在现代集约化家禽养殖中，病原微生物感染、热或冷应激、以及各类应激原均会导致家禽肝脏和肠道氧化应激损伤和炎症反应。当肠道发生氧化应激和炎症损伤后，肠道屏障功能受损且通透性增加，肠道内细菌及其产生的内毒素（LPS）释放入血，引起更加严重的全身性损伤，甚至导致家禽的猝死。因此以往养殖过程中通常在饲料里添加抗生素来降低家禽发病率和死亡率，随着我国法律规定禁止滥用抗生素，养殖业迫切需求安全、高效的饲用抗生素替代品。因此探究纯天然植物提取物作为家禽养殖的饲料添加剂以此提高肉鸡的免疫保护作用具有重要的意义和实际应用价值。鼠尾草酸(Carnosic acid，CA)是普遍存在于迷迭香和鼠尾草科植物中的一种天然苯二酚松香二萜，具有很强的抗氧化、抗炎症、抗菌及抗肿瘤等功能。CA作为一种脂溶性天然抗氧化剂因其具有良好的药理活性被广泛应用于生物医药、食品、化妆和保健品等行业中。各种研究也表明了CA在体外和体内实验模型中能够发挥一定药用价值，添加鼠尾草酸作为家禽养殖的饲料添加剂使用也符合目前国家减抗限抗的方针政策。本试验选用爱拔益加（Arbor Acres，AA）肉鸡、鸡肝细胞（LMH）为试验对象，以LPS构建氧化应激和炎症模型，来探究鼠尾草酸减轻家禽脏器（尤其肝脏、肠道）的氧化应激和炎症损伤的效果及其抗损伤机制。本试验包括以下三个实验部分：

实验一：鼠尾草酸对LPS诱导鸡肝脏损伤的保护作用

将120只18日龄AA肉鸡按平均体重分为8组，每个试验组10只鸡。鸡舍内各组保持一致的温度和湿度，鸡笼卫生环境按时清洁，且各组均为自由采食和饮水。试验期一共14天，前期一周让鸡群适应环境避免额外应激，后一周开始饲喂鼠尾草酸。对照组（CON）与LPS组不做鼠尾草酸处理，其余组分别按照低剂量（20 mg/kg）、中剂量（40 mg/kg）、高剂量（80 mg/kg）灌胃CA，灌胃维持一周后，腹腔注射LPS，注射剂量为200 mL/kg，12 h后采样。试验结果表明：（1）在灌胃鼠尾草酸一周后，CA对肉鸡的体重无显著性影响。（2）在肉鸡血清生化指标中，与单独接受LPS刺激的肉鸡相比，鼠尾草酸能够降低肉鸡血清中IL-6、MDA、IL-1β、CK-MB、AST、iNOS、TNF-α、LDH、CK-MB的含量（P < 0.05）并且增加SOD和T-AOC的含量（P < 0.05）。（3）与对照组相比LPS组肉鸡肝脏有较重的炎症反应，炎性细胞浸润、肝细胞索排列结构紊乱、细胞核固缩，CA干预后病变症状有明显的改善。（4）肝脏的免疫组化实验表明试验组与对照组中均有Hsp60、Hsp70和Nrf2的表达，LPS刺激下主要分布在胞质里的Hsp60、Hsp70阳性信号明显增多，肝细胞核中的表达量较少，CA中剂量组的阳性信号较LPS组有一定的下调。正常情况下Nrf2位于胞质中，LPS作用后的Nrf2大量转移至胞核中，表达量也明显升高，而LPS + CA组则极显著升高。（5）在Western blot水平上与CON组比，CA组Hsp70蛋白的表达水平有少量增加，而LPS能显著上调Hsp70、p38、ERK的表达（P < 0.05），在LPS + CA组中Hsp60、Hsp70、p38、ERK蛋白表达量显著下降（P < 0.05）。其中 JNK蛋白经灰度值统计分析发现各组个体数据差异较大，数据差异不明显。

