許 寧，平 芬，徐 鑫，諸葛銘寧，張鳳蕊，韓書芝

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·中醫(yī)·中西醫(yī)結(jié)合研究·

連花清瘟對(duì)細(xì)顆粒物致大鼠肺部炎性損傷的拮抗作用研究

許 寧，平 芬，徐 鑫，諸葛銘寧，張鳳蕊，韓書芝

目的 探討細(xì)顆粒物(PM2.5)急性暴露對(duì)大鼠肺部炎性損傷的作用，及低、中、高劑量連花清瘟對(duì)肺部炎性損傷的拮抗作用。方法 2013年6—12月選取48只健康成年Wistar大鼠，采用隨機(jī)數(shù)字表法分為空白對(duì)照組、0.9%氯化鈉溶液對(duì)照組、PM2.5染塵組及低、中、高劑量連花清瘟組，每組8只。由石家莊市環(huán)境監(jiān)測(cè)中心提供PM2.5，制備PM2.5懸液?？瞻讓?duì)照組大鼠無(wú)任何干預(yù)措施；0.9%氯化鈉溶液對(duì)照組大鼠給予氣管滴注0.9%氯化鈉溶液(1 ml/kg)；PM2.5染塵組大鼠給予氣管滴注PM2.5懸液1 ml/kg(7.5 mg/kg)；低、中、高劑量連花清瘟組大鼠首先分別連續(xù)灌胃給予低(2 g/kg)、中(4 g/kg)、高(8 g/kg)劑量連花清瘟溶液10 ml/kg,共4 d，第4天灌胃給藥后分別氣管滴注PM2.5懸液1 ml/kg(7.5 mg/kg)，24 h后處死。光鏡下觀察肺組織病理形態(tài)變化，酶聯(lián)免疫吸附試驗(yàn)(ELISA)法測(cè)定各組大鼠支氣管肺泡灌洗液(BALF)及血清中白介素(IL)1、IL-6、腫瘤壞死因子α(TNF-α)水平。結(jié)果 空白對(duì)照組及0.9%氯化鈉溶液對(duì)照組大鼠肺組織病理切片光鏡下未見異常表現(xiàn)；PM2.5染塵組大鼠肺組織病理切片光鏡下可見炎性細(xì)胞滲出，肺間質(zhì)纖維組織增生，間質(zhì)水腫；低、中、高劑量連花清瘟組大鼠肺組織病理切片光鏡下可見隨連花清瘟劑量增加,肺泡腔內(nèi)炎性細(xì)胞滲出逐漸減輕。0.9%氯化鈉溶液對(duì)照組大鼠BALF及血清中IL-1、IL-6、TNF-α水平與空白對(duì)照組比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；PM2.5染塵組大鼠BALF中IL-1水平較0.9%氯化鈉溶液對(duì)照組升高，血清中IL-1水平、BALF及血清中IL-6、TNF-α水平較空白對(duì)照組和0.9%氯化鈉溶液對(duì)照組升高(P<0.05)；高劑量連花清瘟組大鼠BALF中IL-1水平較空白對(duì)照組、0.9%氯化鈉溶液對(duì)照組、PM2.5染塵組、低劑量連花清瘟組、中劑量連花清瘟組降低，BALF和血清中IL-6水平較空白對(duì)照組、0.9%氯化鈉溶液對(duì)照組、PM2.5染塵組、低劑量連花清瘟組降低，BALF中TNF-α水平和血清中IL-1水平較PM2.5染塵組、低劑量連花清瘟組、中劑量連花清瘟組降低，血清中TNF-α水平較PM2.5染塵組、低劑量連花清瘟組降低(P<0.05)。結(jié)論 PM2.5急性暴露可以導(dǎo)致大鼠肺部炎性損傷，連花清瘟對(duì)肺部炎性損傷有拮抗作用。

肺炎；顆粒物；支氣管肺泡灌洗液；白細(xì)胞介素；腫瘤壞死因子α

許寧，平芬，徐鑫，等.連花清瘟對(duì)細(xì)顆粒物致大鼠肺部炎性損傷的拮抗作用研究[J].中國(guó)全科醫(yī)學(xué)，2015，18(27)：3355-3359.[www.chinagp.net]

Xu N,Ping F,Xu X，et al.Antagonistic effects of Lianhuaqingwen on rat′s pulmonary inflammatory injury induced by airborne fine particulate matters[J].Chinese General Practice，2015，18(27)：3355-3359.

