Researchers found 380 differentially expressed transcripts (DETs) involved in the physiopathological processes that characterize idiopathic pulmonary fibrosis (IPF) such as lipid metabolism, extracellular matrix (ECM) remodeling, and immune activity, as published in Frontiers in Molecular Biosciences.

In an effort to determine possible biomarkers for an early diagnosis, they conducted a study of 9 patients diagnosed with IPF and 6 healthy subjects as the control group. Lung tissue samples were collected from both groups with analyzed transcriptional messenger RNA. Out of 101,590 transcripts, 380 DETs were only present in patients with IPF.

Twenty-one of the DETs were verified using real-time quantitative polymerase chain reaction, and 3 were further confirmed at a protein level: DMD, FASN, MMP7. To determine which cell was responsible for regulating the 3 confirmed DETs, single-cell RNA sequencing was done.


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Ciliated cells, club cells, alveolar macrophages (AM), and alveolar type 1/2 epithelial (AT) cells were the primary sources of DMD. Only AT cells, club cells, and AMs originated MMP7, and lastly, FASN derived from AT cells, ciliated cells, and AMs. Regardless of radiologic and histological patterns previously identified as characteristics of IPF, the focus has recently shifted to molecular and genetic analysis where MMP7 and 2 other genes have already been linked to IPF.

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Nevertheless, most specimens studied belonged to patients in the late stages of the disease, while in this study, 7 out of 9 patients corresponded to early stages, aiming to determine premature changes in the genetic expression of IPF molecules that could aid in a timely diagnosis.

Moreover, although the inflammatory and immune-mediated effects in IPF remain controversial, this study revealed that 5 immune factors were upregulated (CXCL5, CXCL13, CXCL14, IL5RA, and TNFRSF19), and 4 (CSF3R, S100A8, S100A9, and S100A12) were downregulated. This corresponds to previous reports where S100A12 has been linked to the activation of proinflammatory pathways in endothelial, vascular smooth muscle, and inflammatory cells.

On the other hand, the role of DMD in IPF was newly reported. “We found that DMD was mainly expressed by ciliated cells and secondarily expressed in AT and club cells in the lung tissue,” the authors said. “The role of DMD in IPF development may be cell type-dependent.”

“ECM remodeling, lipid metabolism, and immune effect are complex during the early development of IPF, suggesting that no single cell, gene, or pathway can contribute to the complex and heterogeneous nature of the disease,” Qian and colleagues concluded. “In addition, our findings supplement and reinforce the present transcriptome profile of human IPF disease.”

Reference

Qian W, Xia S, Yang X et al. Complex involvement of the extracellular matrix, immune effect, and lipid metabolism in the development of idiopathic pulmonary fibrosis. Front Mol Biosci. Published online January 31, 2022. doi:10.3389/fmolb.2021.800747