Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Abstract

Background Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.

Identification of key genes increasing susceptibility to atrial fibrillation in nonalcoholic fatty liver disease and the potential mechanisms: mitochondrial dysfunction and systemic inflammation

“…Although COX2 (PTGS2) is usually considered to induce inflammation, previous studies have found that COX-2 deficient mice, or those treated with COX inhibitors, display exaggerated inflammatory responses in the lungs, leading to the development of asthma ( Peebles et al, 2002 ). PTGS2, also known to modulate mitochondrial function and lipid metabolism pathways, plays a crucial role in ferroptosis during cardiac and pulmonary disease processes, challenging the traditional view of its sole pro-inflammatory role ( Chen et al, 2022 ; Lv et al, 2023 ). These pathways are also enriched with SOCS3 (suppressor of cytokine signaling 3), an essential molecule for negatively regulating cellular signaling pathways, by inhibiting inflammatory cytokines such as interleukin-6 (IL-6) and interferon (IFN) ( Zhang et al, 2020 ).…”

ANGPTL2 knockdown induces autophagy to relieve alveolar macrophage pyroptosis by reducing LILRB2‐mediated inhibition of TREM2

“…35 LPS has been generally used to develop a clinically correlative model of ALI. 36,37 Here, the model of ALI was also built on mice and MH-S cells by the management of LPS in vivo and in vitro, respectively. This study revealed that the level of ANGPTL2 was upregulated in lung injury both in vivo and in vitro.…”

Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice

“…Hence, the accumulation of iron and ROS, GSH depletion and GPX4 inactivation are distinguishing features of ferroptosis. Previous studies have demonstrated the involvement of ferroptosis in ALI [ [20] , [21] , [22] ]. The present study showed that the inhibition of ferroptosis significantly mitigated LPS-induced lung injury, which is consistent with the findings of the previous studies.…”