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  • The increased levels of proinflammatory cytokines

    2021-09-18

    The increased levels of proinflammatory cytokines in BALF are noted during ALI/ARDS, and the persistent elevation of these mediators may exaggerate systemic or focal inflammatory reaction with a worse outcome. These cytokines, particularly TNF-α and IL-6, play essential roles in ALI [16,17]. The over-release of these cytokines in the serum and BALF from ALI patients is associated with a worse prognosis [18], and the instillation of TNF-α into the lung results in inflammatory injury [19]. Moreover, the neutralization of TNF-α or IL-6 improves the survival rate of septic mice [20,21]. Here, mice challenged with LPS expressed a larger amount of cytokines in the BALF compared with the control group. GYY4137 treatment was found to downregulate TNF-α and IL-6 secretion to the lung 6 h after challenge. Because TNF-α and IL-6 are both generated by activated macrophages that appear in BALF and plasma in ALI [22] and macrophages also play vital roles in ALI [23]. We then evaluated the pharmacological and biological effects of GYY4137 on these cytokines secretion in LPS-stimulated RAW264.7 macrophages. We found that GYY4137 suppressed TNF-α and IL-6 release from the LPS-induced cells. These results indicate that GYY4137 protects against LPS-induced ALI by inhibiting the release of TNF-α and IL-6. PGE2 is a mediator that is considered to play a critical role in pulmonary edema formation and mainly synthesized by cyclooxygenase-2 (COX-2) [24]. COX-2 is an inducible enzyme that catalyzes the conversion of arachidonic YK-4-279 into inflammatory prostaglandins, which plays an important role in exacerbating the inflammatory response and lung injury [25]. Specifically, the COX-2 level increase concomitantly with an increase in the severity of ALI, whereas the inhibition of COX-2 attenuates ALI in an acid aspiration-induced rat model of ALI [25,26]. In this study, we determined that GYY4137 treatment decreased PGE2 content and inhibited COX-2 expression in the LPS-induced ALI mouse model and LPS-stimulated RAW264.7 cells, indicating that the protective role of GYY4137 in ALI may be related to PGE2 and COX-2 downregulation. NO has been implicated in the pathophysiology of ALI in animals and humans and mainly produced by the inducible isoforms of NO synthase (iNOS) during lung inflammation. Over-production of NO promotes cytokines and matrix metalloproteinase release, mitochondria damage and apoptosis, following the exacerbation of inflammatory response and lung injury [27]. Mice deficient in iNOS gene are more resistant to LPS-induced acute lung injury than are wild-type mice [28]. Therefore, the reduction in NO production and iNOS down-regulation have been suggested effective in improving lung injury. In the lung, alveolar macrophages are the major cells expressing iNOS [29]. In our study, it's shown that GYY4137 not only suppressed LPS dependent secretion of NO but also iNOS protein expression in vitro and in vivo, indicating that GYY4137 exerts the beneficial role in ALI probably through iNOS and NO reduction. NF-κB is well-characterized transcriptional regulator responsible for promoting the expression of various proinflammatory cytokines during inflammation. Sustained NF-κB activation correlates with severity of lung injury, and interdiction in the NF-κB pathway is beneficial even after the onset of lung inflammation [30]. Accumulating data reported that NF-κB activation is accompanied by IκB phosphorylation and degradation, leading to NF-κB p65 phosphorylation and nuclear translocation [31]. Because NF-κB activation occurs in alveolar macrophages, the major source for releasing proinflammatory cytokines [32], we conducted in vitro cell culture studies by using macrophages cell line RAW264.7. GYY4137 significantly inhibited NF-κB activation in RAW264.7 cells stimulated with LPS. By inhibiting NF-κB activation, GYY4137 results in decreasing the expression of proinflammatory mediators and improving the lung inflammatory injury [33]. H2S has been reported to block LPS-induced NF-κB transactivation in endothelial cells [34], therefore, the effect of GYY4137 on the NF-κB activity and mediators release may be secondary to H2S.