TGFBR2 Accelerates the Oxidative Stress and Inflammation in Septic Acute Lung Injury VIA METTL14-MEDIATED M6A...

Acute lung injury (ALI) is a serious complication of sepsis and a major cause of death. This study aims to clarify the mechanism of transforming growth factor beta receptor II (TGFBR2) in sepsis-induced ALI.

The study stimulated human pulmonary microvascular endothelial cells (HPMECs) using lipopolysaccharides (LPS) to establish an in vitro ALI model. The protein and mRNA levels were detected using western blot and qRT-PCR, respectively. The cell viability, proliferation, and apoptosis were assessed using CCK-8, EdU, and flow cytometry. The factors related to inflammation and oxidative stress were examined using corresponding detection kits. RIP, Me-RIP, and dual-luciferase reporter assay were used to identify the association of TGFBR2 with METTL14 and IGF2BP2. The Ubibrowser database, Co-IP, and deubiquitination assays were performed to validate the relationship between USP7 and TGFBR2. A mouse model of polymicrobial sepsis was established to analyze the effects of TGFBR2 on lung injury in vivo .

TGFBR2 levels were highly expressed in the serum of sepsis-ALI patients and in LPS-induced HPMECs. TGFBR2 knockdown remitted LPS-induced inhibition of viability and proliferation, as well as LPS-induced promotion of apoptosis, inflammation, and oxidative stress. METTL14 and IGF2BP2 stabilized TGFBR2 mRNA expression through m6A modification. Furthermore, silencing METTL14 protected HPMECs from LPS-induced injury by decreasing TGFBR2. USP7 could stabilize the expression of TGFBR2 via deubiquitination, and si-USP7 ameliorated LPS-induced HPMEC damage via inhibiting TGFBR2. TGFBR2 knockdown alleviated sepsis-induced ALI in vivo .

TGFBR2 facilitates the inflammation and oxidative stress in sepsis-induced ALI via METTL14/IGF2BP2-mediated m6A modification or USP7-regulated deubiquitination.