Capsaicin Protects Against Lipopolysaccharide-Induced Acute Lung Injury Through the HMGB1/NF-κB and PI3K/AKT/mTOR Pathways

Abstract

Capsaicin (8-methyl-N-geranyl-6-nonamide; CAP) is an alkaloid isolated from chili peppers, which has complex pharmacological properties, including beneficial effects against various diseases. The aim of this study was to investigate the role of CAP in lipopolysaccharide (LPS)-induced acute lung injury (ALI), and the possible underlying mechanisms. Materials and Methods: ALI was induced by intranasal administration of LPS (0.5 mg/ kg), and CAP (1 mg/kg) injected intraperitoneally 3 days before exposure to LPS. Then, the histopathological changes were evaluated by hematoxylin and eosin staining. Enzyme-linked immunosorbent assay and qPCR were used to detect pro-inflammatory cytokines in serum and lung tissue. The expressions of HMGB1/NF-κB, PI3K/AKT/mTOR signaling pathways and apoptosis-associated molecules were determined by Western blot and/or qPCR. In addition, the lung cell apoptosis was analyzed by TUNEL staining, and the expression and location of cleaved caspase-3 were detected by immunofluorescence analysis. Results: CAP pretreatment significantly protected mice from LPS-induced ALI, with reduced lung wet/dry weight ratio, lung histological damage, myeloperoxidase (MPO) activity, malondialdehyde (MDA) content and pro-inflammatory cytokine levels, and significant increased superoxide dismutase (SOD) activity. In addition, CAP pretreatment significantly inhibited the high-mobility group protein B1 (HMGB1) expression, nuclear factor-kappa B (NF-κB) activation, and the PI3K/AKT/mTOR signaling pathway. Furthermore, mice pre-treated with CAP exhibited reduced apoptosis of lung tissues, with associated down-regulation of caspase-3, cleaved caspase-3, and BAX expression, and up-regulation of BCL-2. Conclusion: Our data demonstrate that CAP can protect against LPS-induced ALI by inhibiting oxidative stress, inflammatory responses and apoptosis through down-regulation of the HMGB1/NF-κB and PI3K/AKT/mTOR pathways.

H3K27 tri-demethylase JMJD3 inhibits macrophage apoptosis by promoting ADORA2A in lipopolysaccharide-induced acute lung injury

“…Gram-negative bacterial infection in the lung or intestines is known to be an important factor in the development of ALI, owing to the bacterially secreted endotoxins (mainly LPS) [17]. During ALI, there is a prominent increase in the number of macrophages due to disruption of the alveolar vascular epithelial barrier and inflammatory recruitment [18].…”

“…Four histopathologic signs were used for this score including hyperaemia, haemorrhage, oedema of the alveolar wall, and inflammatory cell infiltration. Each sign was graded from 0 to 4 (0 = normal, 1 = very small amount, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe) [17]. The total score was the summation of all item scores, and it was used to evaluate the degree of lung injury.…”

Acteoside attenuates RSV-induced lung injury by suppressing necroptosis and regulating metabolism

“…The outcomes herein also demonstrated that HMGB1 expression was remarkably regulated upward following RSV infection, but such an increase was suppressed by AC, revealing that AC could function as a HMGB1 suppressor. NF-κB is a vital transcription factor for HMGB1 biosynthesis; when stimulated, it is translocated to the nucleus and binds to several targeted genes, promoting inflammation and injury events (Chen et al, 2021). Our findings showed that AC treatment significantly inhibited NF-κB activation and HMGB1 release in the RSV-infected mice and A549 cells.…”

Inhibition of inflammatory liver injury by the HMGB1-A box through HMGB1/TLR-4/NF-κB signaling in an acute liver failure mouse model

“…As a nonhistone nucleoprotein, HMGB1 is widely present in the cells of various mammalian organs, such as the brain (Dehghani et al, 2021), lungs (Chen et al, 2021), heart (Pellegrini et al, 2019), liver (Arshad et al, 2012;, kidneys (Chen et al, 2017) and spleen (Valdes-Ferrer et al, 2013). Under normal physiological conditions, HMGB1 is localized in the nucleus of most cells and its structure is highly FIGURE 7 Suppression of cell apoptosis and decrease in proinflammatory cytokine levels in LPS-induced Huh7 cells following HMGB1-A box treatment.…”