Sini decoction alleviates LPS-induced sepsis partly via restoration of metabolic impairments in the hypothalamic-pituitary-adrenal microenvironment.

Ethnopharmacological Relevance: The hypothalamic-pituitary-adrenal (HPA) axis plays a vital role in the protection against sepsis. Sini decoction (SND) could improve HPA axis function.

Aim Of The Study: This work aimed to explore the effective mechanism of SND against lipopolysaccharide (LPS)-induced sepsis in rats from the metabolic regulation of the HPA axis microenvironment.

Materials And Methods: We evaluated the multiorgan injury-associated enzymatic indicators and histopathological changes as well as the ultrastructural changes in the hypothalamus, pituitary gland, and adrenal gland associated with LPS-induced sepsis. Serum inflammatory cytokines, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were determined by ELISA. The target tissues metabolomics of the HPA axis (hypothalamus, pituitary gland, and adrenal gland), based on ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOFMS), were conducted to dissect the metabolic network regulated by SND. Western blotting was further used to validate the key metabolic pathways. In addition, the absorbed chemical constituents in serum and cerebrospinal fluid were identified by UHPLC-Q-TOFMS combined with solid-phase extraction.

Results: Forty and twenty-three components of SND were absorbed into the serum and cerebrospinal fluid, respectively. SND could decrease multiorgan injury-associated indicators, including serum creatine kinase, urea nitrogen, creatinine, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase, inhibit inflammatory cytokines IL-6 and TNF-α, regulate the serum levels of CRH, ACTH and CORT in LPS-induced septic rats, and alleviate the sepsis-induced morphological changes in the heart, liver, spleen, lung, and kidney and HPA tissues. SND had the ability to regulate the unbalanced glycerophospholipid metabolism, fatty acid β-oxidation, fatty acid amide metabolism, tryptophan metabolism and arachidonic acid metabolism to improve the LPS-induced sepsis. The results of western blotting analysis demonstrated that SND could decrease the expressions of LPCAT1 and IDO1 and increase the expressions of CPT1A and FAAH1 to regulate the above metabolic disorders.

Conclusion: SND could alleviate LPS-induced sepsis partly via restoration of metabolic impairments in the HPA axis microenvironment, which provided important insights to future work to ascertain the mechanisms undergoing the HPA axis response to SND against sepsis.