CAVIN2 attenuates ventilator-induced lung injury in rats by MAPK/ERK1/2 signaling pathway

Qian Zhu; Ke Wu; Jun Lv; Rui Yang; Chunyu Li; Wenqu Liu; Jiayi Zhang; Siyu Lian; Li Wang; Xianming Zhang

doi:10.1016/j.intimp.2024.113669

CAVIN2 attenuates ventilator-induced lung injury in rats by MAPK/ERK1/2 signaling pathway

Int Immunopharmacol. 2024 Nov 24:144:113669. doi: 10.1016/j.intimp.2024.113669. Online ahead of print.

Authors

Qian Zhu¹, Ke Wu¹, Jun Lv², Rui Yang³, Chunyu Li⁴, Wenqu Liu⁵, Jiayi Zhang¹, Siyu Lian¹, Li Wang¹, Xianming Zhang⁶

Affiliations

¹ Department of Respiratory and Critical Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China; School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, China.
² Jinan Obstetrics and Gynecology Hospital, Jinan, Shandong, China.
³ Department of Internal Medicine, Guiyang First People's Hospital, Guiyang, China.
⁴ Department of Respiratory and Critical Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
⁵ Department of Respiratory and Critical Care Medicine, People's Hospital of Anshun City Guizhou Province, Anshun, China.
⁶ Department of Respiratory and Critical Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: zhangxianming@gmc.edu.cn.

PMID: 39586229
DOI: 10.1016/j.intimp.2024.113669

Abstract

Background: Mechanical ventilation is an important treatment in medical treatment, but it may cause or aggravate lung injury, which is called ventilator-induced lung injury (VILI). Studies have shown that CAVIN2 plays an important role in regulating inflammatory responses and cell death. However, its functional mechanism in VILI remains unclear. This study explores the potential role and mechanisms of CAVIN2 in the pathogenesis of VILI.

Methods: We constructed rat and cell models of VILI. Real-time quantitative polymerase chain reactions (qRT-PCR), Western blot (WB), immunohistochemistry (IHC) and immunofluorescence (IF) were used to detect CAVIN2, ERK1/2, p-ERK1/2, autophagy-associated marker proteins LC3II/I, Beclin1 and P62, and the expression level of pro-inflammatory factors IL-1β and IL-6. Hematoxylin and eosin (H&E) staining were used to evaluate the degree of pathological injury of lung tissue, and the lung permeability was evaluated by measuring the wet-dry ratio of lung tissue and the total protein content in bronchoalveolar lavage fluid (BALF). Molecular docking, co-immunoprecipitation and immunofluorescence were used to verify the binding of CAVIN2 and ERK1/2, and the regulatory mechanisms of both were investigated by rescue experiments.

Results: CAVIN2 expression was downregulated in VILI rat lung tissues and ATII cells, whereas p-ERK1/2 expression was up-regulated. Overexpressing CAVIN2 alleviated pathological damage in VILI rat lung tissues and reduced the expression of pro-inflammatory factors and autophagy-related marker proteins in both lung tissues and ATII cells. Conversely, knockdown of CAVIN2 led to increased expression of pro-inflammatory factors and autophagy-related marker proteins in ATII cells. Further mechanism studies showed that CAVIN2 binds to ERK1/2 and inhibits ERK1/2 phosphorylation. Conversely when treated with the p-ERK1/2 agonist Ro67-7476, the protective, anti-inflammatory, and anti-autophagic effects of overexpressing CAVIN2 in VILI rats and ATII cells were reversed.

Conclusion: CAVIN2 can bind to ERK1/2 and inhibit the activation of MAPK/ERK1/2 signaling pathway to reduce inflammatory response and autophagy in VILI, thereby reducing lung injury. Therefore, CAVIN2 may be a potential intervention target to provide a new strategy for the treatment of VILI.

Keywords: Autophagy; CAVIN2; ERK1/2; Ventilator-induced lung injury.