Department of Biological Sciences, School of Dentistry of Bauru, University of São Paulo, Bauru, São Paulo, Brazil.
Department of Structural and Molecular Biology and Genetics, State University of Ponta Grossa, Ponta Grossa, Parana, Brazil.
J Endod. 2019 Oct;45(10):1228-1236. doi: 10.1016/j.joen.2019.06.013. Epub 2019 Aug 8.
The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions.
Periapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects.
VIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4.
Our results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells.
宿主促炎免疫反应与抗炎和修复反应之间的平衡，据推测决定了根尖周病变的结局。在此情况下，血管活性肠肽 (VIP) 因其显著的免疫调节能力，可能发挥保护作用。在本研究中，我们以因果关系的方式研究了 VIP 参与人类和实验性根尖周病变发展的潜在作用。
通过实时聚合酶链反应比较评估根尖周肉芽肿（n = 124）和对照样本（n = 48）中 VIP 和多种免疫/活性标志物的表达。评估实验性根尖周病变（C57Bl/6 野生型小鼠）中内源性 VIP 表达与病变发展的相关性，以及重组 VIP 治疗对病变结局的影响。使用 CCR4KO 和 IL4KO 品系以及抗糖皮质激素诱导的 TNFR 相关蛋白抑制剂来测试 Treg 和 Th2 细胞在 VIP 介导作用中的参与。
与对照相比，根尖周肉芽肿中 VIP 表达更为普遍，与免疫调节因子呈正相关，与促炎介质和核因子 κB 配体/骨保护素受体的比例呈负相关/负相关。内源性 VIP 表达上调与病变免疫调节和骨丢失减少呈时间相关。在小鼠中进行 VIP 治疗可促使病变发展停滞，与抗炎和促修复反应相关，从而限制根尖周的促炎、Th1、Th17 和破骨细胞生成反应。VIP 的保护作用依赖于 Treg 的迁移和活性，且与白细胞介素 4 无关。
我们的研究结果表明，人类和实验性根尖周病变中 VIP 的过度表达与病变不活动有关，VIP 治疗可导致实验性病变进展减弱，这与涉及 Treg 细胞的免疫抑制反应有关。
