CN102884434A - 用于诊断、控制和预防犬科动物炎症及减轻犬科动物炎性病况的方法 - Google Patents

用于诊断、控制和预防犬科动物炎症及减轻犬科动物炎性病况的方法 Download PDF

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CN102884434A
CN102884434A CN2011800236131A CN201180023613A CN102884434A CN 102884434 A CN102884434 A CN 102884434A CN 2011800236131 A CN2011800236131 A CN 2011800236131A CN 201180023613 A CN201180023613 A CN 201180023613A CN 102884434 A CN102884434 A CN 102884434A
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N.Z.弗兰茨
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Abstract

本发明涉及诊断、控制和预防犬科动物炎症及减轻犬科动物炎性病况特别是关节炎和关节痛的方法，其包括测量炎性生物标志物，其中血液中生物标志物水平的提高与炎症减少相关联，而血液中水平的降低与组织中水平的升高相关联。本发明进一步提供用于治疗或控制炎症的方法，其包括给予包含升高水平的DHA、EPA、维生素C、维生素E和/或L-肉碱中的一种或多种的饮食。

Description

用于诊断、控制和预防犬科动物炎症及减轻犬科动物炎性病况的方法
发明领域
本发明涉及诊断、控制和预防犬科动物炎症及减轻犬科动物炎性病况特别是关节炎和关节痛的方法，其包括测量炎性生物标志物，其中血液中生物标志物水平的提高与炎症减少相关联，而血液中水平的降低与组织中水平的升高相关联。本发明进一步提供用于治疗或控制炎症的方法，其包括给予包含升高水平的DHA、EPA、维生素C、维生素E和/或L-肉碱中的一种或多种的饮食(diet)。
发明背景
退行性关节病，更常与骨关节炎有关，是最常见的犬科动物肌肉骨骼疾病之一。从生物化学上来说，骨关节炎是滑膜关节中存在的关节软骨的合成和降解之间的失衡。其可包括常常涉及滑膜的炎症。炎症循环引起关节面的进一步降解，导致疼痛和跛行。在犬科动物中关节炎是跛行的最常见原因，已报道其发生率影响20%的1岁以上的犬科动物。关节炎可作为异常荷载、创伤、感染/炎症和十字韧带破裂的结果发生。诱病因素包括年龄、品种、尺寸、肥胖和遗传学。了解犬科动物关节炎中软骨代谢相关基因的表达如何改变可为治疗和/或帮助控制关节炎病况提供有用的深刻见解。
骨关节炎是由一个或多个关节的软骨、骨和软组织的进行性炎症和退化引起的慢性退行性关节病。类风湿性关节炎为引起炎症和关节损伤的自身免疫病况。二者均为慢性炎性病况。由于关节损伤是进行性的且在很大程度上不可逆，主动确定和处理炎性过程是合乎需要的。不幸的是，已证实血液中生物标志物的表达难以与组织中的表达相关联，使得在疾病导致剧烈疼痛和不可逆的组织损伤前诊断困难。
发明概述
令人惊讶地，在犬科动物中我们发现许多炎性生物标志物在血液中的表达与在组织中的表达相比呈负相关。生物标志物的血液水平在组织水平和相关炎症减少时较高。该负相关是出乎意料的，并为评估早期炎症的存在情况提供了新的方法。
因此在第一个实施方案中本发明提供检测犬科动物中炎性病况的方法，其包括测量一种或多种炎性生物标志物的血液水平，其中血液中表达的增加与组织中炎症的治愈和减少相关联。
在进一步的实施方案中，本发明提供控制和/或预防犬科动物炎症或减轻犬科动物炎性病况，特别是关节炎和关节痛的方法，其包括通过测量血液中较低水平的炎性标志物确定病况，和给予包含升高水平的DHA、EPA、维生素C、维生素E和/或L-肉碱中的一种或多种的饮食例如至少两周的时间。
发明详述
用于本文方法的饮食包括例如，包含升高水平的DHA、EPA、维生素C、维生素E和/或L-肉碱中的一种或多种，例如包含以干重计0.25 – 5% DHA+EPA的犬科动物饮食，例如包含以干重计的以下的饮食：
DHA + EPA：0.5-2.5%,
维生素C：75-1000mg/kg
维生素E：250 – 1000 mg/kg
L-肉碱：100-1000 mg/kg，
例如，具有近似实施例1的试验饮食的营养组成，例如具有表1确定的近似量(以干重计+/- 10%)成分的饮食。
当在组织中减少时在血液中增加的炎症生物标志物包括，例如，选自IL-6、ADAMTS-4、IFNG、HAS2、BGN、SOX-9、ADAMTS-5、MMP3、ACP5、IL1A、TNC、HAS3、COMP、IGF-1、GHR、Xaa-前肽酶、RANKL、SMAD7、PGE2、TLR9、PLOD1和SCL2A9的一种或多种生物标志物。
实施例1-饮食对关节炎犬科动物中炎性生物标志物的影响
进行研究以评估喂养患有骨关节炎(OA)犬科动物时试验饮食对全血中所选关节炎相关基因的影响。该研究包括31只比格犬(beagle) (初始体重为13.5 ± 1.27 kg，年龄1.0 ± 2.23岁)，其在至少一个关节处具有与OA一致的跛行和放射照相学改变。所有的犬科动物用对照维持食物喂养28天，随后用包含升高水平的EPA和DHA、维生素C和E以及L-肉碱的试验饮食喂养。在对照食物的最后一天和试验饮食14天后收集全血样品。记录试验饮食14天后这些犬科动物中提高的骨科检查分数。消耗试验配方14天后，OA犬科动物中22个基因(IL-6、ADAMTS-4、IFNG、HAS2、BGN、SOX-9、ADAMTS-5、MMP3、ACP5、IL1A、TNC、HAS3、COMP、IGF-1、GHR、Xaa-前肽酶、RANKL、SMAD7、PGE2、TLR9、PLOD1和SCL2A9)的表达增加，而这22个基因先前证明在OA老年犬科动物中相对健康老年犬科动物下调，且先前显示上调的ANXA1的表达降低。总之，用试验配方喂养患有骨关节炎的犬科动物导致先前在关节炎老年犬科动物相对健康老年犬科动物的血液中观测到的基因表达模式在14天后逆转。
表1：试验饮食的营养组分
营养物 干物质
蛋白质(%) 20
脂肪(%) 16
碳水化合物(%) 51
粗纤维(%) 9
肉碱(mg/kg) 351
维生素C (ppm) 225
维生素E (ppm) 585
DHA (%) 0.3
EPA (%) 0.5
本研究使用基因组全血Nanostring基因分析确定骨关节炎犬科动物消耗试验饮食后所选基因基于先前文献的变化。
本研究确定了具有不同程度放射照相学迹象的骨关节炎和跛行病史的31只阉割/切除卵巢的比格犬(初始体重为13.5 ± 1.27 kg，年龄11.0 ± 2.23岁)。通过身体检查和血清化学概况(profile)，所有的犬科动物在其它方面均被认为是健康的。所有的犬科动物针对犬瘟热、腺病毒、细小病毒、博德特氏菌和狂犬病进行免疫，且基于体格检查、全血计数测定、血清生化分析、尿分析和排泄物寄生虫检测的结果无一具有慢性全身性疾病。通过彼此间的互动、与看守人的日常互动和玩耍时间、每日户外奔跑和运动及获得玩具的机会，犬科动物经历行为充实(behavioral enrichment)。在收集样品前，所有的犬科动物用基础维持对照食物喂养28天。抽血并收集入PAXgene管中，-80oC保存直至进行评估。基于发表的文献和具有可用的犬科动物序列的基因选择用于分析的基因。使用Nanostring技术(表达分析)产生89个选择基因的数据。
基于所有样品中最稳定的基因将基因标准化。认为两组间P < 0.05 (Q=1的错误发现率调整后)且倍数变化为至少1.25的基因是不同的。上调基因显示为正的倍数变化。下调基因显示为负的倍数变化。
表2：14天后试验食物对基因调控的影响
Figure 2011800236131100002DEST_PATH_IMAGE001
Figure 499188DEST_PATH_IMAGE002
利用Nanostring技术分析全血基因表达概况发现23个所选基因在骨关节炎和正常老年犬科动物之间存在差异。大多数这些基因的表达与先前报道的在犬科动物骨关节炎软骨组织中的表达方向相反。然而，骨关节炎犬科动物消耗试验配方后，基因表达模式逆转至与健康老年犬科动物更相似。该数据证实了所测量的包括提高的骨科分数和软骨生物标志物的临床反应。
当前研究的结果显示，在消耗试验配方后，发现与正常老年犬科动物相比，骨关节炎老年犬科动物中所选基因的完全逆转不同。除基因表达变化外，观察到骨科分数和软骨生物标志物的提高。这些可为表明治疗性食物在OA犬科动物中的功效的有用标志。

