Table_1_Involvement of Vasopressin in the Pathogenesis of Pulmonary Tuberculosis: A New Therapeutic Target?.pdf

Tuberculosis (TB) is a highly complex infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). It is characterized by chronic granulomatous inflammation of the lung and systemic immune–neuroendocrine responses that have been associated with pathophysiology and disease outcome. Vasopressin (VP), a neurohypophysial hormone with immunomodulatory effects, is abnormally high in plasma of some patients with pulmonary TB, and is apparently produced ectopically. In this study, a BALB/c mouse model of progressive pulmonary TB was used to determine whether VP may play a role in TB pathophysiology. Our results show that VP gene is expressed in the lung since early infection, increasing as the infection progressed, and localized mainly in macrophages, which are key cells in mycobacterial elimination. Pharmacologic manipulation using agonist and antagonist compounds showed that high and sustained stimulation of VPR resulted in increased bacillary burdens and fibrosis at lungs, while blockade of VP receptors reduced bacterial loads. Accordingly, treatment of infected alveolar macrophages with VP in cell cultures resulted in high numbers of intracellular Mtb and impaired cytokine production. Thus, we show that VP is ectopically produced in the tuberculous lungs, with macrophages being its most possible target cell. Further, it seems that chronic vasopressinergic stimulation during active late disease causes anti-inflammatory and tissue reparative effects, which could be deleterious while its pharmacologic suppression reactivates protective immunity and contributes to shorten conventional chemotherapy, which could be a new possible form of immune-endocrine therapy.

结核病（Tuberculosis, TB）是一种由胞内病原菌结核分枝杆菌（Mycobacterium tuberculosis, Mtb）引起的高度复杂的传染性疾病。其特征为肺部慢性肉芽肿性炎症，以及与病理生理学和疾病转归相关的全身性免疫-神经内分泌应答。血管加压素（Vasopressin, VP）是一种具有免疫调节作用的神经垂体激素，部分肺结核患者血浆中的VP水平异常升高，且其似乎为异位合成。本研究采用BALB/c进行性肺结核小鼠模型，探究VP是否在结核病病理生理学中发挥作用。研究结果显示，VP基因自感染早期即在肺部表达，并随感染进展而上调，其主要定位于巨噬细胞——这是清除分枝杆菌的关键细胞。使用激动剂与拮抗剂化合物进行的药物干预实验表明，对血管加压素受体（Vasopressin Receptor, VPR）的高强度持续刺激会导致肺部细菌负荷增加与纤维化，而阻断VP受体则可降低细菌载量。相应地，在细胞培养中用VP处理感染后的肺泡巨噬细胞，可导致胞内Mtb数量增多，并削弱细胞因子产生。综上，本研究证实VP在结核病灶肺部异位合成，巨噬细胞或是其最主要的靶细胞。进一步研究发现，活动性晚期疾病期间的慢性血管加压素能刺激可产生抗炎与组织修复效应，此类效应或具有危害性；而VP受体的药理学抑制则可重新激活保护性免疫，并有助于缩短常规化疗周期，这或可成为一种新型免疫内分泌治疗手段。