本文選題：Kupffer細(xì)胞 + 骨髓間充質(zhì)干細(xì)胞��； 參考：《重慶醫(yī)科大學(xué)》2017年博士論文

【摘要】：第一部分:BMSCs在內(nèi)毒素導(dǎo)致的小鼠急性肝損傷中的保護(hù)作用目的:觀察靜脈給予外源性BMSCs能否抑制內(nèi)毒素(LPS)誘導(dǎo)的小鼠急性肝損傷以及肝臟KCs中的NLRP3炎癥小體活化及血清中的炎癥介質(zhì)表達(dá)水平,闡明BMSCs在膿毒癥導(dǎo)致的急性肝損傷中的意義及潛在機(jī)制。方法:全骨髓細(xì)胞選擇性貼壁法從Balb/C小鼠脛骨、股骨中分離BMSCs,采用慢病毒轉(zhuǎn)染ptges及ptges sh RNA至BMSCs,建立穩(wěn)定的ptges過表達(dá)BMSCs細(xì)胞株(BMSCs-PGE2(+))及ptges沉默的BMSCs細(xì)胞株(BMSCs-PGE2(-));30只Balb/C小鼠隨機(jī)分為5組:(1)對照組,(2)LPS組,(3)LPS+BMSCs組,(4)LPS+BMSCs-PGE2(+)組,(5)LPS+BMSCs-PGE2(-)。對照組小鼠腹膜腔及尾靜脈均注射PBS,另外四組小鼠先予以腹膜腔注射LPS(10 mg/kg)處理12小時,然后分別尾靜脈注射PBS、BMSCs、BMSCs-PGE2(+)及BMSCs-PGE2(-)(1×106個)處理12小時;獲取小鼠肝臟,采用HE染色評估肝臟炎癥程度,以TUNEL染色評估肝臟細(xì)胞凋亡情況;分離肝臟KCs,通過Western blotting檢測KCs中NLRP3,ASC,Pro-Casp1,Caspase-1及Pro-IL-1β蛋白表達(dá)水平;熒光實時定量PCR檢測KCs中NLRP3,ASC,Pro-Casp1及Caspase-1 m RNA表達(dá)水平;收集小鼠血液,ELISA法測定血清中ALT、AST、IL-1β、IL-10及PGE2水平。結(jié)果:(1)LPS組肝細(xì)胞明顯水腫,肝臟內(nèi)大量炎細(xì)胞浸潤;LPS+BMSCs組肝細(xì)胞水腫減輕,炎細(xì)胞浸潤減少,LPS+BMSCs-PGE2(+)處理組,肝臟炎癥程度進(jìn)一步減輕,而LPS+BMSCs-PGE2(-)組較LPS組無明顯變化。肝臟炎細(xì)胞浸潤數(shù)量于LPS組最多,LPS+BMSCs組明顯下降,LPS+BMSCs-PGE2(+)處理后炎細(xì)胞數(shù)量進(jìn)一步減少,差異具有統(tǒng)計學(xué)意義(P0.05);而LPS+BMSCs-PGE2(-)組較LPS組無明顯變化,差異無統(tǒng)計學(xué)意義(P0.05)。(2)LPS組中TUNEL染色陽性表現(xiàn)的肝臟凋亡細(xì)胞較對照組明顯增加,LPS+BMSCs組肝臟凋亡細(xì)胞較LPS組明顯減少(P0.05),LPS+BMSC-PGE2(+)組肝臟內(nèi)僅見零星分布的凋亡細(xì)胞(P0.05),差異具有統(tǒng)計學(xué)意義;而LPS+BMSC-PGE2(-)組,肝臟內(nèi)凋亡細(xì)胞較LPS組無明顯變化,差異不具有統(tǒng)計學(xué)意義(P0.05)。(3)KCs中NLRP3,ASC及caspase-1 m RNA相對表達(dá)量在LPS組最高,LPS+BMSC組較LPS組明顯下降,LPS+BMSC-PGE2(+)組較LPS+BMSC組進(jìn)一步下降,差異具有統(tǒng)計學(xué)意義(P0.05);與LPS組比較,LPS+BMSC-PGE2(-)組無明顯下降,差別不具有統(tǒng)計學(xué)意義(P0.05)。(4)KCs中NLRP3,ASC,Pro-Casp1,Caspase-1及Pro-IL-1β蛋白表達(dá)量在LPS組最高,LPS+BMSC組較LPS組明顯減低,LPS+BMSC-PGE2(+)組較LPS+BMSC組進(jìn)一步下降,差異具有統(tǒng)計學(xué)意義;而LPS+BMSC-PGE2(-)組較LPS組無明顯變化(P0.05)。(5)血清PGE2水平在對照組最低,LPS組略有升高;LPS+BMSC組較LPS組明顯升高,差異具有統(tǒng)計學(xué)意義(P0.05);LPS+BMSC-PGE2(+)組最高,明顯高于LPS+BMSCs組,差異具有統(tǒng)計學(xué)意義(P0.05);而在LPS+BMSC-PGE2(-)組與LPS組及空白對照組無明顯差異(P0.05)。(6)血清ALT,AST及IL-1β濃度在LPS組明顯最高;LPS+BMSC組較LPS組明顯降低,LPS+BMSC-PGE2(+)組較LPS+BMSC組進(jìn)一步下降,差異均具有統(tǒng)計學(xué)意義(P0.05);而LPS+BMSC-PGE2(-)組較LPS組無明顯下降,差異無統(tǒng)計學(xué)意義(P0.05)。血清IL-10濃度在LPS組較空白對照組輕度上升;LPS+BMSC組明顯高于LPS組;LPA+BMSC-PGE2(+)組較BMSCs處理組進(jìn)一步升高,差異具有統(tǒng)計學(xué)意義(P0.05);而在LPS+BMSC-PGE2(-)組,IL-10水平較LPS組無明顯變化(P0.05)。結(jié)論:尾靜脈注射BMSCs可以減輕腹膜腔注射LPS誘導(dǎo)的小鼠急性肝損傷,并可抑制LPS誘導(dǎo)的小鼠肝臟KCs中NLRP3炎癥小體的表達(dá);過表達(dá)ptges增加了BMSCs分泌PGE2的能力,并加強(qiáng)了BMSCs的肝臟保護(hù)作用及對肝臟KCs中NLRP3炎癥小體的抑制。第二部分:觀察BMSCs對Kupffer細(xì)胞中NLRP3炎癥小體活化的影響目的:進(jìn)一步證實BMSCs可以直接抑制的KCs中NLRP3炎癥小體的活化,觀察BMSCs是否通過分泌PGE2達(dá)到抑制KCs中NLRP3炎癥小體的活化。