目标:控制不佳的糖尿病常加重肺部感染,从而使治疗策略复杂化。最近的研究表明,exendin-4不仅具有降血糖作用,还具有抗炎作用。本研究旨在探讨exendin-4在糖尿病合并肺部感染中的作用。以及它与NOD1/NF-κB和T1R2/T1R3甜味受体的关联。
方法:用分离自铜绿假单胞菌(PA)的脂多糖(LPS)刺激用20mM葡萄糖培养的16HBE人支气管上皮细胞。此外,Sprague-Dawley大鼠喂食高脂肪饮食,然后腹膜内注射链脲佐菌素和气管内滴注PA。TNF-α的水平,使用ELISA和RT-qPCR评估IL-1β和IL-6。采用免疫印迹和免疫荧光染色检测T1R2、T1R3、NOD1和NF-κBp65的表达。使用苏木精和伊红(H&E)染色观察大鼠肺中的病理变化。
结果:在相同剂量的LPS下,20mM葡萄糖组产生更多的促炎细胞因子(TNF-α,IL-1β和IL-6),T1R2,T1R3,NOD1和NF-κBp65的水平高于正常对照组(含5.6mM葡萄糖)。然而,exendin-4的预先干预显著降低了上述促炎细胞因子和信号分子的水平.同样,感染PA的糖尿病大鼠肺部促炎细胞因子水平升高,T1R2,T1R3,NOD1和NF-κBp65的表达增加,这些作用被exendin-4逆转。
结论:糖尿病高血糖可加重肺部感染时的炎症,促进NOD1/NF-κB的增加,并推广T1R2/T1R3。Exendin-4可改善PA相关性肺炎伴糖尿病和NOD1/NF-κB的过表达。此外,exendin-4可能通过其降血糖作用或通过直接机制抑制T1R2/T1R3.T1R2/T1R3的高表达与糖尿病肺部感染中炎症反应加剧之间的相关性需要进一步研究。
OBJECTIVE: Poorly controlled diabetes frequently exacerbates lung infection, thereby complicating treatment strategies. Recent studies have shown that exendin-4 exhibits not only hypoglycemic but also anti-inflammatory properties. This study aimed to explore the role of exendin-4 in lung infection with diabetes, as well as its association with NOD1/NF-κB and the T1R2/T1R3 sweet taste receptor.
METHODS: 16HBE human bronchial epithelial cells cultured with 20 mM glucose were stimulated with lipopolysaccharide (LPS) isolated from Pseudomonas aeruginosa (PA). Furthermore, Sprague‒Dawley rats were fed a high-fat diet, followed by intraperitoneal injection of streptozotocin and intratracheal instillation of PA. The levels of TNF-α, IL-1β and IL-6 were evaluated using ELISAs and RT‒qPCR. The expression of T1R2, T1R3, NOD1 and NF-κB p65 was assayed using western blotting and immunofluorescence staining. Pathological changes in the lungs of the rats were observed using hematoxylin and eosin (H&E) staining.
RESULTS: At the same dose of LPS, the 20 mM glucose group produced more proinflammatory cytokines (TNF-α, IL-1β and IL-6) and had higher levels of T1R2, T1R3, NOD1 and NF-κB p65 than the normal control group (with 5.6 mM glucose). However, preintervention with exendin-4 significantly reduced the levels of the aforementioned proinflammatory cytokines and signaling molecules. Similarly, diabetic rats infected with PA exhibited increased levels of proinflammatory cytokines in their lungs and increased expression of T1R2, T1R3, NOD1 and NF-κB p65, and these effects were reversed by exendin-4.
CONCLUSIONS: Diabetic hyperglycemia can exacerbate inflammation during lung infection, promote the increase in NOD1/NF-κB, and promote T1R2/T1R3. Exendin-4 can ameliorate PA-related pneumonia with diabetes and overexpression of NOD1/NF-κB. Additionally, exendin-4 suppresses T1R2/T1R3, potentially through its hypoglycemic effect or through a direct mechanism. The correlation between heightened expression of T1R2/T1R3 and an intensified inflammatory response in lung infection with diabetes requires further investigation.