Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease.

Abstract

BACKGROUND:

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the main factor that leads to the deterioration of the disease. Currently, the diagnosis of AECOPD mainly relies on clinical manifestations, good predictors or biomarkers are lacking. We aim to reveal specific biomarkers and potential pathogenesis of AECOPD and provide a research basis for the diagnosis and treatment.

METHODS:

Four patients with AECOPD, four patients with stable COPD, and five control subjects were enrolled for RNA sequencing and KEGG analysis. The mRNA level of target genes was verified by quantitative real-time PCR (qPCR) with an expanded sample size (30 patients with AECOPD, 27 patients with stable COPD, and 35 control subjects). ELISA and immunofluorescence were used to identify the target proteins. Furthermore, the expression and function of WNT/β-catenin signaling pathway were assessed in animal models of COPD.

RESULTS:

RNA sequencing showed that 54 genes were up-regulated and 111 genes were down-regulated in the AECOPD. Differentially expressed genes were mainly enriched in WNT signaling pathway, et al. QPCR revealed that multi-genes of the WNT/β-catenin signaling were significantly down-regulated in AECOPD (P < 0.05), and β-catenin protein was significantly decreased in plasma of AECOPD and stable COPD (P < 0.01), while phosphorylated β-catenin was significantly up-regulated in peripheral blood mononuclear cells of AECOPD (P < 0.05). Similarly, WNT ligands, WNT receptors, and downstream signaling molecules were down-regulated, with an increased phosphorylated β-catenin protein in animal models of COPD. Activation of WNT/β-catenin signaling pathway by lithium chloride reduced the expression of phosphorylated β-catenin and ameliorated the COPD-like airway inflammation in mice.

CONCLUSION:

WNT/β-catenin signaling pathway is down-regulated in AECOPD patients and in animal models of COPD. Increased expression of phosphorylated β-catenin in the blood might be a potential biomarker of AECOPD. Activation of WNT/β-catenin pathway may also represent a therapeutic target for AECOPD.

• Authors: Huijie Wang, Yonghong Zhong, Na Li, Min Yu, Lin Zhu, Lina Wang, Fei Chen, Yaping Xu, Jian Liu, Huaqiong Huang
• Journal: Respiratory research (Respir Res) Vol. 23 Issue 1 Pg. 27 (Feb 12 2022) ISSN: 1465-993X [Electronic] England
• PMID: 35151329 (Publication Type: Journal Article, Validation Study)
• Copyright: © 2022. The Author(s).

Chemical References

• Biomarkers
• RNA, Messenger
• Wnt Proteins
• beta Catenin

Topics

• Aged
• Animals
• Biomarkers (blood)
• Disease Models, Animal
• Disease Progression
• Down-Regulation
• Gene Expression Profiling (methods)
• Gene Expression Regulation
• Humans
• Leukocytes, Mononuclear (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Pulmonary Disease, Chronic Obstructive (diagnosis, genetics, metabolism)
• RNA, Messenger (genetics)
• Transcriptome (genetics)
• Wnt Proteins (biosynthesis, genetics)
• Wnt Signaling Pathway
• beta Catenin (biosynthesis, genetics)