方法:KCs以2×106/皿接種在Transwell上室中,隨機(jī)分為5組,對照組,LPS處理組,LPS+BMSC組,LPS+BMSC-PGE2(+)組及LPS+BMSC-PGE2(-)組,共培養(yǎng)三組中將BMSC/BMSC-PGE2(+)/BMSC-PGE2(-)以1×106/皿種于Transwell下室。根據(jù)分組將KCs與BMSC/BMSC-PGE2(+)/BMSC-PGE2(-)置入Tranwell共培養(yǎng)體系,LPS組及共培養(yǎng)體系組予以終濃度為10 ng/ml LPS的無血清培養(yǎng)基共培養(yǎng)5 h,然后以終濃度為5m M的ATP的無血清培養(yǎng)基共培養(yǎng)1h。以Western blotting檢測KCs中NLRP3,ASC,Pro-Casp1,Caspase-1及Pro-IL-1β蛋白表達(dá)水平,RT-q PCR檢測KCs中NLRP3,ASC及Caspase-1 m RNA表達(dá)水平,ELISA檢測培養(yǎng)上清中PGE2、IL-1β、IL-18、IL-10及TNF-α。結(jié)果:(1)NLRP3,ASC及caspase-1 m RNA相對表達(dá)量在LPS組中較對照組明顯上升(P0.05);與LPS組相比較,LPS+BMSC組明顯下降,并在LPS+BMSC-PGE2(+)組進(jìn)一步下降;然而與LPS組比較,LPS+BMSC-PGE2(-)組中NLRP3,ASC及caspase-1 m RNA相對表達(dá)量并未明顯下降(P0.05)。(2)NLRP3,ASC,Pro-Casp1,Caspase-1及Pro-IL-1β蛋白表達(dá)量在LPS組中較空白對照組明顯升高(P0.05);與LPS組相比較,在LPS+BMSC組中的表達(dá)明顯減低,且在LPS+BMSC-PGE2(+)組進(jìn)一步下降(P0.05);而LPS+BMSC-PGE2(-)組較LPS組無明顯變化(P0.05)。(3)培養(yǎng)上清液中PGE2水平LPS組較空白對照組略有上升;LPS+BMSC組較LPS組明顯升高(P0.05);LPS+BMSC-PGE2(+)組最高,明顯高于LPS+BMSCs組(P0.05);而在LPS+BMSC-PGE2(-)組顯著低于LPS+BMSC-PGE2(+)組(P0.05),且與LPS組及空白對照組無明顯差異(P0.05)。(4)培養(yǎng)上清液IL-1β,IL-18及TNF-α濃度在LPS組最高;在LPS+BMSCs組較LPS組明顯降低,在LPS+BMSC-PGE2(+)組進(jìn)一步下降(P0.05);而LPS+BMSC-PGE2(-)組較LPS組無明顯下降(P0.05)。培養(yǎng)上清液中IL-10水平在LPS組較空白對照組輕度升高,在給予BMSCs處理后,IL-10明顯增加,給予BMSC-PGE2(+)處理后,IL-10水平進(jìn)一步升高(P0.05);而在LPS+BMSC-PGE2(-)組,IL-10水平較LPS組無明顯變化(P0.05)。結(jié)論:共培養(yǎng)實驗進(jìn)一步證實BMSCs擁有抑制LPS+ATP誘導(dǎo)的KCs中NLRP3炎癥小體活化的作用;過表達(dá)PGE2加強(qiáng)了BMSCs對NLRP3炎癥小體的抑制作用,沉默PGE2抑制了BMSCs對NLRP3炎癥小體的抑制作用。第三部分:PGE2抑制Kupffer細(xì)胞中NLRP3炎癥小體活化的分子機(jī)制目的:為探索PGE2是直接抑制了KCs中NLRP3炎癥小體,還是通過促使KCs增加IL-10的分泌而間接抑制了NLRP3炎癥小體的活化。方法:KCs隨機(jī)分為4組:Group A為對照組;Group B予以LPS(10ng/ml)處理5小時,然后在予以ATP(5m M)處理1小時;Group C在Group B組處理因素基礎(chǔ)上,于最后30分鐘加入PGE2(終濃度為0.1m M);Group D在C組處理因素基礎(chǔ)上,于PGE2加入前30分鐘加入FR180204)。Western blotting檢測KCs中NLRP3,ASC,Caspase-1及p-ERK1蛋白表達(dá)水平。RT-q PCR檢測KCs中NLRP3,ASC及Caspase-1 m RNA。ELISA檢測培養(yǎng)上清中IL-1β,IL-18,TNF-α及IL-10水平。結(jié)果:(1)在B組中給予LPS+ATP處理后,NLRP3,ASC及Caspase-1蛋白表達(dá)水平較A組明顯升高(P0.05);p-ERK1蛋白表達(dá)水平較A組無明顯變化;C組NLRP3,ASC及Caspase-1蛋白表達(dá)水平較B組明顯降低,p-ERK1蛋白表達(dá)水平較及B組明顯增高;D組,NLRP3,ASC及Caspase-1蛋白表達(dá)水平較C組升高(P0.05),但仍略低于B組(P0.05);p-ERK1蛋白表達(dá)水平較C組顯著降低,(P0.05),與B組差異不明顯(P0.05)。(2)NLRP3,ASC及caspase-1m RNA相對表達(dá)量與蛋白表達(dá)趨勢基本一致。(3)培養(yǎng)上清液中IL-1β,IL-18及TNF-α濃度在LPS+ATP處理的B組中明顯最高,顯著高于A組及C組(P0.05);C組中給予PGE2處理后以上促炎因子較B組明顯降低(P0.05);D組中給予FR180204處理后IL-1β,IL-18及TNF-α水平明顯升高,與B組相當(dāng)(P0.05),顯著高于C組(P0.05)。(4)培養(yǎng)上清液中IL-10 LPS+ATP處理的B組較A組略有升高,C組中給予PGE2處理后IL-10較B組明顯升高(P0.05);D組中給予FR180204處理后IL-10水平顯著底于C組(P0.05),恢復(fù)至B組水平(P0.05)。結(jié)論:KCs中ERK1信號通路介導(dǎo)的IL-10分泌可能是PGE2抑制NLRP3炎癥小體活化的關(guān)鍵點。
