Infectious, inflammatory and 'autoimmune' male factor infertility: how do rodent models inform clinical practice?
Infectious, inflammatory and 'autoimmune' male factor infertility: how do rodent models inform clinical practice?
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传染性，炎症和“自身免疫性”男性因素不育：啮齿动物模型如何为临床实践提供依据？
DOI：
10.1093/humupd/dmy009
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发表时间：
2018-07-01
影响因子：
13.3
通讯作者：
Meinhardt A
中科院分区：
文献类型：
--
作者：
Fijak M;Pilatz A;Hedger MP;Nicolas N;Bhushan S;Michel V;Tung KSK;Schuppe HC;Meinhardt A
生殖道感染和炎症是男性因素性不育症的重要原因。由性传播细菌或尿路病原体引起的上升感染是附睾睾丸炎最常见的病因，但病毒、血液传播也是一个促成因素。在适当的诊断和治疗的局限性反映了明显需要进一步了解人类附睾和睾丸免疫病理及其对不孕症的贡献。推进我们的知识的一个主要障碍是有限的获取合适的组织样本。同样，影响人类男性生育能力的炎症或自身免疫性病理中的关键事件也很难进行仔细检查。此外，疾病过程通常在患者到诊所进行生育能力评估之前很久就发生了。在这方面，从实验动物模型和相应的比较分析中获得的数据显示有希望在人类中克服这些限制。这篇叙述性综述将集中在感染和炎症引起的男性生育障碍，以及最常用的动物模型来研究这些情况的有用性。在Medline数据库中进行了广泛的搜索，直到2018年1月，使用以下搜索词：“感染”和/或“炎症”和“睾丸”和/或“附睾”，“感染”和/或“炎症”和“男性生殖道”，“男性不育”，“睾丸炎”，“附睾炎”，“实验性自身免疫”和“睾丸炎”或“附睾-睾丸炎”，抗精子抗体”，“输精管结扎术”。除此之外，每个作者还独立审查了其他出版物的主要文章和评论文章的参考书目。选定的文章分别由两名不同的作者进行核实，并在小组内讨论差异。有明确的证据表明，模拟睾丸和/或附睾炎症和感染的模型对于更好地理解疾病的发生和发展机制具有指导意义。因此，急性细菌性附睾炎啮齿动物模型在模拟感染途径、病原菌选择、观察纤维化转化等损伤方面最能反映临床情况。同样，使用脂多糖的急性睾丸和附睾炎症动物模型显示生殖、内分泌功能和组织学组织结构受损，在男性中也可见。自身免疫反应可以在实验性自身免疫性睾丸炎（EAO）和输精管切除术模型中进行研究。特别是，EAO发展的早期阶段表现为小管周围淋巴细胞浸润、受影响小管固有层增厚、针对睾丸抗原的自身抗体产生或促炎介质的分泌等炎症反应，在精子发生“混合性萎缩”患者的睾丸精子提取样本中重复观察。输精管切除术，以精子抗体和慢性炎症的形式，也可以在动物模型中进行研究，为人类反应提供有价值的见解。本文首次全面综述了睾丸/附睾感染性和自身免疫性疾病的啮齿动物模型及其临床意义，即它们对理解与生殖器官感染性和非感染性/自身免疫性疾病相关的男性不育的重要性。
Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or urinary tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor. Limitations in adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility. A major obstacle for advancing our knowledge is the limited access to suitable tissue samples. Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination. Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment. In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans. This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions. An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: ‘infection’ and/or ‘inflammation’ and ‘testis’ and/or ‘epididymis’, ‘infection’ and/or ‘inflammation’ and ‘male genital tract’, ‘male infertility’, ‘orchitis’, ‘epididymitis’, ‘experimental autoimmune’ and ‘orchitis’ or ‘epididymitis’ or ‘epididymo-orchitis’, antisperm antibodies’, ‘vasectomy’. In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author. Selected articles were verified by each two separate authors and discrepancies discussed within the team. There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression. In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed. Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men. Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy. In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with ‘mixed atrophy’ of spermatogenesis. Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response. This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
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