Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.
Acute lung injury (ALI) is a life‐threatening medical condition with higher mortality and morbidity in elderly patients. Recently, metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, has been shown to be an effective anti‐inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In our study, we found that epithelial cell senescence was elevated after lipopolysaccharide (LPS) exposure in vivo and in vitro, accompanied by decreased expression of ATG5 and impaired autophagy activity. To further discover the molecular regulation mechanism between cellular senescence and autophagy in LPS‐treated MLE‐12 cells, we demonstrated that inhibition of ATG5 could decrease autophagy levels and promote the senescence of MLE‐12 cells. On the contrary, elevating the expression of ATG5 could effectively suppress LPS‐induced cellular senescence via enhancing autophagy activity. In addition, we demonstrated that metformin could protect MLE‐12 cells from LPS‐induced senescence via increasing the expression of ATG5 and augmenting autophagy activity. Our data implicate that activation of autophagy by metformin may provide a preventive and therapeutic strategy for ALI.
Background: Kawasaki disease (KD) is the leading cause of acquired heart disease in children, and is steadily increasing in prevalence in East Asia. KD is often complicated by coronary artery damage, including dilatation and/ or aneurysms. Aspirin is used with intravenous immunoglobulin (IVIG) to prevent coronary artery abnormalities in KD. However, the role and optimal dose of aspirin remain controversial. Identifying the dose of aspirin in the acute phase will facilitate development of a more appropriate treatment strategy in improving the outcome of KD. Methods: A total of 2369 patients with KD were retrospectively analyzed and divided into three groups according to the aspirin dose: 510 in group 1 (20-29 mg/kg/day), 1487 in group 2 (30-39 mg/kg/day), and 372 in group 3 (40-50 mg/kg/day). The differences in laboratory data, rate of IVIG resistance and coronary artery damage were compared among the groups. Results: There was no difference in the incidence of coronary artery aneurysms (CAAs) in group 1 compared with groups 2 and 3 (2 weeks of illness: 2.94% vs. 1.90% vs. 3.36%; 3-4 weeks of illness: 1.94% vs. 2.32% vs. 2.65%). The risk for developing CAA was not reduced at 2 weeks of illness onset in groups 2 and 3 compared with group 1 (adjusted OR = 1.05, 95% confidence interval: 0.34-3.18; aOR = 1.81, 95% CI: 0.42-7.83). Furthermore, the risk for developing CAA was not reduced at 3-4 weeks of illness onset in groups 2 and 3 (aOR = 2.63, 95% CI: 0.61-11.28; aOR = 0.52, 95% CI: 0.03-9.54). There was no significant difference in the rate of IVIG resistance among the groups. Platelet levels after IVIG treatment in group 1 were significantly lower than those in groups 2 and 3 (522.29 × 10 9 /L, 544.69 × 10 9 /L, and 557.77 × 10 9 /L, p = 0.013). C reactive protein of the 30-40 mg/kg*day group was slightly higher than the other two groups. (7.76, 8.00, and 7.01 mg/L, p = 0.028). Conclusions: Aspirin at the dose of 20-29 mg/kg/day dose not increase the risk of coronary artery damage and IVIG resistance compared with the dose of 30-50 mg/kg/day. This low dose may have a lower risk for a potential effect on liver function.
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