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Published on: March 2, 2016
Xiao-Chai-Hu granule alleviates influenza virus-induced pneumonia by regulating TLR4-PI3K-Akt/p38 MAPK-NF-κB pathways
Jin-Jin Li1, Zi-Hao Chen1, Wan-Ting Liang1
1Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Science, Guangxi Normal University, Guilin, 541004, PR China.
Ethnopharmacological Relevance:
Xiao-Chai-Hu granule (XCH) originates from the classical formula Xiao-Chai-Hu decoction, documented in Zhang Zhongjing's Treatise on Febrile and Miscellaneous Diseases (205 AD). Clinically used in China for decades to treat influenza, its mechanism against influenza virus (IFV)-induced pneumonia remains unclear.
Aim Of The Study:
This work aimed to evaluate the anti-influenza viral pneumonia effects and mechanism of XCH.
Materials And Methods:
Influenza virus A/PR/8/34 (PR8)-induced pneumonia mouse model was established to evaluate the effects of XCH, including pharmacological indexes of body weight, survival rates after 21 days post-infection, lung index, spleen index, and cytokines in bronchoalveolar lavage fluid (BALF) in day 5. Meanwhile, pathological status of the lung tissue profiled by H&E staining and white blood cells (neutrophils, monocytes, and lymphocytes) in the BALF were measured to assess the host inflammatory state. Chemical components of XCH were profiled using UPLC-Q/TOF MS in vitro and in vivo. Network pharmacology further predicted potential targets and pathways of XCH against influenza based on the identified prototypes. Western blotting analysis was used to verify the mechanism.
Results:
XCH (21 g/kg/day) markedly improved survival rates (40% vs 10%), delayed weight loss, and reduced lung damage (lower lung index and histopathological scores), compared with the PR8 group. Additionally, it increased spleen index, indicating enhanced immune response. XCH treatment significantly suppresses the excessive recruitment of neutrophils and monocytes in the lungs and the high levels of TNF-α, IL-6, IL-1β, IL-17A, IFN-β, IFN-γ in BALF induced by PR8, while significantly increased IL-10 level. Chemical analysis using UPLC-Q/TOF MS identified 197 compounds in XCH and 68 prototypes in vivo. Network pharmacology analysis further revealed that the PI3K-Akt, MAPK, and NF-κB pathways are potential key pathways mediating XCH's anti-influenza effects. Western blotting analysis indicated that XCH markedly down-regulated the levels of NP, TLR4, p-Akt/Akt, p-p38/p38, p-p65/p65, which was in line with the predicted results.
Conclusions:
TLR4-PI3K-Akt/p38 MAPK-NF-κB pathways is one of the signal pathways for XCH treating influenza virus pneumonia and reducing influenza virus titer in the lung.
