Restraint stress-induced neurogenic bladder inflammation
抑制应激诱发的神经源性膀胱炎症
基本信息
- 批准号:6751596
- 负责人:
- 金额:$ 24.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-06-01 至 2007-04-30
- 项目状态:已结题
- 来源:
- 关键词:autoradiographycorticotropin releasing factorfemalegel mobility shift assaygenetically modified animalshistaminehormone regulation /control mechanisminflammationinterleukin 6laboratory mouselight microscopymast cellneurogenic urinary bladder disorderneurotensinnuclear factor kappa betastresssubstance Ptumor necrosis factor alphavascular endothelium permeability
项目摘要
DESCRIPTION (provided by applicant): The urinary bladder is often the site of subacute or chronic inflammation, in the absence of infection, as in interstitial cystitis (IC), a painful bladder disorder occurring mostly in women. Symptoms of urinary frequency and pelvic pain commonly worsen perimenstrually and under stress in IC. Bladder mastocytosis with mast cell activation has been documented in IC. We also showed that acute immobilizationstress in rodents induced bladder mast cell activation, a process that was dependent on the neuropeptides neurotensin (NT) and substance P (SP), as it was absent in rodents treated with capsaicin to deplete sensory nerve fibers of their SP content and was also inhibited by the NT receptor antagonist SR48692. Moreover, pretreatment of bladder with estradiol increased the stimulatory effect of SP, by activating high affinity estrogen receptors that we have identified on bladder mast cells. It was recently shown that bladder inflammation could not occur in mast cell deficient mice infected with the neurotropic pseudorabies virus. Mast cells are located perivascularly close to nerve processes and may secrete many vasoactive, proinflammatory and neurosensitizing molecules in response to allergic triggers, as well as by direct nerve stimulation and by acute immobilization stress. Corticotropin releasing hormone (CRH) is released from the hypothalamus under stress and activates the hypothalamic-pituitary-adrenal (HPA) axis. However, both CRH and its structurally related urocortin (Ucn) are also released in the periphery where they have proinflammatory effects. CRH and Ucn induced rat skin mast cell activation and increased vascular permeability, both of which were inhibited by pretreatment with neutralizing antiserum to CRH or the CRH-receptor (CRH-R) antagonist, antalarmin. CRH or acute stress-induced skin vascular permeability was absent in W/W v mast cell deficient mice, but was present in their +/+ controls indicating it is mast cell dependent. Acute stress also triggered rat bladder mast cell activation that was blocked by a NT-receptor antagonist. The proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosisfactor-alpha (TNF-alpha) were recently shown to be elevated in urine of IC patients. We are hypothesizing that acute stress releases (CRH) and/or (Ucn) in the bladder leading, directly or through SP or NT, to mast cell activation, increased vascular permeability and the expression of proinflammatory molecules. We propose to use normal and genetically deficient female mice to investigate the effect of acute stress and CRH/Ucn on: (1) bladder mast cell and urothelial Nuclear Factor kappa B (NF-kappaB)activation, as well as the levels of histamine,lL-6 and TNF-alpha in the urine collected from an indwelling catheter; (2) bladder vascular permeability quantitated by 99Technetium-gluceptate (99Tc) extravasation; (3) Vascular permeability, urine mediator release, as well as NF-kappaB activation in W/W v mast cell deficient mice, as well as in CRH knock-out mice and their +/+ controls; (4) mouse bladder mast cell and urothelial NF-KB activation, as well as secretion of histamine, IL-6 or TNF-alpha induced by intravesical administration of CRH/Ucn. These studies will help us understand how acute stress triggers bladder mast cell activation leading to increased vascular permeability and proinflammatory molecule release. Our findings may be relevant to the pathophysiology of IC and may suggest new therapeutic approaches.
