Synergistic Enhancement of Isoforskolin and Dexamethasone Against Sepsis and Acute Lung Injury Mouse Models

Yan Fang; Chuang Xiao; Lueli Wang; Youlan Wang; Jun Zeng; Yaping Liang; Rong Huang; Yunke Shi; Sha Wu; Xiaohua Du; Shibo Sun; Min Li; Yuanyuan Zheng; Hongxiang Wu; Qiuzhe Guo; Weimin Yang

doi:10.2147/JIR.S421232

Synergistic Enhancement of Isoforskolin and Dexamethasone Against Sepsis and Acute Lung Injury Mouse Models

J Inflamm Res. 2023 Dec 7:16:5989-6001. doi: 10.2147/JIR.S421232. eCollection 2023.

Authors

Yan Fang^#^{1

2}, Chuang Xiao^#¹, Lueli Wang^#¹, Youlan Wang³, Jun Zeng¹, Yaping Liang¹, Rong Huang¹, Yunke Shi², Sha Wu¹, Xiaohua Du², Shibo Sun², Min Li², Yuanyuan Zheng², Hongxiang Wu¹, Qiuzhe Guo⁴, Weimin Yang¹

Affiliations

¹ School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, People's Republic of China.
² The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China.
³ Kunming Institute of Medical Sciences, Kunming, People's Republic of China.
⁴ Fuwai Yunnan Cardiovascular Hospital, Kunming, People's Republic of China.

^# Contributed equally.

Abstract

Background: Sepsis is initiated by the dysfunctional response of the host immune system to infection. Septic shock and acute lung injury (ALI) are the main etiology of death caused by sepsis. Glucocorticoids, which are commonly used in clinic to antagonize the inflammatory response of sepsis, may cause serious side effects. Isoforskolin (ISOF) from the plant Coleus forskohlii stimulates adenylyl cyclase, increases the cAMP level and inhibits inflammatory response. The aim of this study was to investigate the synergistic effect of ISOF with dexamethasone (DEX) to prevent and ameliorate septic inflammation.

Methods: Lipopolysaccharide (LPS) of 30 and 5 mg/kg (iv.) was used to induce sepsis and ALI mice model respectively in vivo. BEAS-2B cells stimulated by LPS were applied as cell model in vitro. The cumulative survival of mice with LPS-induced sepsis and the histopathological changes of lungs in mice with acute lung injury were observed, and the secretion of pro-inflammatory cytokines was analyzed by ELISA. The expression of RGS2 in BEAS-2B cells was detected by immunoblotting assay and PCR.

Results: In the sepsis mice model, ISOF (10 mg/kg) combined with DEX (10 mg/kg.) (ip.) pretreatment significantly increased mice survival rate from 33.3% to 58.3%, which was significantly higher than that of ISOF or DEX treated alone. In the ALI mice model, ISOF, DEX pretreatment alone and combined application attenuated pulmonary pathological changes in ALI mice. Furthermore, ISOF, DEX alone or combined administration decreased MPO, MDA, IL-6, and IL-8 levels, while significantly synergistic effects were observed in the combined treatment group compared with ISOF or DEX alone. In BEAS-2B cells, combined pretreatment with ISOF and DEX significantly decreased the expression of IL-8 and increased the expression of RGS2.

Conclusion: The results indicated that ISOF in combination with DEX synergistically improves survival rate and attenuates ALI in mice model through anti-inflammatory and antioxidant effects.

Keywords: acute lung injury; glucocorticoids; isoforskolin; pulmonary inflammation; regulator of G-protein signaling 2; sepsis.