Background: The cannabinoid receptor 2 (CNR2) plays a critical role in relieving asthma, with the mechanism still unclear. We aimed to investigate the mechanism of the CNR2 agonist (β-caryophyllene, β-Car) in regulating the balance of regulatory T cells (Treg) and T helper cell 17 (Th17) and thus its role in asthma. Methods:The study group of 50 pathogen-free female BALB/c mice were randomly divided at 6-8 weeks old into five groups of Control, Asthma, Asthma + β-Car (10 mg/kg), Asthma + β-Car + SR144528 (specific CNR2 antagonist, 3 mg/kg), and Asthma + β-Car + CMD178 (inhibitor of Treg cell, 10 mg/kg). ELISA was conducted to evaluate the main inflammatory cytokines [interleukin (IL)-6, IL-8, and tumor necrosis factor-α], and those secreted by Treg (transforming growth factor-β and IL-10), and Th17 (IL-17A and IL-22).Markers of Treg and Th17 cells were assessed by flow cytometry. In vitro, the CD4 + T cells were sorted and directed to differentiate to Treg and Th17 cells. The expression levels of CNR2, STAT5 and JNK1/2 were investigated by western blot and immunofluorescence assay.Results: β-Car relieved neutrophilic asthma severity in mice by elevating the marker genes' expression of Treg and inhibiting those of Th17, causing an increased proportion of Treg to Th17. β-Car also promoted the directed differentiation of CD4 + T cells into Treg, but not Th17. Activation of the CNR2 regulated the Treg/Th17 balance and relieved neutrophilic asthma possibly through promotion of phosphorylation of STAT5 and JNK1/2. Conclusions:The effect of the selective CNR2 agonist activating STAT5 and JNK1/2 signaling was to change the Treg/Th17 balance and reduce the inflammatory reaction, thus ameliorating neutrophilic asthma in a mouse model.

Steroid-resistant asthma is a troublesome clinical problem in public health. The pathogenesis of steroid-resistant asthma is complex and remains to be explored. In our work, the online Gene Expression Omnibus microarray dataset GSE7368 was used to explore differentially expressed genes (DEGs) between steroid-resistant asthma patients and steroid-sensitive asthma patients. Tissue-specific gene expression of DEGs was analyzed using BioGPS. The enrichment analyses were performed using GO, KEGG, and GSEA analysis. The protein–protein interaction network and key gene cluster were constructed using STRING, Cytoscape, MCODE, and Cytohubba. A steroid-resistant neutrophilic asthma mouse model was established using lipopolysaccharide (LPS) and ovalbumin (OVA). An LPS-stimulated J744A.1 macrophage model was prepared to validate the underlying mechanism of the interesting DEG gene using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 66 DEGs were identified, most of which were present in the hematologic/immune system. Enrichment analysis displayed that the enriched pathways were the IL-17 signaling pathway, MAPK signal pathway, Toll-like receptor signaling pathway, and so on. DUSP2, as one of the top upregulated DEGs, has not been clearly demonstrated in steroid-resistant asthma. In our study, we observed that the salubrinal administration (DUSP2 inhibitor) reversed neutrophilic airway inflammation and cytokine responses (IL-17A, TNF-α) in a steroid-resistant asthma mouse model. We also found that salubrinal treatment reduced inflammatory cytokines (CXCL10 and IL-1β) in LPS-stimulated J744A.1 macrophages. DUSP2 may be a candidate target for the therapy of steroid-resistant asthma.

Previous studies suggest that sepsis remains a common critical illness with a global incidence of 31.5 million. The aim of this study was to evaluate the comparative therapeutic value of recombinant human thrombopoietin (rhTPO) in treating sepsis patients with thrombocytopenia. We conducted a comprehensive electronic search of PubMed, EMBASE, the Cochrane Library, and CNKI from its inception through December 31, 2021. Thirteen randomized controlled trials (RCTs) involving 963 patients were included. Network meta-analyses showed that rhTPO 300 U/kg/day and rhTPO 15000 U/day significantly increased the platelet (PLT) levels on the 7th day and decreased the requirement of transfusion of red blood cells (RBCs), plasma, and PLT compared with IVIG and NAT. SUCRA showed that rhTPO 300 U/kg/day ranked first in terms of 28-day mortality (85.5%) and transfusion, including RBC (88.7%), plasma (89.6%), and PLT (95.2%), while rhTPO 15000 U/day ranked first for the length of the intensive care unit (ICU) stay (95.9%) and PLT level at day 7 (91.6%). rhTPO 300 U/kg/day may be the optimal dose to reduce 28-day mortality and transfusion requirements. However, rhTPO 15000 U/day may be the optimal dose for shortening the ICU stay and increasing the PLT level on the 7th day. However, additional studies to further validate our findings are needed.