Mechanisms of pain from urinary tract infection.
Mechanisms of pain from urinary tract infection.
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DOI：
10.1111/iju.12309
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Klumpp DJ
中科院分区：
文献类型：
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作者：
Rosen JM;Klumpp DJ
尿路感染（UTI）的疼痛反应在很大程度上是不明确的，但对UTI的症状反应与无症状性细菌尿（ASB）个体缺乏疼痛反应形成对比。在小鼠尿路感染模型中量化盆腔疼痛，尿路致病性大肠杆菌（UPEC）诱导短暂的盆腔疼痛，而ASB大肠杆菌分离物不会引起疼痛，从而概括了膀胱内大肠杆菌的临床反应谱。这些不同的疼痛反应与膀胱定植或炎症无关，而是大肠杆菌脂多糖（LPS）固有的，依赖于LPS受体TLR4。流行病学数据表明间质性膀胱炎（IC）与尿路感染史之间存在联系，因此评估了重复UPEC滴注是否会通过中枢致敏导致慢性疼痛。野生型UPEC反复感染只会导致短暂的急性疼痛发作，而缺乏o抗原的UPEC突变体会导致慢性尿路感染后盆腔疼痛。同样，缺乏o抗原的K-12大肠杆菌菌株诱导慢性疼痛，在细菌清除后持续很长时间，表达o抗原使疼痛表型无效。从uti后慢性疼痛小鼠中分离的脊髓显示出与中枢致敏一致的短期抑郁缺陷。从UPEC菌株中删除o抗原基因复合物和随后o抗原基因簇的异源表达表明，单个细菌分离物可以表现出从零表型、急性疼痛表型到慢性疼痛表型的疼痛表型。尿路感染后慢性疼痛还与排尿功能障碍和焦虑/抑郁行为有关。这些作用也由TRPV1在疼痛建立水平和CCR2在疼痛维持水平介导。总之，这些发现表明，短暂感染大肠杆菌可能导致慢性内脏疼痛与神经性疼痛的标志。这种行为模式模拟了IC症状的频谱，因此支持IC感染病因的可能性。
The pain response to urinary tract infection (UTI) is largely uncharacterized, but the symptomatic response to UTI contrasts with the lack of pain response among individuals with asymptomatic bacteriuria (ASB). Quantifying pelvic pain in a murine UTI model, uropathogenic E. coli (UPEC) induce transient pelvic pain, whereas an ASB E. coli isolate causes no pain, thus recapitulating the spectrum of clinical responses to intravesical E. coli. These differential pain responses are not correlated with bladder colonization or inflammation but instead are intrinsic to E. coli lipopolysaccharide (LPS) and dependent upon the LPS receptor TLR4. Epidemiologic data suggest a link between interstitial cystitis (IC) and a history of UTI, so it was evaluated whether repetitive UPEC instillation would result in chronic pain via central sensitization. While repeated infection with wild type UPEC result in only transient episodes of acute pain, a UPEC mutant lacking O-antigen causes chronic, post-UTI pelvic pain. Similarly, a K-12 E. coli strain lacking O-antigen induces chronic pain that persisted long after bacterial clearance, and expressing O-antigen nullified the pain phenotype. Spinal cords isolated from mice with post-UTI chronic pain exhibited deficits in short term depression consistent with central sensitization. Deleting O-antigen gene complex from a UPEC strain and subsequent heterologous expression of O-antigen gene clusters demonstrates that a single bacterial isolate can exhibit pain phenotypes ranging from a null phenotype, an acute pain phenotype, to a chronic pain phenotype. Post-UTI chronic pain is also associated with voiding dysfunction and anxious/depressive behavior. These effects are also mediated by TRPV1 at the level of pain establishment and CCR2 at the level of pain maintenance. Together, these findings demonstrate that transient infection with E. coli may result in chronic visceral pain with the hallmarks of neuropathic pain. This pattern of behaviors mimics the spectrum of IC symptoms, thus supporting the possibility of an infectious etiology of IC.