| 摘要: | 幽門螺旋桿菌是一種革蘭氏陰性的微需氧螺旋菌，它會附著於人類的胃中，估計已全球人口的一半以上曾被感染。持續性幽門螺桿菌感染與數種上消化道疾病有關，如胃炎、消化性潰瘍和胃腺癌。
儘管幽門螺旋桿菌一般被認為是細胞內病原體，但該生物體生活在粘膜層並緊密粘附於胃上皮表面。值得注意的是，幽門螺桿菌的毒性可以在巨噬細胞內延緩攝取並促進巨胞體的形成，其包含幽門螺桿菌誘導的發病機制的關鍵特徵。此外，發現負責巨噬細胞中膽固醇葡糖基化的膽固醇-α-葡糖基轉移?有助於保護幽門螺桿菌免受吞噬作用。這些證據指出幽門螺旋桿菌可以在巨噬細胞的特定區室內細胞內存活以避免吞噬作用介導的毒殺。
3-羥基-3-甲基-戊二?基-輔?A（HMG-CoA）還原?的抑製劑，通常被稱為statins，被廣泛用於降低血清膽固醇。值得注意的是，statins也顯示可降低嚴重細菌感染的風險，包括肺炎衣原體（Chlamydia pneumonia），困難梭狀桿菌（Clostridium difficile），金黃色葡萄球菌（Staphylococcus aureus）和肺炎鏈球菌（Streptococcus pneumoniae）的感染。然而，statins藥物的免疫調節性質只能解釋部分這些化合物抑制細菌感染的機制。
人體免疫系統採用各種機制來抑制細菌感染。儘管自噬作用是一種細胞過程，通常作為循環途徑作用，降解非功能性和不必要的成分，並重新排列這些成分以支持細胞存活，但該過程也被發現通過降解入侵病原體而有助於免疫防禦。因此，這些發現指出刺激細胞自噬可能會減弱幽門螺桿菌誘導的發病機制。
抗幽門螺旋桿菌藥物，特別是由質子泵抑製劑（proton-pump inhibitor），阿莫西林（amoxicillin）和克拉黴素（clarithromycin）組成的三重治療方案是根除幽門螺旋桿菌感染的最有效手段。儘管不同國家的治愈率不相同，但三聯療法仍然是幽門螺桿菌感染的推薦治療方案。值得注意的是，這種三聯療法與statins類藥物一起使用可以加速幽門螺桿菌的清除並減少幽門螺旋桿菌相關炎症。然而，statins類藥物對幽門螺旋桿菌誘導發病機制調控作用的分子機制需要進一步研究。在這項研究中，我們首先假設statins類藥物可能通過上調自噬作用和抑制幽門螺旋桿菌誘導的炎症來影響免疫反應。我們利用幽門螺旋桿菌感染的體外和離體巨噬細胞模型來研究statins類藥物介導的幽門螺旋桿菌發病機制緩解的機制。我們還探討了statins藥物如何通過上調細胞自噬作用並因此減輕幽門螺旋桿菌相關致病機制來影響細菌負荷並減輕炎症。
Helicobacter pylori (H. pylori) is a Gram-negative microaerophilic spirochete that colonizes the human stomach and is estimated to have infected greater than half of the global population (Marshall, 2002). Persistent H. pylori infection is associated with several upper gastrointestinal disorders such as gastritis, peptic ulcers, and gastric adenocarcinoma (Wroblewski et al., 2010).
Although H. pylori is generally considered an intracellular pathogen, this organism lives in the mucosal layer and tightly adheres to the gastric epithelial surface. Notably, virulent strains of H. pylori, can delay uptake and promote the formation of megasomes within macrophages, which comprises a crucial feature of H. pylori-induced pathogenesis (Allen et al., 2000). Moreover, cholesterol-α-glucosyltransferase, which is responsible for cholesterol glucosylation in macrophages, was found to contribute to the protection of H. pylori from phagocytosis (Wunder et al., 2006). These lines of evidence suggest that H. pylori can survive intracellularly within specific compartments of macrophages to avoid phagocytosis-mediated killing.
The inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, commonly known as statins, are widely prescribed for lowering serum cholesterol (Armitage, 2007). Notably, statins have also been shown to reduce the risk of severe bacterial infections, including infections by Chlamydia pneumoniae (Erkkila et al., 2005), Clostridium difficile (Motzkus-Feagans et al., 2012), Staphylococcus aureus (Chow et al., 2010), and Streptococcus pneumoniae (Boyd et al., 2012). However, the immunomodulatory properties of statins provide only a partial explanation for the mechanism by which these compounds inhibit bacterial infections (Jain and Ridker, 2005).
The human immune system employs various mechanisms to inhibit bacterial infections. While autophagy is a cell process that typically functions as a recycling pathway, degrading nonfunctional and unnecessary components and rearranging these components to support cellular survival (Marino et al., 2014), this process was also found to contribute to immune defense by degrading invading pathogens (Mizushima et al., 2008; Zhao et al., 2008). As such, these findings indicate that stimulation of cellular autophagy may attenuate H. pylori-induced pathogenesis (Yang and Chien, 2009).
Antimicrobial agents, particularly a triple therapy regimen consisting of a proton-pump inhibitor, amoxicillin, and clarithromycin, are the most effective means of eradicating H. pylori infections (O’Connor et al., 2013). Although the cure rate varies between countries, the triple therapy regimen remains the recommended treatment for H. pylori infection (O’Connor et al., 2013). Notably, the administration of this triple therapy regimen along with statins has been shown to accelerate the clearance of H. pylori and reduce H. pylori-related inflammation (Tariq et al., 2007; Yamato et al., 2007; Nseir et al., 2012). However, the molecular mechanisms underlying the regulatory effects of statins on H. pylori-induced pathogenesis require further investigation. In this study, we first hypothesized that statins may influence the immune response via upregulation of autophagy and attenuation of H. pylori-induced inflammation. We utilized in vitro and ex vivo macrophage models of H. pylori infection to investigate the mechanism underlying the statin-mediated mitigation of H. pylori pathogenesis. We also explored how statin influences the bacterial burden and reduces inflammation by upregulating cellular autophagy and consequently alleviating H. pylori-associated pathogenesis. |
