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. 2024 Mar 28;25(7):3750.
doi: 10.3390/ijms25073750.

Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis

Daisuke Ishii  1 , Takeshi Kawasaki  1 , Hironori Sato  2 , Koichiro Tatsumi  1 , Takuro Imamoto  1 , Keiichiro Yoshioka  1 , Mitsuhiro Abe  1 , Yoshinori Hasegawa  3 , Osamu Ohara  3 , Takuji Suzuki  1   4
Affiliations

Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis

Daisuke Ishii et al. Int J Mol Sci. .

Abstract

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-β/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be _targeted for therapy.

Keywords: RNA sequencing; idiopathic pulmonary fibrosis; nintedanib; peripheral blood mononuclear cells (PBMCs); pirfenidone; transcriptome.

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Conflict of interest statement

Mitsuhiro Abe reports personal speaking and lecture fees from Boehringer Ingelheim, Japan. Takuji Suzuki reports on the personal speaking and lecture fees received from Boehringer Ingelheim, Japan.

Figures

Figure 1
Figure 1
(a) Principal component analysis (PCA). PCA showing that two groups of idiopathic pulmonary fibrosis (IPF) and healthy controls (HCs) are well-differentiated. (b) Volcano plot of differentially expressed genes (DEGs). Volcano plot showing the distribution of log2-fold change and p-value for the 12,347 genes. Colored dots represent 207 DEGs between IPF and HCs. Red dots represent high expression, and blue dots represent low expression. (c). Heatmap of DEGs in IPF vs. HCs. Red bars represent high expression, and blue bars represent low expression. A heatmap with detailed gene names is shown in Supplementary Figure S1.
Figure 2
Figure 2
(a) Principal component analysis (PCA). PCA showing that the two groups before and after PFD administration are well-differentiated. (b) Volcano plot of DEGs. Volcano plot showing the distribution of log2-fold change and p-value for the 11,962 genes. Colored dots represent 170 DEGs between before and after PFD administration. Red dots represent high expression, and blue dots represent low expression. (c) Heatmap of differentially expressed genes (DEGs). Heatmap showing the DEGs before and after PFD administration. Red bars represent high expression, and blue bars represent low expression. A heatmap with detailed gene names is shown in Supplementary Figure S2.
Figure 3
Figure 3
(a) Principal component analysis (PCA). PCA showing that the two groups before and after NTD administration are well-differentiated. (b) Volcano plot of DEGs. Volcano plot showing the distribution of log2-fold change and p-value for the 12,123 genes. Colored dots represent 198 DEGs between before and after NTD administration. Red dots represent high expression, and blue dots represent low expression. (c) Heatmap of DEGs. Heatmap showing the DEGs before and after NTD administration. Red bars represent high expression, and blue bars represent low expression. A heatmap with detailed gene names is shown in Supplementary Figure S4.
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