Role and mechanism of IGFBP5 in the real-ambient particulate matter exposure-induced chronic lung injury.

BACKGROUND

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.

METHODS

In the present study, mice were housed in an individual ventilated cage (IVC)-based real-ambient PM exposure system for eight weeks. Transcriptomics was employed to analyze gene expression alterations.

RESULTS

IGFBP5 was significantly downregulated after PM exposure. 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.

CONCLUSION

This study 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.