[Abstract]:Part one: the protective effect of BMSCs in acute liver injury induced by endotoxin: whether intravenous administration of exogenous BMSCs can inhibit acute liver injury induced by endotoxin (LPS) in mice and the activation of NLRP3 inflammatory corpuscles in the liver KCs and the level of inflammatory mediators in serum, and to clarify the acute liver caused by BMSCs in sepsis Methods: all bone marrow cells were selectively attached to the bone marrow cells from the tibia and the femur of Balb/C mice. BMSCs was isolated from the tibia and femur of the Balb/C mice. The stable ptges and ptges sh RNA to BMSCs were used to establish a stable ptges overexpressed BMSCs cell line (BMSCs-PGE2 (+)) and ptges silent BMSCs cell line. 5 groups: (1) control group, (2) LPS group, (3) LPS+BMSCs group, (4) LPS+BMSCs-PGE2 (+) group, (5) LPS+BMSCs-PGE2 (-). PBS was injected into the peritoneal cavity and tail vein of the control group, the other four groups were injected with LPS (10 mg/kg) for 12 hours, then the tail vein was injected with PBS, BMSCs, BMSCs-PGE2 (+) and BMSCs-PGE2 (1 * 106) treatment 12 HE staining was used to evaluate the degree of liver inflammation, TUNEL staining was used to evaluate the liver cell apoptosis, and the liver KCs was isolated and the expression level of NLRP3, ASC, Pro-Casp1, Caspase-1 and Pro-IL-1 beta protein in KCs was detected by Western blotting. The blood of mice was collected and the serum levels of ALT, AST, IL-1 beta, IL-10 and PGE2 were measured by ELISA. Results: (1) there were obvious edema of the liver cells in the LPS group and the infiltration of large number of inflammatory cells in the liver; the edema of the liver cells in the group LPS+BMSCs, the decrease of inflammatory cell infiltration, the group of LPS+BMSCs-PGE2 (+), the degree of liver inflammation were further reduced, and the LPS+BMSCs-PGE2 (-) group was more than the LPS group. There was no obvious change in the number of liver inflammatory cells in the LPS group, the LPS+BMSCs group decreased significantly, and the number of inflammatory cells decreased further after LPS+BMSCs-PGE2 (+) treatment, and the difference was statistically significant (P0.05), but there was no significant difference between the LPS+BMSCs-PGE2 (-) group and the LPS group (P0.05). (2) the positive expression of the liver in LPS group was positive. The apoptotic cells in the LPS+BMSCs group were significantly lower than those in the control group (P0.05). The apoptotic cells in the LPS+BMSC-PGE2 (+) group had only sporadic apoptotic cells (P0.05) in the liver of LPS+BMSC-PGE2 (+) group, and the difference was statistically significant in the LPS+BMSC-PGE2 (-) group, and there was no significant difference in the number of apoptotic cells in the liver (P0.), and the difference was not statistically significant (P0.). 