描述(由申请人提供):在没有感染的情况下,膀胱通常是亚急性或慢性炎症的部位,如间质性膀胱炎(IC),这是一种主要发生在女性身上的膀胱疼痛疾病。在IC中,尿频和盆腔疼痛的症状通常会在月经周围和应激下恶化。膀胱肥大细胞增多症伴肥大细胞激活已在IC中得到证实。我们还发现,啮齿动物急性固定应激诱导膀胱肥大细胞激活,这一过程依赖于神经肽神经紧张素(NT)和P物质(SP)。因为在用辣椒素处理的啮齿动物中,它不存在以消耗其SP含量的感觉神经纤维,并且也被NT受体拮抗剂SR48692所抑制。此外,用雌二醇预处理膀胱,通过激活我们在膀胱肥大细胞上发现的高亲和力雌激素受体,增加了SP的刺激作用。最近的研究表明,肥大细胞缺陷小鼠感染嗜神经性伪狂犬病毒后不会发生膀胱炎症。肥大细胞位于血管周围,靠近神经突,可能在过敏触发、直接神经刺激和急性固定应激下分泌许多血管活性、促炎和神经致敏分子。促肾上腺皮质激素释放激素(CRH)在压力下从下丘脑释放,激活下丘脑-垂体-肾上腺(HPA)轴。然而,CRH及其结构相关的尿皮质素(Ucn)也在外周释放,具有促炎作用。CRH和Ucn诱导大鼠皮肤肥大细胞活化和血管通透性增加,这两种作用均可通过中和抗CRH血清或CRH受体拮抗剂安特拉明预处理来抑制。在W/W / v肥大细胞缺陷小鼠中不存在CRH或急性应激诱导的皮肤血管通透性,但在+/+对照中存在,表明它依赖肥大细胞。急性应激也触发了被nt受体拮抗剂阻断的大鼠膀胱肥大细胞的激活。最近发现IC患者尿液中促炎细胞因子白介素-6 (IL-6)和肿瘤坏死因子- α (tnf - α)升高。我们假设膀胱中的急性应激释放(CRH)和/或(Ucn)直接或通过SP或NT导致肥大细胞活化,血管通透性增加和促炎分子的表达。我们拟用正常和基因缺陷雌性小鼠研究急性应激和CRH/Ucn对:(1)膀胱肥大细胞和尿路上皮核因子κ B (nf - κ B)活化,以及留置导尿中组胺、il -6和tnf - α水平的影响;(2) 99Tc外渗法测定膀胱血管通透性;(3) W/W / v肥大细胞缺陷小鼠、CRH敲除小鼠及其+/+对照的血管通透性、尿介质释放和NF-kappaB活化;(4)膀胱给药CRH/Ucn诱导小鼠膀胱肥大细胞和尿路上皮NF-KB活化,以及组胺、IL-6或tnf - α的分泌。这些研究将帮助我们了解急性应激如何触发膀胱肥大细胞活化,导致血管通透性增加和促炎分子释放。我们的发现可能与IC的病理生理有关,并可能提出新的治疗方法。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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THEOHARIS C. THEOHARIDES其他文献
THEOHARIS C. THEOHARIDES的其他文献
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{{ truncateString('THEOHARIS C. THEOHARIDES', 18)}}的其他基金
Mast cells, antidepressants and chronic fatigue syndrome
肥大细胞、抗抑郁药和慢性疲劳综合症
- 批准号:
7296142 - 财政年份:2006
- 资助金额:
$ 24.57万 - 项目类别:
Mast cells, antidepressants and chronic fatigue syndrome
肥大细胞、抗抑郁药和慢性疲劳综合症
- 批准号:
7125762 - 财政年份:2006
- 资助金额:
$ 24.57万 - 项目类别:
Restraint stress-induced neurogenic bladder inflammation
抑制应激诱发的神经源性膀胱炎症
- 批准号:
6889614 - 财政年份:2003
- 资助金额:
$ 24.57万 - 项目类别:
Restraint stress-induced neurogenic bladder inflammation
约束应激诱发的神经源性膀胱炎症
- 批准号:
7060529 - 财政年份:2003
- 资助金额:
$ 24.57万 - 项目类别:
Restraint stress-induced neurogenic bladder inflammation
抑制应激诱发的神经源性膀胱炎症
- 批准号:
6558273 - 财政年份:2003
- 资助金额:
$ 24.57万 - 项目类别:
STRESS INDUCED SKIN MAST CELL ACTIVATION & VASODILATION
压力引起的皮肤肥大细胞激活
- 批准号:
7315757 - 财政年份:2001
- 资助金额:
$ 24.57万 - 项目类别:
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