Claims (9)

1.检测犬科动物中炎性病况的方法，其包括测量一种或多种炎性生物标志物的血液水平，其中血液中表达的增加与组织中炎症的减少相关联。
2.权利要求1的方法，其中待测量的生物标志物选自以下的一种或多种：IL-6、ADAMTS-4、IFNG、HAS2、BGN、SOX-9、ADAMTS-5、MMP3、ACP5、IL1A、TNC、HAS3、COMP、IGF-1、GHR、Xaa-前肽酶、RANKL、SMAD7、PGE2、TLR9、PLOD1和SCL2A9。
3.权利要求1或2的方法，还包括测量ANXA1的血液水平，其中ANXA1水平的水平降低与组织中炎症的减少相关联。
4.权利要求1、2或3的方法，其中相对于标准饮食，通过给予包含升高水平的DHA、EPA、维生素C、维生素E和/或L-肉碱中的一种或多种的饮食来治疗或控制所述炎性病况。
5.权利要求4的方法，其中给予所述饮食至少两周的时间。
6.权利要求4或5的方法，其中所述饮食包含以干重计的量为0.25 – 5%的DHA+EPA。
7.权利要求4的方法，其中以干重计，所述饮食包含以下：
DHA + EPA：0.5-2.5%
维生素C：75-1000mg/kg
维生素E：250 – 1000 mg/kg 
L-肉碱：100-1000 mg/kg。
8.权利要求4的方法，其中所述饮食近似具有实施例1的试验饮食的营养组成。
9.前述权利要求中任一项的方法，其中待控制或治疗的病况为骨关节炎。
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