实验二：鼠尾草酸对LPS诱导鸡肠道损伤的保护作用

试验设计同试验一。（1）与CON组比，CA组能提高肠道绒毛的高度和隐窝深度。LPS组肠道组织炎性损伤较为明显，肠绒毛长度降低、脱落断裂，并且炎性细胞浸润明显，CA干预后能够缓解LPS造成的损伤，绒毛高度和隐窝深度都有显著提高。（2）在肉鸡肠道的免疫组化里Hsp60、Hsp70在试验组与对照组中均有表达，CA高剂量组中Hsp60、Hsp70的表达量有所上调，LPS组中Hsp70表达上升趋势较为显著（P < 0.05），而LPS+CA组中Hsp70有明显下降趋势（P < 0.05）。在对照组和LPS组中Connexin表达量较少，而低剂量组与中剂量鼠尾草酸均可在一定程度上引起Connexin表达量上调（P < 0.05）。CD45在正常情况下的CON组中无阳性信号表达，LPS组中CD45作为炎症细胞标记有显著提高，LPS+CA组表达量略微下调。（3）在Western blot水平中与CON组比，CA可以提高Hsp70、Hsp60蛋白的表达，降低p38、ERK蛋白的表达，LPS能显著上调Hsp70、Hsp60、p38、ERK的表达，而添加了鼠尾草酸干预后Hsp70、Hsp60、p38、ERK蛋白表达量均有所下降（P < 0.01）。

实验三：鼠尾草酸对LPS诱导鸡肝细胞系损伤的保护作用

本试验选用鸡肝细胞系（LMH），分组为CON组、CA组、LPS组、CA+ LPS组，每组设3个重复。根据前期实验结果CA溶解在二甲基亚砜（DMSO）中最佳浓度为3.5 μg/mL，LPS 用PBS溶解浓度为1 μg/mL。待细胞贴壁后去上清，加CA和DMSO给药反应24 h，再用LPS刺激1 h收样。 试验结果：（1）对照CON组LMH细胞形态为上皮细胞样，LPS刺激下部分LMH细胞出现肿胀、胞核溶解固缩，染色加深。（2）根据RNA-Seq结果得知，在CA干预LPS刺激细胞中，差异基因表达有404个，这些差异基因主要参与了蛋白质合成代谢、生物调节、细胞信号转导等重要生物学过程。（3）CON组与LPS组的CryAB蛋白均无明显表达，而添加鼠尾草酸的组别均有显著表达（P < 0.05）。与对照组相比CA组能够使Hsp60、p38、ERK的表达部分下调，而当细胞受到LPS刺激时Hsp60、p38、ERK、Hsp70表达量都有所升高，在鼠尾草酸干预下各蛋白表达都有所下降但无统计学差异。（4）LMH细胞IF结果与Western blot结果一致，CryAB蛋白在CON组与LPS组中仅有少量信号，CA组与CA+ LPS组均有显著表达。Hsp60在正常情况下有少量信号位于胞质中，CA能上调Hsp60的表达量，而LPS组信号显著增多，CA+ LPS组又有下降趋势。CON组中的Nrf2荧光信号主要位于细胞质中，胞核中也有微弱表达；CA组细胞内Nrf2定位于胞质的荧光强度表达稍有提高；在LPS刺激下，Nrf2进入细胞核中的荧光信号表达显著提高，与LPS组相比CA干预后Nrf2入核信号表达有一定下调。（5）鼠尾草酸分组为低（2.5 μg/mL）、中（3.5 μg/mL）、高（4.5 μg/mL）剂量组，测量细胞上清中MDA、SOD、T-AOC、AST/GOT的表达水平，中剂量组鼠尾草酸（3.5 μg/mL）可以显著抑制由LPS引起的MDA及AST/GOT水平上调，且显著上调SOD的表达量。（6）DCHF-DA荧光探针法检测细胞内ROS相对含量，与CON组相比LPS组中的ROS水平升高；与LPS组相比，CA干预后的细胞内ROS水平降低，表明CA对LPS诱导LMH细胞ROS水平上调具有抑制作用。以上体外体内实验结果均表明了鼠尾草酸可以减轻由LPS所导致的家禽脏器（尤其肝脏、肠道）的氧化应激和炎症损伤，鼠尾草酸有望开发为家禽养殖的饲料添加剂使用。

