School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden.
Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
Adv Microb Physiol. 2018;73:1-62. doi: 10.1016/bs.ampbs.2018.05.001. Epub 2018 Jun 20.
Urinary tract infection (UTI) is one of the most common bacterial infections in humans, and the majority are caused by uropathogenic Escherichia coli (UPEC). The rising antibiotic resistance among UPEC and the frequent failure of antibiotics to effectively treat recurrent UTI and catheter-associated UTI motivate research on alternative ways of managing UTI. Abundant evidence indicates that the toxic radical nitric oxide (NO), formed by activation of the inducible nitric oxide synthase, plays an important role in host defence to bacterial infections, including UTI. The major source of NO production during UTI is from inflammatory cells, especially neutrophils, and from the uroepithelial cells that are known to orchestrate the innate immune response during UTI. NO and reactive nitrogen species have a wide range of antibacterial targets, including DNA, heme proteins, iron-sulfur clusters, and protein thiol groups. However, UPEC have acquired a variety of defence mechanisms for protection against NO, such as the NO-detoxifying enzyme flavohemoglobin and the NO-tolerant cytochrome bd-I respiratory oxidase. The cytotoxicity of NO-derived intermediates is nonspecific and may be detrimental to host cells, and a balanced NO production is crucial to maintain the tissue integrity of the urinary tract. In this review, we will give an overview of how NO production from host cells in the urinary tract is activated and regulated, the effect of NO on UPEC growth and colonization, and the ability of UPEC to protect themselves against NO. We also discuss the attempts that have been made to develop NO-based therapeutics for UTI treatment.
尿路感染（UTI）是人类最常见的细菌感染之一，大多数由尿路致病性大肠杆菌（UPEC）引起。UPEC 对抗生素的耐药性不断上升，抗生素经常无法有效治疗复发性 UTI 和导管相关性 UTI，这促使人们研究治疗 UTI 的替代方法。大量证据表明，诱导型一氧化氮合酶（iNOS）激活形成的毒性自由基一氧化氮（NO）在宿主防御细菌感染（包括 UTI）中发挥重要作用。在 UTI 期间，NO 产生的主要来源是炎症细胞，特别是中性粒细胞，以及尿路上皮细胞，这些细胞已知在 UTI 期间协调先天免疫反应。NO 和活性氮物种有广泛的抗菌靶标，包括 DNA、血红素蛋白、铁硫簇和蛋白质巯基。然而，UPEC 已经获得了多种防御机制来对抗 NO，例如 NO 解毒酶黄素血红蛋白和耐受 NO 的细胞色素 bd-I 呼吸氧化酶。NO 衍生中间体的细胞毒性是非特异性的，可能对宿主细胞有害，而平衡的 NO 产生对于维持泌尿道组织完整性至关重要。在这篇综述中，我们将概述尿路宿主细胞中 NO 的产生如何被激活和调节，NO 对 UPEC 生长和定植的影响，以及 UPEC 保护自身免受 NO 侵害的能力。我们还讨论了为治疗 UTI 而开发基于 NO 的治疗方法所做的尝试。
