ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Respiratory Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1604301
This article is part of the Research TopicAcute and Chronic Lung Injury: Therapeutic Targets and DrugsView all 9 articles
Role and mechanism of IGFBP5 in the real-ambient particulate matter exposure-induced chronic lung injury
Provisionally accepted
- 1Jinan Children's Hospital, Jinan, Shandong Province, China
- 2Shandong University, Jinan, China
- 3Qingdao University, Qingdao, Shandong Province, China
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Inflammation and oxidative stress are the main pathological processes of particulate matter (PM)-induced lung injury. Insulin-like growth factor binding protein 5 (IGFBP5) is an important secretory protein related to inflammation and oxidative damage in several tissues, whereas its roles in PM-induced lung adverse effects remain largely unexplored. In the present study, transcriptomic results of lung tissues from mice housed in an individual ventilated cage (IVC)based real-ambient PM exposure system for eight weeks revealed significant downregulation of IGFBP5. Functional investigations demonstrated that IGFBP5 downregulation exacerbated PM-induced oxidative damage, as evidenced by elevated levels of reactive oxygen species (ROS) and malondialdehyde, as well as decreased levels of superoxide dismutase 2 (SOD2). Conversely, IGFBP5 overexpression effectively rescued these oxidative stress phenotypes. Mechanistically, IGFBP5 downregulation attenuated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, thereby impairing SOD2 catalytic activity and amplifying ROS accumulation.Co-treatment with si-IGFBP5 and ERK1/2 signaling pathway inhibitor PD98059 could further aggravate the production of ROS in cells. Moreover, microRNAs (miRNAs) are an important class of gene expression regulators. We found that the upregulated hsa-miR-33a-5p repressed IGFBP5 translation by forming a silencing complex with Argonaute protein 2 (AGO2) in a real-ambient PM exposure system, which further led to the suppression of the ERK1/2-SOD2 signaling pathway and increased levels of ROS. Together, our results revealed that the downregulation of IGFBP5 promoted oxidative damage in lung cells by inhibiting the IGFBP5-ERK1/2-SOD2 pathway, and targeted inhibition of hsa-miR-33a could alleviate PM-induced lung injury by upregulating IGFBP5.
Keywords: PM, Particulate matter, MDA, malondialdehyde, IGFBP5, insulin-like growth factor-binding protein 5, ROS, reactive oxygen species, SOD2, superoxide dismutase 2, 3'UTR, 3' untranslated region, MAPK, mitogen-activated protein kinase, ERK1/2, extracellular signal-related kinases 1 and 2 PM
Received: 01 Apr 2025; Accepted: 09 Jun 2025.
Copyright: © 2025 Chen, Qi, Ma, Zhu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaoying Li, Shandong University, Jinan, China
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