Dehydrocostus Lactone Suppresses LPS-induced Acute Lung Injury and Macrophage Activation through NF-κB Signaling Pathway Mediated by p38 MAPK and Akt

Abstract

Acute lung injury (ALI) is a severe clinical disease marked by dysregulated inflammation response and has a high rate of morbidity and mortality. Macrophages, which play diverse roles in the inflammatory response, are becoming therapeutic targets in ALI. In this study we investigated the effects of dehydrocostus lactone (DHL), a natural sesquiterpene, on macrophage activation and LPS-induced ALI. The macrophage cell line RAW264.7 and primary lung macrophages were incubated with DHL (0, 3, 5, 10 and 30 μmol/L) for 0.5 h and then challenged with LPS (100 ng/mL) for up to 8 hours. C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) to induce acute lung injury (ALI) and then treated with a range of DHL doses intraperitoneally (5 to 20 mg/kg). The results showed that DHL inhibited LPS-induced production of proinflammatory mediators such as iNOS, NO, and cytokines including TNF-α, IL-6, IL-1β, and IL-12 p35 by suppressing the activity of NF-κB via p38 MAPK/MK2 and Akt signaling pathway in macrophages. The in vivo results revealed that DHL significantly attenuated LPS-induced pathological injury and reduced cytokines expression in the lung. NF-κB, p38 MAPK/MK2 and Akt signaling molecules were also involved in the anti-inflammatory effect. Collectively, our findings suggested that DHL is a promising agent for alleviating LPS-induced ALI.

Protective Effect of Piceatannol Against Acute Lung Injury Through Protecting the Integrity of Air-Blood Barrier and Modulating the TLR4/NF-κB Signaling Pathway Activation

“…Although inflammation is generally recognized as a defense against various aggressions, excessive of inflammatory response leads to serious tissue damage (Lin et al, 2018). Development of ALI is due to the uncontrolled inflammation which is connected with the over-production of various inflammatory mediators produced by diversified inflammatory cells (Lee et al, 2010;Nie et al, 2019). LPS, a major element of gram-negative bacterial cell FIGURE 6 | The production of pro-inflammatory cytokines in lung tissues.…”

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

“…Dehydrocostus lactone 63 , also a sesquiterpene extracted from the radix of Aucklandia lappa Decne., exerted protective effects against ALI via anti-inflammatory effects. In vitro and in vivo experiments revealed that dehydrocostus lactone effectively attenuated LPS-induced pathological injury and reduced pro-inflammatory mediator expression (TNF-α, IL-6, IL-1β, iNOS, NO and IL-12) in lung and macrophages through suppressing the p38 MAPK/MK2 and Akt-mediated NF-κB signaling pathways [ 233 ].…”

Evaluation of Anti-Colitis Effect of KM1608 and Biodistribution of Dehydrocostus Lactone in Mice Using Bioimaging Analysis

“…The site in which most dehydrocostus lactone accumulated was the lung. A recent study revealed that dehydrocostus lactone was effective in the attenuation of LPS-induced acute lung injury in mice via the inhibition of nuclear factor-κB [ 29 , 30 ]. Thus, our present results may support those of this previous study.…”