Sphingosine Kinase 1 Plays an Important Role in Atorvastatin-Mediated Anti-Inflammatory Effect against Acute Lung Injury

Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor and inhibits cholesterol synthesis. Recently, atorvastatin also showed anti-inflammatory effect in acute lung injury, ameliorating pulmonary gas-blood exchanging function. Sphingosine kinase 1 plays a central role in endothelial (EC) cytoskeleton rearrangement and EC barrier integrity regulation. In this study, the role of sphingosine kinase 1 in atorvastatin anti-inflammatory effect against acute lung injury was investigated. Both wild-type (WT) and SphK1-/- mice were challenged with high tidal volume ventilation (40 ml/kg body weight, 65 breathing/min, 4 hours). The acute lung injury was evaluated and the mechanisms were explored. In WT mice, atorvastatin treatment significantly decreased acute lung injury responding to high tidal volume ventilation (HT), including protein, cellular infiltration, and cytokine releasing; comparing to WT mice, SphK1-/- mice showed significantly worsen pulmonary injuries on HT model. Moreover, the atorvastatin-mediated anti-inflammatory effect was diminished in SphK1-/- mice. To further confirm the role of SphK1 in VILI, we then compared the inflammatory response of endothelial cells that were isolated from WT and SphK1-/- mice to cyclic stretching. Similarly, atorvastatin significantly decreased cytokine generation from WT EC responding to cyclic stretching. Atorvastatin also significantly preserved endothelial junction integrity in WT EC against thrombin challenge. However, the inhibitory effect of atorvastatin on cytokine generation induced by cyclic stretching was abolished on SphK1-/- mice EC. The endothelial junction integrity effects of atorvastatin also diminished on SphK1-/- mouse EC. Signal analysis indicated that atorvastatin inhibited JNK activation induced by cyclic stretch. SphK1 knockout also blocked atorvastatin-mediated VE-cadherin junction enhancement. In summary, by inhibition of MAPK activity and maintenance of EC junction homeostasis, SphK1 plays a critical role in atorvastatin-mediated anti-inflammatory effects in both cellular and in vivo model. This study also offers an insight into mechanical stress-mediated acute lung injury and potential therapy in the future.

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Vanillin protects lipopolysaccharide-induced acute lung injury by inhibiting ERK1/2, p38 and NF-κB pathway

Future Medicinal Chemistry ◽

10.4155/fmc-2018-0432 ◽

2019 ◽

Vol 11 (16) ◽

pp. 2081-2094 ◽

Cited By ~ 1

Author(s):

Tingting Guo ◽

Zhenzhong Su ◽

Qi Wang ◽

Wei Hou ◽

Junyao Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Western Blot ◽

Lung Inflammation ◽

Macrophage Activation ◽

Myeloperoxidase Activity ◽

Histopathological Changes ◽

Tnf Α ◽

Anti Inflammatory ◽

Inflammatory Effect

Aim: Thus far, the anti-inflammatory effect of vanillin in acute lung injury (ALI) has not been studied. This study aimed to investigate the effect of vanillin in lipopolysaccharide (LPS)-induced ALI. Results & methodology: Our study detected the anti-inflammatory effects of vanillin by ELISA and western blot, respectively. Pretreatment of mice with vanillin significantly attenuated LPS-stimulated lung histopathological changes, myeloperoxidase activity and expression levels of proinflammatory cytokines by inhibiting the phosphorylation activities of ERK1/2, p38, AKT and NF-κB p65. In addition, vanillin inhibited LPS-induced TNF-α and IL-6 expression in RAW264.7 cells via ERK1/2, p38 and NF-κB signaling. Conclusion: Vanillin can inhibit macrophage activation and lung inflammation, which suggests new insights for clinical treatment of ALI.

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Cannabidiol produces a long-term anti-inflammatory effect in a murine model of acute lung injury

Brain Behavior and Immunity ◽

10.1016/j.bbi.2011.07.111 ◽

2011 ◽

Vol 25 ◽

pp. S210 ◽

Cited By ~ 1

Author(s):

A. Ribeiro ◽

V. Ferraz-de-Paula ◽

M.L. Pinheiro ◽

W.M. Quinteiro-Filho ◽

A.T. Akamine ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Murine Model ◽

Anti Inflammatory ◽

Inflammatory Effect

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Anti-Inflammatory Effects of Huberia peruviana Cogn. Methanol Extract by Inhibiting Src Activity in the NF-κB Pathway

Plants ◽

10.3390/plants10112335 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2335

Author(s):

Seung A Kim ◽

Chae Young Lee ◽

Ankita Mitra ◽

Haeyeop Kim ◽

Byoung Young Woo ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Western Blotting ◽

Methanol Extract ◽

Luciferase Assay ◽

Luciferase Reporter ◽

No Production ◽

In Vivo Models ◽

Anti Inflammatory ◽

Inflammatory Effect

There is a growing need to develop anti-inflammatory drugs to regulate inflammatory responses. An extract of Huberia peruviana Cogn. had the best inhibitory effect on nitric oxide (NO) production in screening process undertaken in our laboratory. However, the anti-inflammatory effect of Huberia peruviana Cogn. methanol extract (Hp-ME) has not been studied. In this study, the anti-inflammatory effect of Hp-ME was assessed by using an NO assay, RT-PCR, luciferase reporter gene activity assay, western blotting assay, HCl/EtOH-induced acute gastritis model, and LPS-induced acute lung injury model. The phytochemical components of Hp-ME were determined through LC-MS/MS analysis. When RAW264.7 and HEK293T cells were treated with Hp-ME, NO production was decreased dose-dependently without cytotoxicity and the mRNA levels of iNOS, COX-2, and TNF-α were decreased. In a luciferase assay, the activity of transcription factors, NF-κB in TRIF or MyD88-overexpressing HEK293T cells was extremely reduced by Hp-ME. The western blotting analysis indicated that Hp-ME has anti-inflammatory effects by inhibiting the phosphorylation of Src. Hp-ME showed anti-inflammatory effects on in vivo models of HCl/EtOH-induced gastritis and LPS-induced acute lung injury. LC-MS/MS revealed that Hp-ME contains several anti-inflammatory flavonoids. The final findings of this study imply that Hp-ME could be used as an anti-inflammatory drug in several inflammatory diseases.

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Investigation of anti-inflammatory effects of oxygen nanobubbles in a rat hydrochloric acid lung injury model

Nanomedicine ◽

10.2217/nnm-2020-0338 ◽

2020 ◽

Vol 15 (27) ◽

pp. 2647-2654

Author(s):

Keisuke Yoshida ◽

Yukihiro Ikegami ◽

Shinju Obara ◽

Keiko Sato ◽

Masahiro Murakawa

Keyword(s):

Acute Lung Injury ◽

Mean Arterial Pressure ◽

Hydrochloric Acid ◽

Lung Injury ◽

Arterial Pressure ◽

Rat Model ◽

Injury Model ◽

Lung Injury Model ◽

Anti Inflammatory ◽

Inflammatory Effect

Aim: To investigate the anti-inflammatory effect of oxygen nanobubbles (ONBs) in an acute lung injury rat model. Materials & methods: In a rat hydrochloric acid lung injury model, ONB fluid was administered intravenously in the ONB group (n = 6) and normal saline was administered in the control group (n = 6). 4 h later, arterial partial pressure of oxygen (PaO2), mean arterial pressure and plasma inflammatory cytokines were measured. Results: There were no significant differences in the PaO2, mean arterial pressure or TNF-α and IL-6 levels between the two groups. Conclusions: No anti-inflammatory effect could be confirmed at the present ONB dose in the rat model of acute lung injury.

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