環(huán)境因素在呼吸系統(tǒng)疾病中起著不可忽視的作用，流行病學(xué)研究顯示，環(huán)境中細(xì)顆粒物(PM2.5)濃度與呼吸系統(tǒng)及心血管系統(tǒng)疾病的發(fā)病率、病死率密切相關(guān)[1-2]，其具體機(jī)制尚未明確，而肺部炎性損傷可能是PM2.5暴露誘導(dǎo)肺損傷的重要機(jī)制。PM2.5隨呼吸進(jìn)入肺泡內(nèi)，作用于肺泡巨噬細(xì)胞，巨噬細(xì)胞在肺部炎性反應(yīng)中發(fā)揮著重要作用，PM2.5通過(guò)誘導(dǎo)其釋放大量細(xì)胞因子[3]、激活并增加核因子(NF)κB相關(guān)的基因表達(dá)，使毛細(xì)血管通透性增加、中性粒細(xì)胞浸潤(rùn)[4]，從而造成肺甚至其他器官的炎性損傷[5]。連花清瘟有外疏衛(wèi)表，清熱解毒，宣肺泄熱之效，因其確切的臨床療效，已被廣泛應(yīng)用于多種流感病毒感染引起的呼吸系統(tǒng)疾病[6]。本研究采集石家莊市PM2.5，制備PM2.5懸液，觀察PM2.5暴露后大鼠肺組織病理變化及染塵大鼠支氣管肺泡灌洗液(BALF)及血清中促炎性細(xì)胞因子水平的變化，探討PM2.5對(duì)大鼠肺部炎性損傷的作用，并通過(guò)觀察連花清瘟干預(yù)后染塵大鼠BALF及血清中促炎性細(xì)胞因子水平的變化，進(jìn)一步探討其對(duì)PM2.5所致大鼠肺部炎性損傷的拮抗作用。

1 材料與方法

1.1 PM2.5懸液配制 PM2.5由石家莊市環(huán)境監(jiān)測(cè)中心提供，采用TEOM1405D雙通道顆粒物監(jiān)測(cè)儀收集，洗脫P(yáng)M2.5，冷凍干燥，使用前以滅菌注射用水配制成濃度為7.5 mg/ml PM2.5懸液，超聲震蕩混勻。連花清瘟溶液為連花清瘟干膏粉41.73 g、20.87 g、10.43 g分別加入羥甲基纖維素鈉溶液，配制成80%、40%、20%的高、中、低劑量連花清瘟溶液。

1.2 實(shí)驗(yàn)動(dòng)物分組及給藥方法 2013年6—12月選取48只雄性Wistar大鼠(河北醫(yī)科大學(xué)實(shí)驗(yàn)動(dòng)物中心提供)，體質(zhì)量180～200 g，采用隨機(jī)數(shù)字表法分為2個(gè)對(duì)照組(空白對(duì)照組及0.9%氯化鈉溶液對(duì)照組)和4個(gè)實(shí)驗(yàn)組(PM2.5染塵組及低、中、高劑量連花清瘟組)，每組8只?？瞻讓?duì)照組大鼠不給予任何干預(yù)措施，0.9%氯化鈉溶液對(duì)照組大鼠給予氣管滴注0.9%氯化鈉溶液(1 ml/kg)1次，PM2.5染塵組大鼠給予氣管滴注PM2.5懸液1 ml/kg(7.5 mg/kg)1次，低、中、高劑量連花清瘟組大鼠給予連花清瘟溶液10 ml/kg(連花清瘟2 g/kg、4 g/kg、8 g/kg)灌胃，共給藥4 d，第4天灌胃給藥后給予氣管滴注PM2.5懸液，劑量及次數(shù)同PM2.5染塵組。

1.3 標(biāo)本采集 丙戊酸鈉腹腔注射麻醉下腹主動(dòng)脈采集動(dòng)脈血5 ml后放血處死大鼠(空白對(duì)照組直接處死，0.9%氯化鈉溶液對(duì)照組氣管滴注0.9%氯化鈉溶液24 h后處死，各實(shí)驗(yàn)組均染塵24 h后處死)。所取動(dòng)脈血分離血清，3 000 r/min離心15 min(離心半徑8 cm)；以磷酸鹽緩沖液(PBS)進(jìn)行支氣管肺泡灌洗，2.5 ml/次，反復(fù)3次，所得BALF離心取上清液，1 000 r/min離心10 min(離心半徑8 cm)，于-80 ℃冰箱保存。取大鼠部分右肺，甲醛溶液固定24 h后，常規(guī)石蠟包埋，切片，蘇木素-伊紅(HE)染色，光鏡下觀察。