Intensive poultry farming often leads to oxidative stress damage and inflammatory response in poultry organs due to pathogenic microbial infection, heat or cold stress, and various stressors. This can impair intestinal barrier function, increase permeability, and release endotoxins into the bloodstream, resulting in systemic damage and even sudden death of poultry. The use of antibiotics in feed has been a common practice to reduce morbidity and mortality in the past, but due to the ban on antibiotics in feed, safe and efficient alternatives are urgently needed in the market. Therefore, exploring a pure natural plant extract as a feed additive for poultry breeding to improve the immune protection of broilers is of great practical application value. Carnosic acid (CA), a phenolic diterpenoid found in rosemary and sage plants, has been shown to have strong antioxidant, anti-inflammatory, antibacterial and antitumor functions. It is widely used in various industries such as food processing, biomedicine, cosmetics and health care products due to its good pharmacological activity. Previous studies have also shown that CA has certain medicinal value in in vitro and in vivo experimental models, and the addition of Carnosic acid as a feed additive for poultry breeding is also in line with the current national policy of reducing and limiting resistance.In this experiment, Arbor Acres (AA) broiler chickens and chicken liver cells (LMH) were selected to explore the protective effect of Carnosic acid on poultry organs (especially liver, intestinal tract) and its anti-injury mechanism，and LPS was used for establish oxidative stress and inflammation models in vivo and in vitro. The experiment consisted of the following three experimental parts:

Experiment 1: Protective effect of Carnosic acid on LPS-induced liver injury in chickens

120 18-day-old AA broilers were divided into 8 groups according to their average body weight, with at least 10 chickens in each experiment group. Each group in the chicken coop maintained a consistent temperature and humidity, and the hygienic environment of the chicken cage was cleaned on time, and each group had free access to food and water. The test period was 14 days in total. In the first week, the chickens were allowed to adapt to the environment to avoid additional stress, and then they were fed Carnosic acid in the second week. The control group (CON) and the LPS group were not treated with Carnosic acid, and the other groups were given CA at a low dose (20 mg/kg), a medium dose (40 mg/kg), and a high dose (80 mg/kg) respectively. After one week of gavage maintenance,  LPS was injected intraperitoneally at a dose of 200 mL/kg, and samples were seleted after treatment for 12 hour hours. The experiment results showed that: (1) CA had no significant effect on the body weight of broiler chickens after gavage of Carnosic acid for one week. (2) Among broiler chicken serum biochemical indicators, compared with broiler chickens stimulated only by LPS, Carnosic acid + LPS group significantly redused the damage associated indicaters such as  IL-6, MDA, IL-1β, CK-MB, AST, iNOS, TNF-α, LDH, CK-MB level (P < 0.05) and increased the level of anti-oxidative enzyme SOD and T-AOC (P < 0.05). (3) Our pathological experiment showed that, compared with the control group, broiler livers in the LPS group had severe inflammation response, inflammatory cell infiltration, hepatocyte cord arrangement disorder, and nuclear pyknosis. The groups fed with CA showed much lighter pathological changes in liver. (4) Our immunohistochemistry results showed that, Hsp60, Hsp70 and Nrf2 were expressed in both the experiment and the control group in liver. The positive signals of Hsp60 and Hsp70 were significantly increased under LPS stimulation, and both proteins were mainly distributed in the cytoplasm of hepatocytes. Under normal circumstances, Nrf2 is located in the cytoplasm, and after the treatment with LPS, a large amount of Nrf2 is transferred to the nuclear, and the expression level is also significantly increased, while the LPS + CA group is extremely significantly induced. (5) Our western blot results suggested  LPS significantly upregulated the expression of Hsp70, P38, and ERK in chicken liver (P < 0.05) , and the expression of Hsp70, P38, and ERK proteins were significantly decreased in the LPS+CA group (P < 0.05). Among them, the statistical analysis of the gray value of the JNK protein found that the individual data of each group had a large difference, and the data difference was not obvious.

Experiment 2: Protective effect of Carnosic acid on LPS-induced intestinal injury in chickens

