Objectives. Inflammatory disease characterized by clinical destructive respiratory disorder is called acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Studies have shown that luteolin exerts anti-inflammatory effects by increasing regulatory T cells (Tregs). In this study, we aimed to determine the effects of luteolin on ALI/ARDS and Treg differentiation. Methods. In this paper, we used cecal ligation puncture (CLP) to generate an ALI mouse model to determine the effects of luteolin on ALI/ARDS. Lung tissues were stained for interleukin- (IL-) 17A and myeloperoxidase (MPO) by immunohistochemical analysis. The levels of Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) of mice were detected. The protein levels of NF-κB p65 in lung tissues were measured. Macrophage phenotypes in lung tissues were measured using immunofluorescence. The proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells (PBMCs) was quantified. Furthermore, in vitro, we evaluated the effects of luteolin on Treg differentiation, and the effects of IL-10 immune regulation on macrophage polarization were examined. Results. Luteolin alleviated lung injury and suppressed uncontrolled inflammation and downregulated IL-17A, MPO, and NF-κB in the lungs of CLP-induced mouse models. At this time, luteolin upregulated the level of IL-10 in serum and BALF and the frequency of CD4⁺CD25⁺FOXP3⁺ Tregs in PBMCs and splenic mononuclear cells of CLP mice. Luteolin treatment decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages in lungs of CLP-induced mouse models. In vitro, administration of luteolin significantly induced Treg differentiation, and IL-10 promoted the polarization of M2 macrophages but reduced the polarization of M1 macrophages. Conclusions. Luteolin alleviated lung injury and suppressed uncontrolled inflammation by inducing the differentiation of CD4⁺CD25⁺FOXP3⁺ Tregs and upregulating the expression of IL-10. Furthermore, the anti-inflammatory cytokine IL-10 promoted polarization of M2 macrophages in vitro. Luteolin-induced Treg differentiation from nave CD4⁺ T cells may be a potential mechanism for regulating IL-10 production.

Progranulin (PGRN), which plays an anti-inflammatory role in acute lung injury (ALI), is promising as a potential drug. Studies have shown that regulatory T cells (Tregs) and interleukin- (IL-) 10 can repress inflammation and alleviate tissue damage during ALI. In this study, we built a lipopolysaccharide- (LPS-) induced ALI mouse model to illustrate the effect of PGRN on regulation of Treg differentiation and modulation of IL-10 promoting macrophage polarization. We found that the proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells was higher after treatment with PGRN. The increased proportion of Tregs after PGRN intratracheal instillation was consistent with the decreased severity of lung injury, the reduction of proinflammatory cytokines, and the increase of anti-inflammatory cytokines. In vitro, the percentages of CD4⁺CD25⁺FOXP3⁺ Tregs from splenic naïve CD4⁺ T cells increased after PGRN treatment. In further research, it was found that PGRN can regulate the anti-inflammatory factor IL-10 and affect the polarization of M1/M2 macrophages by upregulating IL-10. These findings show that PGRN likely plays a protective role in ALI by promoting Treg differentiation and activating IL-10 immunomodulation.

Background: Acute lung injury (ALI) significantly impacts the survival rates in intensive care units (ICU). Releasing a lot of pro-inflammatory mediators during the progression of the disease is a core feature of ALI, which may lead to uncontrolled inflammation and further damages the tissues and organs of patients. This study explores the potential therapeutic mechanisms of Dexmedetomidine (Dex) in ALI. Methods: In present study, cecal ligation puncture (CLP)-established ALI model mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cell line were established to discover the influence of Dex. The evaluation of lung injury in vivo using histopathology, TUNEL assay, and analysis of inflammatory factors in bronchoalveolar lavage fluid (BALF) and serum. The receptor for advanced glycation end products (RAGE)/Caspase-11-dependent pyroptosis-related proteins and macrophage polarization markers were analyzed using western blot, immunofluorescence, and flow cytometry. Finally, the mechanism of Dex in macrophages was further verified in vitro. Results: In vivo, Dex alleviated lung injury and decreased TUNEL-positive cell expression in CLP group. Dex decreased tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-17A levels in BALF and serum, while increasing IL-10 expression. Dex treatment decreased the protein levels of RAGE, caspase-11, IL-1β and Gasdermin-D (GSDMD) in both in cells and in mice. Dex also down-regulated the synthesis of inducible nitric oxide synthase (iNOS) of classical activation phenotype (M1) markers, and up-regulated the synthesis of CD206 and Arg-1 of alternate activation phenotype (M2) markers. Conclusions: Dex treatment can inhibit inflammation and reduce lung injury caused by CLP. It could be associated with mediating M1 and M2 polarization and suppressing RAGE/Caspase-11-depended pyroptosis.