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. 2024 Feb 23;14(1):4430.
doi: 10.1038/s41598-024-54924-x.

The underlying molecular mechanism of ciliated epithelium dysfunction and TGF-β signaling in children with congenital pulmonary airway malformations

Gang Zhang  1   2   3 , Lei Lou  3 , Linghui Shen  3 , Huiyi Zeng  3 , Chun Cai  3 , Rongde Wu  1   4 , Dandan Liu  5
Affiliations

The underlying molecular mechanism of ciliated epithelium dysfunction and TGF-β signaling in children with congenital pulmonary airway malformations

Gang Zhang et al. Sci Rep. .

Abstract

The aim of this study was to investigate the variation in gene expression in the complete transcripts of Congenitalpulmonary airwaymalformation (CPAM) of the lung using Next Generation Sequencing (NGS) technology. There were 20 cases involving children with CPAM were used for selection of study sample. NGS was used to establish RNA-Seq libraries for the two groups of samples separately, and both groups were conducted to differential expression analysis and Gene Ontology (GO) functional enrichment analysis. The pathways of the differential genes were analyzed to find the enriched target pathways. A total of 592 genes were expressed with significant differences (CPAM vs. normal tissue, P < 0.05). GO functional analysis of DEGs indicated that abnormal ciliary function played a role in the development of CPAM. Subsequently, analysis of these genes pathways showed the TGF-β signaling pathway was significantly enriched. Finally, the results of immunohistochemical analysis of some DEGs showed that a significant reduction in the expression of SMAD6, a gene related to the TGF-β signaling pathway, led to abnormal activation of the pathway. TGF-β signaling pathway involved in the evolution of the disease obtained by DEGs enrichment pathway analysis. SMAD6, a gene involved in this pathway, might be a potential biomarker for the diagnosis and treatment of CPAM.

Keywords: Congenital pulmonary malformation; RNA-Seq; SMAD6; TGF-β.

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Conflict of interest statement

All authors have no potential conflicts of interest with any companies/organizations whose products or services may be discussed in this article.

Figures

Figure 1
Figure 1
In case 4, a 3-month-old male infant were diagnosed with a suspected right-sided CPAM based on an abnormal 20-week prenatal ultrasound. A chest computed tomography (CT) scan was performed prior to surgery (A), revealing a massive right-sided cystic lesion measuring 63 × 52 × 49 mm, along with poor ventilation of the remaining lungs. The patient underwent a thoracoscopic procedure, wherein the dorsal and basal segments of the right lower lobe were excised (B).
Figure 2
Figure 2
Differentially expressed genes (DEG) analysis. (A) The Volcano Plot illustrates the relationship between gene expression fold change and significance, highlighting significantly upregulated (red) and downregulated (blue) genes; (B) the Heatmap displays gene expression levels across various conditions, with red colors indicating higher expression and blue colors indicating lower expression.
Figure 3
Figure 3
GO and KEGG analysis. (A) GO enrichment bubble plot; (B) Top 20 GO enrichment terms; (C) KEGG pathway enrichment; (D) pathway functional classification.
Figure 4
Figure 4
Epithelial gene expression. (A) The heatmap displays expression of epithelial-related genes in Non-Lesion (NL) and Lesion (LA) conditions. Rows represent genes, columns represent samples. (B) Validation of mRNA expression in tissue samples for epithelial-related genes.
Figure 5
Figure 5
TGF-β signaling pathway differential expression. (A) The heatmap displays differential expression of genes in the TGF-β signaling pathway; (B) validation of mRNA expression in tissue samples for SMAD6; (C) results of the representative immunohistochemistry staining showing the protein level expressions of SMAD6 in NL and LA tissues.
Figure 6
Figure 6
TGF-β signaling pathway related genes expression. (A) Results of the representative immunohistochemistry staining showing the protein level expressions of GDF7 in NL and LA tissues; (B) results of the representative immunohistochemistry staining showing the protein level expressions of InhibinB in Non-Lesion (NL) and Lesion (LA) tissues.
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