PDF(Pubmed)
Abstract：
Cryptococcus neoformans, an opportunistic fungal pathogen, primarily infects immunodeficient patients frequently causing cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a serious complication responsible for increased morbidity and mortality in CM patients. Non-invasive pharmacological agents that mitigate ICP could be beneficial in treating CM patients. The objective of the study was to investigate the efficacy of acetazolamide (AZA), candesartan (CAN), and triciribine (TCBN), in combination with the antifungal fluconazole, on C. neoformans-induced endothelial, brain, and lung injury in an experimental mouse model of CM. Our study shows that C. neoformans increases the expression of brain endothelial cell (BEC) junction proteins Claudin-5 (Cldn5) and VE-Cadherin to induce pathological cell-barrier remodeling and gap formation associated with increased Akt and p38 MAPK activation. All three agents inhibited C. neoformans-induced endothelial gap formation, only CAN and TCBN significantly reduced C. neoformans-induced Cldn5 expression, and only TCBN was effective in inhibiting Akt and p38MAPK. Interestingly, although C. neoformans did not cause brain or lung edema in mice, it induced lung and brain injuries, which were significantly reversed by AZA, CAN, or TCBN. Our study provides novel insights into the direct effects of C. neoformans on BECs in vitro, and the potential benefits of using AZA, CAN, or TCBN in the management of CM patients.
摘要：
新生隐球菌,机会性真菌病原体，主要感染经常引起隐球菌性脑膜脑炎（CM）的免疫缺陷患者。颅内压（ICP）升高是导致CM患者发病率和死亡率增加的严重并发症。减轻ICP的非侵入性药物在治疗CM患者中可能是有益的。该研究的目的是研究乙酰唑胺（AZA）的疗效，坎地沙坦(CAN),和曲西瑞宾（TCBN），与抗真菌药物氟康唑联合使用，关于新生梭菌诱导的内皮，大脑,和CM实验小鼠模型的肺损伤。我们的研究表明，新生梭菌增加脑内皮细胞（BEC）连接蛋白Claudin-5（Cldn5）和VE-Cadherin的表达，以诱导与Akt和p38MAPK激活增加相关的病理性细胞屏障重塑和间隙形成。所有三种药物均抑制新生梭菌诱导的内皮间隙形成，只有CAN和TCBN显着降低新生梭菌诱导的Cldn5表达，只有TCBN能有效抑制Akt和p38MAPK。有趣的是,虽然新生梭菌不会引起小鼠的脑或肺水肿，它引起了肺和脑损伤，被AZA显著逆转，CAN,或者TCBN。我们的研究提供了新的见解，以直接影响的新的梭菌对BECs的体外，以及使用AZA的潜在好处，CAN,或TCBN在CM患者的管理中。