1.4 指標(biāo)檢測(cè) 采用酶聯(lián)免疫吸附試驗(yàn)(ELISA)法測(cè)定(試劑盒購(gòu)自美國(guó)BG公司，用Multiskan型全自動(dòng)酶標(biāo)儀測(cè)OD值)BALF及血清中促炎性細(xì)胞因子白介素(IL)1、IL-6、腫瘤壞死因子α(TNF-α)水平，操作步驟按試劑盒說(shuō)明書進(jìn)行。

2 結(jié)果

2.1 大鼠肺組織病理所見 空白對(duì)照組及0.9%氯化鈉溶液對(duì)照組大鼠肺組織病理切片光鏡下未見異常表現(xiàn)；PM2.5染塵組大鼠肺組織病理切片光鏡下可見肺泡間隔增厚，肺泡腔縮小，炎性細(xì)胞滲出，小支氣管壁增厚，管腔內(nèi)杯狀細(xì)胞增生，周圍炎性細(xì)胞浸潤(rùn)，肺間質(zhì)纖維組織增生，間質(zhì)水腫，毛細(xì)血管充血，小血管管壁增厚，周圍可見嗜酸粒細(xì)胞浸潤(rùn)；低、中、高劑量連花清瘟組大鼠肺組織病理切片光鏡下可見隨連花清瘟劑量增加,肺泡腔內(nèi)炎性細(xì)胞滲出逐漸減輕(見圖1)。

2.2 各組大鼠BALF及血清中促炎性細(xì)胞因子水平變化 各組大鼠BALF及血清中IL-1、IL-6、TNF-α水平比較，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；其中0.9%氯化鈉溶液對(duì)照組大鼠BALF及血清中IL-1、IL-6、TNF-α水平與空白對(duì)照組比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；PM2.5染塵組大鼠BALF中IL-1水平較0.9%氯化鈉溶液對(duì)照組升高，血清中IL-1水平、BALF及血清中IL-6、TNF-α水平較空白對(duì)照組和0.9%氯化鈉溶液對(duì)照組升高，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；低劑量連花清瘟組大鼠BALF中IL-6水平較PM2.5染塵組降低，血清中IL-1水平、BALF及血清中TNF-α水平較空白對(duì)照組和0.9%氯化鈉溶液對(duì)照組升高，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；中劑量連花清瘟組大鼠BALF中IL-6水平較空白對(duì)照組、0.9%氯化鈉溶液對(duì)照組、PM2.5染塵組、低劑量連花清瘟組降低，BALF中TNF-α水平和血清中IL-1水平較空白對(duì)照組和0.9%氯化鈉溶液對(duì)照組升高、較PM2.5染塵組降低，血清中IL-6水平較PM2.5染塵組、低劑量連花清瘟組降低，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；高劑量連花清瘟組大鼠BALF中IL-1水平較空白對(duì)照組、0.9%氯化鈉溶液對(duì)照組、PM2.5染塵組、低劑量連花清瘟組、中劑量連花清瘟組降低，BALF和血清中IL-6水平較空白對(duì)照組、0.9%氯化鈉溶液對(duì)照組、PM2.5染塵組、低劑量連花清瘟組降低，BALF中TNF-α水平和血清中IL-1水平較PM2.5染塵組、低劑量連花清瘟組、中劑量連花清瘟組降低，血清中TNF-α水平較PM2.5染塵組、低劑量連花清瘟組降低，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05，見表1)。

注：PM2.5=細(xì)顆粒物

圖1 各組大鼠肺組織病理切片光鏡下表現(xiàn)(HE染色，×200)

注：與空白對(duì)照組比較，aP<0.05；與0.9%氯化鈉溶液對(duì)照組比較，bP<0.05；與PM2.5染塵組比較，cP<0.05；與低劑量連花清瘟組比較，dP<0.05；與中劑量連花清瘟組比較，eP<0.05；PM2.5=細(xì)顆粒物,BALF=支氣管肺泡灌洗液，IL-1=白介素1，IL-6=白介素6，TNF-α=腫瘤壞死因子α

