ABSTRACT
BACKGROUND: Severe respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC. PURPOSE: Our study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection. STUDY DESIGN AND METHODS: A murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed. RESULTS: PTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner. CONCLUSION: In conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases.
Subject(s)
Acute Lung Injury , Apoptosis , Influenza A Virus, H1N1 Subtype , Orthomyxoviridae Infections , Sirtuin 1 , Stilbenes , Animals , Stilbenes/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/virology , Mice , Influenza A Virus, H1N1 Subtype/drug effects , Apoptosis/drug effects , Sirtuin 1/metabolism , Orthomyxoviridae Infections/drug therapy , RAW 264.7 Cells , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Macrophages/drug effects , Disease Models, Animal , Mice, Inbred C57BL , AMP-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Lung/drug effects , Lung/virology , Lung/pathology , FemaleABSTRACT
Ag(0) nanoparticles were immobilized on various pyridine salt, imidazole salt and quaternary ammonium functionalized polyacrylonitrile fibers (PANFs) to prepare Ag(0)-immobilized fiber catalysts. The catalytic activities of these immobilized catalysts for 4-nitrophenol (4-NP) reduction were detected. Among them, the quaternary ammonium fiber with butyl group immobilized Ag(0) nanoparticle catalyst PANQA-C4F-Ag(0) showed the best catalytic activity, and can effectively catalyze 4-nitrophenol (4-NP) reduction with a high conversation rate of 99.6%. Furthermore, PANQA-C4F-Ag(0) can be easily recovered, and it was reused 20 times with little decrease in catalytic activity and moderate Ag retention (53.5%). Notably, the cationic groups in the functionalized fibers can stabilize Ag(0) nanoparticles through electrostatic interactions and steric effects, and play an important role in phase transfer catalysis. Accordingly, possible mechanisms for the 4-NP reduction catalyzed by PANQA-C4F-Ag(0) were proposed.