Post-Traumatic Inflammatory Signaling in CRPS

CRPS 中的创伤后炎症信号传导

• 批准号: 8857404
• 负责人: DAVID J. CLARK
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857404
• 关键词: Adverse effects; Affect; Afferent Neurons; Age; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Attenuated; Biological Assay; Blast Injuries; Blood Cell Count; Blood Vessels; Bulla; Calcitonin Gene-Related Peptide; Cell Count; Cells; Characteristics; Chronic; Clinical; Clinical Management; Clinical Trials; Complex Regional Pain Syndromes; Confocal Microscopy; Consensus; Contracture; Contralateral; Cutaneous; Cytokine Activation; Data; Development; Disease; Distal; Edema; Effectiveness; Endothelial Cells; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Etanercept; Etiology; Extravasation; FDA approved; Foundations; Fracture; Functional disorder; Future; Generations; Goals; Growth Factor; Head; Healthcare Systems; Hindlimb; Hypersensitivity; Immobilization; Immunohistochemistry; In Situ Hybridization; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-6; Intravenous; Joints; Lead; Light; Limb structure; Lymphocyte; Maps; Mediating; Mediator of activation protein; Methods; Modeling; Nerve; Nerve Growth Factors; Neuraxis; Neurogenic Inflammation; Neuropeptides; Neutrophil Infiltration; Nociception; Opiates; Osteoporosis; Pain; Pathologic; Patients; Pattern; Pentoxifylline; Perfusion; Peripheral; Pharmaceutical Preparations; Phase; Population; Process; Production; Proteins; Quality of life; Rattus; Redness; Risk; Risk Factors; Role; Safety; Sampling; Sedimentation process; Sensory; Side; Signal Pathway; Signal Transduction; Skin; Skin Temperature; Source; Staging; Stimulus; Substance P; Substance P Receptor; Symptoms; Syndrome; T-Lymphocyte; Testing; Therapeutic Effect; Time; Touch sensation; Translating; Trauma; Treatment Efficacy; Tryptase; Tumor Necrosis Factor-alpha; Up-Regulation; Vasodilation; Veterans; War; Western Blotting; Work; abstracting; allodynia; anakinra; base; bisphosphonate; body system; bone; bone loss; chronic pain; control trial; cytokine; disability; drug efficacy; effective therapy; improved; inhibitor/antagonist; injured; keratinocyte; limb fracture; mRNA Expression; macrophage; mast cell; new therapeutic target; novel; prevent; protein expression; receptor; receptor expression; research study; response; sex; sound; tibia; translational study; tumor necrosis factor-alpha inhibitor; vascular inflammation

DESCRIPTION (provided by applicant): 6. Project Summary/Abstract: Limb trauma can lead to the development of a complex regional pain syndrome (CRPS). At onset this syndrome presents a baffling array vascular, bone, and nociceptive changes in the injured limb that can evolve into chronic edema, pain, weakness, contractures, and osteoporosis. Currently there is no consensus on either the pathophysiology or treatment for CRPS and there is a need for translational studies to identify therapeutic targets and novel pharmacologic approaches. The most common etiology for CRPS is distal limb fracture and we have developed a rat fracture model resembling CRPS. After distal tibia fracture and cast immobilization for 4 weeks the rats develop chronic unilateral hindlimb warmth, edema, increased spontaneous protein extravasation, periarticular osteoporosis, hindlimb unweighting, and allodynia, changes paralleling those observed in CRPS patients. The vascular and nociceptive changes characteristic of the early stages of CRPS suggest an inflammatory process, yet there is little evidence for an immunocyte response. On the other hand, there is compelling evidence that neurogenic inflammatory responses mediated by substance P (SP) signaling are exaggerated in the CRPS limb and in the rat fracture model. Substance P signaling stimulates keratinocyte proliferation, activation, and cytokine and growth factor production in vitro, including tumor necrosis factor alpha (TNF), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and nerve growth factor (NGF). TNF and IL-6 are up-regulated in experimental skin blisters in CRPS limbs and we have observed that all these inflammatory cytokines and NGF are up-regulated in the hindpaw skin of the fracture rats. When we administered an SP receptor antagonist to the fracture rats the increase in cutaneous cytokines and NGF was prevented. Fracture rats treated with cytokine inhibitors or anti-NGF failed to develop allodynia and had attenuated hindlimb unweighting, indicating an important role for cytokine and growth factor signaling in the development of trauma induced pain. Based on these data we propose that fracture and immobilization enhance SP endothelial signaling in the injured limb, resulting in vascular inflammation with increased extravasation, edema and warmth. We also postulate that facilitated SP signaling activates keratinocyte expression of pronociceptive cytokines and NGF, resulting in post-traumatic pain symptoms. The primary objective of this proposal is to identify target-specific treatments for CRPS using approved or soon to be approved medications. This work is directed at understanding the peripheral sources of mediators supporting post-traumatic inflammation and pain sensitization and determining whether these mediators are associated with risk factors for the development of post-traumatic CRPS. We will also determine whether peripheral inflammatory mediators contribute to the transition of post-traumatic pain into a chronic pain state. The specific aims are; 1) to use immunohistochemistry methods to map post-traumatic changes in SP, inflammatory cytokine, and NGF signaling in keratinocytes, endothelial cells, and mast cells in the skin of CRPS patients and in a rat fracture model of CRPS, 2) identify risk factors for development of CRPS-like sequelae in the rat fracture model, including age, sex, ACE inhibitor usage, and immobility, and then use PCR, EIA, western blotting and extravasation assays to determine whether facilitated SP signaling and increased inflammatory cytokine and NGF expression are associated with an increased risk of developing post-traumatic CRPS in these conditions, and 3) establish the efficacy of the global cytokine inhibitor pentoxifylline, the SP receptor antagonist LY303870, and the NGF antibody tanezumab in preventing or attenuating the transition from early post-traumatic pain to chronic pain, and to evaluate their efficacy for treating chronic pain (16 weeks post-fracture) in the CRPS fracture model. These studies are expected to generate translational data supporting future clinical CRPS trials, with the potential for improving the efficacy and safety of the clinical management of post-traumatic pain syndromes.