05) (3) the relative expression of NLRP3, ASC and caspase-1 m RNA in the KCs group was the highest in the LPS group, and the LPS+BMSC group was significantly lower than the LPS group. The LPS+BMSC-PGE2 (+) group was further decreased than the LPS+BMSC group, and the difference was statistically significant (P0.05). The expression of -Casp1, Caspase-1 and Pro-IL-1 beta protein in the LPS group was the highest, the LPS+BMSC group was significantly lower than the LPS group, and the LPS+BMSC-PGE2 (+) group was further decreased than that in the LPS+BMSC group. The LPS+BMSC-PGE2 (-) group had no significant difference compared with the LPS group (P0.05). (5) the level of the serum PGE2 was the lowest in the control group and a slight increase in the control group. The difference was statistically significant (P0.05), and LPS+BMSC-PGE2 (+) group was the highest, obviously higher than group LPS+BMSCs (P0.05), but there was no significant difference between LPS+BMSC-PGE2 (-) group and LPS group and blank control group (P0.05). (6) the concentration of serum ALT, AST and IL-1 beta in LPS group was the highest, and the LPS+BMSC group was significantly lower than those in the LPS+BMSC group. The PS+BMSC-PGE2 (+) group was further lower than the LPS+BMSC group, and the difference was statistically significant (P0.05), while the LPS+BMSC-PGE2 (-) group had no significant decrease compared with the LPS group (P0.05). The serum IL-10 concentration was slightly higher in the LPS group than that in the blank control group; the LPS+BMSC group was significantly higher than the LPS group; LPA+BMSC-PGE2 (+) group was further than the BMSCs treatment group. The difference was statistically significant (P0.05), but in the LPS+BMSC-PGE2 (-) group, there was no significant change in the level of IL-10 in the group LPS (P0.05). Conclusion: the tail vein injection of BMSCs could reduce the acute liver injury induced by peritoneal injection of LPS in mice and inhibit the expression of NLRP3 inflammatory corpuscles in LPS induced mice liver KCs, and the ptges increased the BMSCs fraction. The ability to secrete PGE2 and enhance the protective effect of BMSCs liver and the inhibition of NLRP3 inflammatory bodies in the liver KCs. Second: To observe the effect of BMSCs on the activation of NLRP3 inflammatory corpuscles in Kupffer cells: to further confirm the activation of BMSCs that can directly