亚急性瘤胃酸中毒引发肉牛瘤胃上皮炎性反应的信号转导机制

Subacute ruminal acidosis (SARA) not only triggers the inflammatory reaction of the rumen, but also cause the occurrence of systemic inflammatory diseases, and it has seriously hampered the development of the the pastoral beef cattle breeding industry. Therefore, understanding the factors and mechanisms on that SARA triggers rumen epithelial cell inflammation is the key to the prevention of SARA and secondary disease. The project proposes that SARA can change the rumen environment by high concentration of VFAs, and release large amounts of endotoxin and histamine and other biologically active substances, and destroy the rumen epithelial cell structure and its barrier function,and activate the inflammation reaction of the rumen epithelial cells in part and system.By the use of molecular biology and cell biology techniques, both in vivo and in vitro, we study the effect of the VFAs,LPS,histamine and other factors on rumen epithelial cell structure and function,the barrier function and its inflammatory signaling pathways,in order to confirming that SARA can destroy rumen epithelial cell barrier function and trigger the signal transduction mechanisms of the inflammation in rumen epithelial．

亚急性瘤胃酸中毒（SARA）是肉牛群发性疾病，不仅可以触发瘤胃的炎性反应，还能引起全身性炎性疾病的发生，严重制约了牧区肉牛养殖业的发展。因此，了解SARA触发瘤胃上皮细胞炎性反应的因素和机制，是防治SARA及其继发疾病的关键。本项目提出SARA可通过瘤胃高浓度的VFAs改变瘤胃内环境，释放出大量的内毒素（LPS）与组织胺等生物活性物质，破坏瘤胃上皮细胞结构及其屏障机能，激活瘤胃上皮细胞局部及全身性炎性反应的科学假设。运用分子生物学和细胞生物学等技术，拟通过SARA病牛实验和体外瘤胃上皮细胞模拟SARA实验，从VFAs、LPS、组胺等因素对瘤胃上皮细胞结构、功能等屏障机能及其细胞炎症信号通路的作用入手，确证SARA破坏瘤胃上皮细胞屏障机能，触发瘤胃上皮炎性反应的信号转导机制，为防治SARA引起的瘤胃上皮局部炎性反应及由此而引发的全身性炎性反应提供干预靶点，进一步提高肉牛SARA的防治效果。

本项目运用细胞生物学和分子生物学技术，重点研究肉牛亚急性瘤胃酸中毒时瘤胃炎症发生机制，瘤胃内环境变化及代谢产物对炎性损伤的调控作用。获得如下研究成果：（1）证实肉牛发生SARA时，血液LPS和组胺浓度显著升高，瘤胃上皮细胞角质化减弱，瘤胃乳头充血、肌层水肿，表现为炎性反应。（2）证实瘤胃内pH降低，VFAs、LPS和组胺蓄积引起瘤胃上皮细胞NF-κB信号通路的激活，诱发炎症反应。（3）证实黄连素会显著抑制LPS诱导的TLR4-NF-κB 和 MAPK信号通路的活化。以上研究新发现，不仅从分子水平揭示了亚急性瘤胃酸中毒时瘤胃炎症的发生机制，同时也发现中药黄连素具有较好的抗瘤胃炎症作用，为制订针对瘤胃炎性损伤为目的的防治措施奠定了理论基础。