描述（由申请人提供）： 6。项目摘要/摘要：肢体创伤可以导致复杂的区域疼痛综合征（CRP）的发展。该综合征在一开始就表现出令人困惑的阵列血管，骨骼和伤害性肢体的伤害性变化，可以演变为慢性水肿，疼痛，无力，染色体和骨质疏松症。当前，关于CRP的病理生理学或治疗均未达成共识，需要翻译研究来鉴定治疗靶标和新型药理学方法。 CRP的最常见病因是远端肢体骨折，我们开发了类似于CRP的大鼠断裂模型。胫骨远端裂缝和施加固定后，大鼠会出现慢性单侧后肢温暖，浮肿，自发蛋白质外渗出，周围骨质疏松症，后肢不重要和异形，在CRPS患者中观察到的那些会改变。 CRP早期阶段的血管和伤害感受的变化表明了炎症过程，但几乎没有证据表明免疫细胞反应。另一方面，有令人信服的证据表明，在CRPS的肢体和大鼠断裂模型中，通过物质P（SP）信号传导介导的神经源性炎症反应被夸大了。物质P信号传导刺激体外刺激角质形成细胞的增殖，激活以及细胞因子和生长因子的产生，包括肿瘤坏死因子alpha（TNF），白介素-1β（IL-1），白介素6（IL-6）（IL-6）和NEVER生长因子（NGF）。 TNF和IL-6在CRPS的实验性皮肤水泡中被上调，我们观察到所有这些炎性细胞因子和NGF在骨折大鼠的后爪皮中都上调。当我们对骨折大鼠的SP受体拮抗剂施用SP受体拮抗剂时，可以防止皮细胞因子和NGF的增加。用细胞因子抑制剂或抗NGF治疗的骨折大鼠未能发育异常性疾病，并减弱了后肢不体，这表明细胞因子和生长因子信号传导在创伤引起的疼痛的发展中起重要作用。基于这些数据，我们建议裂缝和固定化增强了受伤的肢体中的SP内皮信号传导，从而导致血管炎症随着渗出，水肿和温暖的增加而导致血管炎症。我们还假设，促进SP信号传导会激活pro摄影性细胞因子和NGF的角质形成细胞的表达，从而导致创伤后疼痛症状。 该提案的主要目的是使用批准或即将获得批准的药物来识别CRP的特定目标治疗方法。这项工作旨在理解支持创伤后炎症和疼痛敏化的介体的外围来源，并确定这些介体是否与创伤后CRP的危险因素有关。我们还将确定外围炎症介质是否有助于创伤后疼痛向慢性疼痛状态过渡。具体目标是； 1）使用免疫组织化学方法来绘制角质形成细胞，内皮细胞，内皮细胞和CRPS患者皮肤中的内皮细胞和肥大细胞中SP，炎症细胞因子和NGF信号传导的创伤后变化，以及CRP的大鼠骨折模型中的CRPS型和2）在CRP型frectier的风险因素中识别出类似于CRP的风险因素，包括年龄段的frectire模型，包括大鼠frectire的风险。 immobility, and then use PCR, EIA, western blotting and extravasation assays to determine whether facilitated SP signaling and increased inflammatory cytokine and NGF expression are associated with an increased risk of developing post-traumatic CRPS in these conditions, and 3) establish the efficacy of the global cytokine inhibitor pentoxifylline, the SP receptor antagonist LY303870, and the NGF antibody Tanezumab预防或减弱从创伤后疼痛到慢性疼痛的过渡，并评估其在CRPS骨折模型中治疗慢性疼痛（骨折后16周）的疗效。预计这些研究将产生转化数据，以支持未来的临床CRP试验，并有可能提高创伤后疼痛综合征的临床管理的功效和安全性。