inhibit the inflammatory corpuscle of NLRP3 in KCs, and to observe whether BMSCs is suppressed through secretory PGE2. Methods: the activation of NLRP3 inflammatory body in KCs. Methods: KCs was inoculated in the upper room of Transwell with 2 x 106/. It was randomly divided into 5 groups, the control group, LPS treatment group, LPS+BMSC group, LPS+BMSC-PGE2 (+) group and LPS+BMSC-PGE2 (-) group. The BMSC/BMSC-PGE2 (+) /BMSC-PGE2 (-) was planted in the lower chamber in the three groups. GE2 (+) /BMSC-PGE2 (+) was implanted into the Tranwell co culture system. The LPS group and the co culture system group gave a total concentration of 10 ng/ml LPS in a serum-free medium. Q PCR detected the expression level of NLRP3, ASC and Caspase-1 m RNA in KCs, and PGE2, IL-1 beta, IL-18, and alpha in the ELISA detection culture. Compared with the LPS group, the relative expression of NLRP3, ASC and caspase-1 m RNA in the LPS+BMSC-PGE2 (-) group was not significantly decreased (P0.05). (2) NLRP3, ASC, Pro-Casp1, the expression of Caspase-1 and beta protein in the group was significantly higher than that in the blank control group. The group was further decreased (P0.05), while the LPS+BMSC-PGE2 (-) group had no obvious changes in the group LPS (P0.05). (3) the PGE2 level in the culture supernatant was slightly higher than that in the blank control group; the LPS+BMSC group was significantly higher than that in the LPS group (P0.05), and the LPS+BMSC-PGE2 (+) group was higher than the LPS+BMSCs group (P0.05), and the group (+) was significantly lower than that in the LPS+BMSCs group (+). Group (P0.05), and no significant difference between group LPS and blank control group (P0.05). (4) the concentration of IL-1 beta, IL-18 and TNF- alpha in the culture supernatant was the highest in LPS group, and decreased in LPS+BMSCs group compared with LPS group, and decreased in LPS+BMSC-PGE2 (+) group (P0.05), while LPS+BMSC-PGE2 (-) group had no obvious decline. Compared with the blank control group, the IL-10 increased significantly after BMSCs treatment, and the level of IL-10 increased further after BMSC-PGE2 (+) treatment (P0.05). In LPS+BMSC-PGE2 (-) group, there was no significant change in IL-10 level compared with that of LPS group (P0.05). Conclusion: co culture tests further confirmed that BMSCs has the inhibition of inflammatory corpuscles in LPS+ATP induced KCs. Activation effect; overexpression of PGE2 enhanced the inhibitory effect of BMSCs on NLRP3 inflammatory bodies. Silence PGE2 inhibited the inhibitory effect of BMSCs on NLRP3 inflammatory bodies. The third part: