Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.

中文翻译：

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反复感染通过感觉神经萌芽和肥大细胞活动导致持续的膀胱功能障碍和疼痛

尿路感染 (UTI) 几乎占女性感染的 25%。许多尿路感染是复发性的（rUTI），尽管抗生素治疗后菌尿已清除，但患者仍经常出现慢性盆腔疼痛和尿频。为了阐明这些与细菌无关的膀胱症状的基础，我们检查了 rUTI 患者的膀胱。我们注意到固有层中神经肽含量显着增加，并且有伤害性活动增强的迹象。在遭受 rUTI 的小鼠中，我们观察到感觉神经萌芽，这与招募的单核细胞和组织驻留肥大细胞产生的神经生长因子 (NGF) 相关。用 NGF 中和抗体治疗 rUTI 小鼠，可防止神经萌芽并减轻盆腔敏感性，而将天然 NGF 注入幼鼠膀胱中可模拟神经萌芽和疼痛行为。神经激活、疼痛和尿频均与近端肥大细胞的存在相关，因为肥大细胞缺陷或针对几种直接或间接肥大细胞产物的受体拮抗剂的治疗均在治疗上有效。因此，我们的研究结果表明，膀胱中 NGF 驱动的感觉萌芽与慢性肥大细胞激活相结合，代表了导致 rUTI 患者经历的细菌非依赖性疼痛和排尿缺陷的潜在机制。