LncRNA H19 aggravates primary graft dysfunction after lung transplantation via KLF5-mediated activation of CCL28.

Abstract

The present study aims to elucidate the possible involvement of H19 in primary graft dysfunction (PGD) following lung transplantation (LT) and the underlying mechanism. The transcriptome data were obtained through high-throughput sequencing analysis, and the differential long noncoding RNAs and messenger RNAs were screened for coexpression analysis. The interaction among H19, KLF5 and CCL28 was analyzed. A hypoxia-induced human pulmonary microvascular endothelial cell injury model was established, in which H19 was knocked down to elucidate its effect on the lung function, inflammatory response, and cell apoptosis. An orthotopic left LT model was constructed for in vivo mechanistic validation. High-throughput transcriptome sequencing analysis revealed the involvement of the H19/KLF5/CCL28 signaling axis in PGD. Silencing of H19 reduced inflammatory response and thus improved PGD. CCL28 secreted by human pulmonary microvascular endothelial cells after LT recruited neutrophils and macrophages. Mechanistic investigations indicated that H19 augmented the expression of CCL28 by binding to the transcription factor KLF5. Abundant expression of CCL28 reversed the alleviating effect of H19 silencing on PGD. In conclusion, the results point out that H19 exerts a promoting effect on PGD through increasing KLF5 expression and the subsequent CCL28 expression. Our study provides a novel insight into the mechanism of action of H19.

• Authors: Jiwei Li, Zhijun Han, Zibo Zhu, Li Wei
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 23 Issue 10 Pg. 1536-1550 (10 2023) ISSN: 1600-6143 [Electronic] United States
• PMID: 37394140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• RNA, Long Noncoding
• MicroRNAs
• CCL28 protein, human
• Chemokines, CC
• KLF5 protein, human
• Kruppel-Like Transcription Factors

Topics

• Humans
• RNA, Long Noncoding (genetics)
• Endothelial Cells (metabolism)
• Primary Graft Dysfunction (etiology)
• Gene Expression Regulation
• Lung Transplantation (adverse effects)
• MicroRNAs (genetics)
• Chemokines, CC (genetics, metabolism)
• Kruppel-Like Transcription Factors (genetics, metabolism)