid metabolism associated with the formation of pulmonary fibrosis, contributing to the understanding of the pathogenesis of pulmonary fibrosis.

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.…”

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

“…In the present study, immunoblotting was used to quantify α-SMA expression; however, no changes were observed. An experimental PF model induced by bleomycin also demonstrated no alterations in α-SMA expression in fibrotic lungs cells [ 38 ]. Nevertheless, further studies are necessary to investigate whether this well-known fibrotic marker is altered in the context of PCM-PF.…”

Elephantopus scaber L. Ethanolic Leaves Extract Modulates IL-2 Production and T-Lymphocyte Activation in Pulmonary Fibrosis Mice Model

“…The decrease in the relative number of IL-2 produced by CD8 T cells in the ESEE treatment group may be caused by suppression of the immune system to prevent excessive inflammation after one week of bleomycin injection [10]. Meanwhile, the increase in the relative number of IL-2 in the second week of bleomycin injection may also be due to the activity of ESEE in increasing the proliferation of immune cells.…”

“…Bleomycin injection as lung fibrosis modeling in mice for seven days causes excessive inflammatory infiltration of the lungs, then fibroblast activation, extracellular matrix deposition, and fibrosis will occur on day 14 [10]. Administering the drug together with bleomycin injection is modeling a preventive measure to prevent fibrosis in the lungs.…”