PGE2 inhibits the molecular mechanism of NLRP3 inflammatory corpuscle activation in Kupffer cells: To explore PGE2 is to directly inhibit KCs NLRP3 inflammatory corpuscles, or by prompting them. Increase the secretion of IL-10 and indirectly inhibit the activation of NLRP3 inflammatory bodies. Methods: KCs was randomly divided into 4 groups: Group A as the control group; Group B was treated with LPS (10ng/ml) for 5 hours, and then treated with ATP (5m M) for 1 hours. On the basis of the factors,.Western blotting was used to detect NLRP3, ASC, Caspase-1 and p-ERK1 protein expression level in KCs 30 minutes before the addition of FR180204), and.RT-q PCR detection of the protein expression level in KCs. The expression level of SE-1 protein was significantly higher than that in the A group (P0.05), and the expression level of p-ERK1 protein was not significantly higher than that in the A group; the expression level of NLRP3, ASC and Caspase-1 protein in the C group was significantly lower than that in the B group, and the expression level of p-ERK1 protein was significantly higher than that of the B group. The expression level of -ERK1 protein was significantly lower than that in the C group (P0.05), and there was no significant difference with the B group (P0.05). (2) NLRP3, the RNA relative expression of ASC and caspase-1m was the same as that of protein expression. (3) the concentration of IL-1 beta, IL-18 and TNF- alpha in the culture supernatant was the highest, significantly higher than that in the group and the group. The above proinflammatory factors were significantly lower than those in the B group (P0.05), and the level of IL-1 beta, IL-18 and TNF- alpha in the group D was significantly higher than that in the B group (P0.05), which was significantly higher than that of the C group (P0.05). (4) the groups in the culture supernatant were slightly higher than those in the group. After treatment with FR180204, the level of IL-10 was significantly lower than that of group C (P0.05) and recovered to B level (P0.05). Conclusion: IL-10 secretion mediated by ERK1 signaling pathway in KCs may be the key point for PGE2 to inhibit the activation of NLRP3 inflammatory corpuscle.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R459.7

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8 楊莉莉;董文;賀巾超;任秀寶;顏煒群;;重組牛胰蛋白酶抑制劑對小鼠急性肝損傷的保護(hù)作用[J];中國藥理學(xué)通報;2008年04期

9 李俊松;余宗亮;王明艷;蔡寶昌;;山茱萸炮制前后對小鼠急性肝損傷保護(hù)作用的研究[J];南京中醫(yī)藥大學(xué)學(xué)報;2008年04期

10 何光力;劉潔;潘嘉;艾麗;彭龍玲;;肝舒膠囊對急性肝損傷動物的保護(hù)作用[J];華西藥學(xué)雜志;2009年06期

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