The experimental design was the same as that of Experiment 1. (1) Compared with the CON group, the CA group can increase the height of intestinal villi and the depth of crypts. In the LPS group, the inflammatory injury of intestinal tissue was more severe, presented the length of intestinal villi was reduced, shed and broken, and inflammatory cells infiltrated significantly. After CA intervention, the damage caused by LPS could be alleviated, and the height of villi and the depth of crypts were significantly improved. (2) Immunohistochemistry results suggested Hsp60 and Hsp70 were expressed in both the experiment and the control group. The expression of Hsp60 and Hsp70 in the high-dose CA group was up-regulated, with a significant upward trend in the LPS group (P < 0.05) and a significant downward trend in the LPS+CA group (P < 0.05). The expression of Connexin was less in the control group and LPS group, while both the low-dose group and the middle-dose Carnosic acid could up-regulate the expression of Connexin to a certain extent (P < 0.05). CD45 had no positive signal expression in the CON group under normal conditions, CD45 as an inflammatory cell marker was significantly increased in the LPS group. However in LPS+CA group, CD45 showed weaker signal which suggested that Carnosic acid could reduce LPS induced inflammation resopnse. (3) Western blot results showed that CA can increase the expression of Hsp70, Hsp60 protein, reduce the expression of p38, ERK protein, LPS can significantly up-regulate the expression of Hsp70, Hsp60, p38, ERK in chicken intestine. And after fed with Carnosic acid the expression of Hsp70, Hsp60, P38 and ERK were decreased compared with the LPS treatment group (P < 0.01).

Experiment 3: Protective effect of Carnosic acid on LPS-induced hepatocellular carcinoma cell injury in vitro

Chicken hepatocytes (LMH) were used in this experiment, and they were divided into CON group, CA group, LPS group, and CA+LPS group, with 3 replicates in each group. According to the previous experimental results, the optimal concentration of CA dissolved in dimethyl sulfoxide (DMSO) was 3.5 μg/mL, and the concentration of LPS dissolved in PBS was 1 μg/mL. After the cells adhered to the wall, the supernatant was removed, and CA and DMSO were added to react for 24 h, and then stimulated with LPS for 1 h to collect the samples. Experimental results were: (1) The morphology of LMH cells in control group CON was epithelial-like, and normal cell morphology could be found in CA group and CA+LPS group. Under LPS stimulation, some LMH cells appeared swelling, nuclear dissolved and pyknotic, and the staining deepened. (2) Based on the RNA-Seq results, we know that compared with LPS group，404 differential genes were expressed in CA+LPS group, and these differential genes are mainly involved in protein anabolism, bioregulation, cell signaling and other important biological processes. (3) CryAB protein level was not significantly expressed in the CON group and the LPS group, while it was significantly expressed in the group with the addition of Carnosic acid (P < 0.05). Hsp60, P38, and ERK in the CA group showed downregulate  expression  level compared with CON group. The expression of Hsp60, P38, ERK, and Hsp70 were all increased when the cells were stimulated by LPS. However the expression of each protein was decreased but not statistically different under Carnosic acid intervention. (4) The results of immunofluorescence staining of LMH cells were consistent with the results of Western blot results. CryAB protein had only a small amount of signal in the CON group and the LPS group, but it was significantly expressed in the CA group and the CA+ LPS group. Under normal circumstances, a small amount of Hsp60 signal is located in the cytoplasm, and CA can up-regulate the expression of Hsp60, while the signal in the LPS group increased significantly, and the CA+LPS group showed a downward trend. In the CON group, the Nrf2 fluorescence signal is mainly located in the cytoplasm, and there is also a weak expression in the nucleus; in the CA group, the expression of the fluorescence intensity of Nrf2 localized in the cytoplasm is slightly increased; under the stimulation of LPS, the expression of the fluorescence signal of Nrf2 entering the nuclear is significant. Compared with the LPS group, the expression of Nrf2 nuclear import signal was down-regulated after CA intervention. (5) The expression levels of MDA, SOD, T-AOC and AST/GOT in cell supernatants were measured in low (2.5 μg/mL), medium (3.5 μg/mL) and high (4.5 μg/mL) dose groups. CA in the medium dose group  (3.5 μg/mL) significantly inhibited the upregulation of MDA and AST/GOT levels caused by LPS, and significantly upregulated the expression of SOD. (6) The relative content of intracellular ROS was detected by DCHF-DA fluorescent probe method. Compared with the CON group, the ROS level in the LPS group increased; compared with the LPS group, the intracellular ROS level after CA intervention decreased, indicating that CA has an effect on LPS-induced up-regulation of ROS levels in LMH cells has an inhibitory effect. The above in vitro experimental results show that carnoic acid can reduce oxidative stress and inflammatory damage in poultry organs (especially liver and intestines) caused by LPS, and CA is expected to be developed as a feed additive for poultry farming.

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