Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways

Abstract

Background Oxidative stress and the resulting inflammation are essential pathological processes in acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2), a vital transcriptional factor, possesses antioxidative potential and has become a primary target to treat many diseases. Oridonin (Ori), isolated from the plant Rabdosia Rrubescens, is a natural substance that possesses antioxidative and anti-inflammatory effects. Our aim was to study whether the anti-inflammatory and antioxidant effects of Ori on LPS-induced ALI were mediated by Nrf2. Methods MTT assays, Western blotting analysis, a mouse model, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Ori exerts a protective effect on LPS-induced lung injury in RAW264.7 cells and in a mouse model. Results Our results indicated that Ori increased the expression of Nrf2 and its downstream genes (HO-1, GCLM), which was mediated by the activation of Akt and MAPK. Additionally, Ori inhibited LPS-induced activation of the pro-inflammatory pathways NLRP3 inflammasome and NF-κB pathways. These two pathways were also proven to be Nrf2-independent by the use of a Nrf2 inhibitor. In keeping with these findings, Ori alleviated LPS-induced histopathological changes, the enhanced production of myeloperoxidase and malondialdehyde, and the depleted expression of GSH and superoxide dismutase in the lung tissue of mice. Furthermore, the expression of LPS-induced NLRP3 inflammasome and NF-κB pathways was more evident in Nrf2-deficient mice but could still be reversed by Ori. Conclusions Our results demonstrated that Ori exerted protective effects on LPS-induced ALI via Nrf2-independent anti-inflammatory and Nrf2-dependent antioxidative activities.

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

“…Among these factors which can induce HO-1 expression, Nrf2 has a key role in regulating cellular antioxidant stress and eliminating reactive oxygen species (ROS) [11]. Recently research found that Nrf2 prevents oxidative stress-induced pulmonary diseases [12,13]. However, whether or not Nrf2 is responsible for HO-1 induction in seawater-induced ALI is still unknown.…”

Progranulin Improves Acute Lung Injury through Regulating the Differentiation of Regulatory T Cells and Interleukin-10 Immunomodulation to Promote Macrophage Polarization

“…Even with the increased recognition of ARDS, its identification still depends on various clinical and imaging signs [4], and the treatment of ARDS relies on supportive therapy [5]. Lipopolysaccharide (LPS), a part of the outer membrane of gram-negative bacteria, is one of the most important causes of ALI [6,7]. Intratracheal administration of LPS in mice leads to edema caused by alveolar inflammation, which simulates ARDS in experimental animal model, visually [8].…”

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

“…Among these factors that induce HO-1 expression, Nrf2 has a key role in regulating cellular antioxidant stress and eliminating reactive oxygen species (ROS) [11]. Recent research found that Nrf2 prevents oxidative stressinduced pulmonary diseases [12,13]. However, whether or not Nrf2 is responsible for HO-1 induction in seawater-induced ALI is still unknown.…”