Peroxisome proliferator‐activated receptor gamma coactivator‐1α/HSF1 axis effectively alleviates lipopolysaccharide‐induced acute lung injury via suppressing oxidative stress and inflammatory response

Abstract

Acute lung injury (ALI) interferes with lung function by causing pulmonary inflammation and oxidative stress. Suppressing intracellular reactive oxygen species (ROS) may block intracellular inflammation. Thus, the purpose of the current study was to investigate the roles of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α)/HSF1 axis in an lipopolysaccharide (LPS)-induced ALI murine model and in RAW264.7 macrophages. In the LPS-administrated mouse model, the addition of PGC1α obviously ameliorated secretion of pro-inflammatory mediators tumor necrosis factor-α and Interleukin 6 as well as MCP-1 expression triggered by LPS stimulation, accompanied with reduced infiltration of inflammatory cells. Meanwhile, introduction of PGC1α strongly diminished the expression of cyclooxygenase-2 and inducible nitric oxide synthase as well as their products PGE2 and NO. In addition, administering PGC1α also dramatically alleviated LPS-triggered oxidative stress, as reflected by a reduction of ROS production, and also reduced malondialdehyde and O content, concomitant with enhancement of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, PGC1α effectively ameliorated LPS-induced inflammation response and oxidative stress, as exemplified by reduced pro-inflammatory cytokines and ROS production in LPS-induced RAW264.7 macrophages. Interestingly, PGC1α modulated the expression of HSF1 and the transcriptional activity of X-linked inhibitor of apoptosis (XIAP)-associated factor 1, whereas silencing of HSF1 abolished these effects. More importantly, deletion of HSF1 impeded the anti-inflammatory and anti-oxidant effects of PGC1α in LPS-induced macrophages. Taken together, PGC1α/HSF1 axis have an anti-oxidant and anti-inflammatory effects, indicating that PGC1α/HSF1 may protect against LPS-induced ALI, and thus may be a promising therapy to treat ALI.

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

“…Numerous studies have demonstrated the crucial role of the infiltration of inflammatory cells, which is caused by the inflammatory cytokines during the progress of LPSinduced ALI. Furthermore, some researchers also noted that the increased infiltration of inflammatory cells could enhance the synthesis and accumulation of ROS in lung tissues [2,4,6,12,13]. In our study, the levels of IL-6 and TNF-α in BAL were increased in the LPS-induced ALI, and treatment with the ferroptosis inhibitor Fer-1 decreased the levels of both IL-6 and TNF-α in BAL, indicating the relationship between ferroptosis and inflammatory cytokines.…”

“…Thus, the use of LPS provides information about the effects of host inflammatory responses, which occur in bacterial infections [8,9]. Researchers have demonstrated that the intratracheal administration of LPS can induce the production of inflammatory mediators and reactive oxygen species (ROS), and worsen the lung tissue injury in an experimental animal model of ALI [10][11][12][13]. Therefore, the development of a novel treatment mode against LPS-induced ALI, which is based on inhibition of inflammation and oxidative stress, has attracted scientists' attention in both clinical and pre-clinical studies.…”

Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

“…Further, we also observed that puerarin-V significantly inhibited the expression of IL-6 and translation activity of NF-κB/IκB-α/IKKα/β. The probable reason for this effect is inhibition of the phosphorylation of downstream target proteins NF-κB/IκB-α/IKKα/β associated with PPAR-γ activation as PPAR-γ is considered as a master regulator in inhibiting recruitment of pro-inflammatory cytokines [37]. Moreover, as illustrated in the previous literature, puerarin-V has shown to suppress inflammatory mediators including IL-6, IL-2, iNOS, NF-κB/IKK-α and COX-2 expression [38,39].…”

Mechanism of the Switch from NO to H2O2 in Endothelium-Dependent Vasodilation in Diabetes

“…These data suggest PGC1α signaling to be involved in the NO-to-H2O2 switch in EDD in diabetic coronary arteries and miR-21 regulates PGC1α signaling. PGC1α is reported to have a host of functions including; antioxidant effects [23], prevention of oxidative stress [54], reduction of the expression of antioxidant-associated genes [11], reversed the overexpression of Sod1, Sod2 and catalase induced by ROS [16], diminished iNos as well as its NO by-product [18], promote eNOS expression [14] and is involved in regulating Cav-1 promoters [34]. Importantly, the loss of PGC-1α in non-CAD coronary arterioles produced a diseased (CAD) phenotype characterized by a shift from NO-to H2O2mediated dilation [28].…”