3 討論

PM2.5可隨空氣進(jìn)入小氣管和肺泡并持續(xù)作用，當(dāng)其到達(dá)肺泡時(shí)，被氣管纖毛系統(tǒng)清除并且/或者被巨噬細(xì)胞吞噬[7]。Maciejczyk等[8]研究報(bào)道，PM2.5被巨噬細(xì)胞吞噬過(guò)程中可通過(guò)與之相關(guān)的編碼轉(zhuǎn)錄因子、炎性相關(guān)因子基因轉(zhuǎn)錄水平的增高誘導(dǎo)大量促炎性細(xì)胞因子釋放，破壞細(xì)胞因子網(wǎng)絡(luò)平衡，從而調(diào)節(jié)和始動(dòng)肺局部炎性反應(yīng)，誘導(dǎo)肺炎性損傷。另一方面，PM2.5對(duì)肺機(jī)械屏障作用的破壞使肺部清除異物作用下降，進(jìn)一步誘導(dǎo)更嚴(yán)重的炎性反應(yīng)，導(dǎo)致促炎性細(xì)胞因子水平的進(jìn)一步升高[9]。本研究中肺組織病理切片光鏡下顯示，PM2.5可導(dǎo)致大鼠肺泡腔內(nèi)炎性細(xì)胞滲出，細(xì)支氣管黏膜損傷，炎性細(xì)胞浸潤(rùn)，肺間質(zhì)水腫，毛細(xì)血管充血，而Riva等[10]及曲紅梅等[11]研究也表明，PM2.5暴露的肺組織病理切片也可見肺泡塌陷及單核細(xì)胞、中性粒細(xì)胞浸潤(rùn)、淋巴細(xì)胞增生。

在巨噬細(xì)胞釋放的大量細(xì)胞因子中，IL-1、IL-6、TNF-α等為早期主要的促炎性細(xì)胞因子[12]，在肺的炎性反應(yīng)中起著重要的作用。這些促炎性細(xì)胞因子除了趨化嗜酸粒細(xì)胞、中性粒細(xì)胞等炎性細(xì)胞向肺組織遷移，還可增高其活性，使之分泌炎性細(xì)胞因子，進(jìn)一步趨化炎性細(xì)胞，形成炎性細(xì)胞與炎性細(xì)胞因子之間的惡性循環(huán)[13]。TNF-α由活化的單核巨噬細(xì)胞等產(chǎn)生，在各種炎性損傷中，TNF-α是最早釋放并發(fā)揮關(guān)鍵作用的細(xì)胞因子。本研究制備的大鼠PM2.5染塵模型BALF及血清中促炎性細(xì)胞因子TNF-α水平較空白對(duì)照組和0.9%氯化鈉溶液對(duì)照組均明顯升高。而Ding等[14]在PM2.5致新生大鼠肺炎癥及氧化應(yīng)激的研究中也發(fā)現(xiàn)，短期暴露于PM2.5即可誘發(fā)肺部炎性反應(yīng)，表現(xiàn)在TNF-α水平升高，而TNF-α可通過(guò)與其特異性受體(TNF-R1和TNF-R2)的結(jié)合誘發(fā)炎性反應(yīng)，使肺部出現(xiàn)炎性損傷。IL-6主要由單核巨噬細(xì)胞及血管內(nèi)皮細(xì)胞等產(chǎn)生，與宿主炎性反應(yīng)和疾病嚴(yán)重程度相關(guān)，血清IL-6水平常作為細(xì)胞因子級(jí)聯(lián)反應(yīng)激活的標(biāo)志。IL-1主要由單核細(xì)胞產(chǎn)生。本研究結(jié)果顯示，大鼠急性暴露于PM2.5可引起B(yǎng)ALF及血清中IL-6、IL-1水平明顯升高，與Phipps等[9]研究肺炎鏈球菌感染的大鼠香煙暴露組較空氣暴露組肺勻漿中IL-1、IL-6、TNF-α水平均增加的結(jié)果一致。

連花清瘟主要藥理作用及機(jī)制有：提高細(xì)胞免疫功能,抑制慢性阻塞性肺疾病(COPD)氣管炎癥,降低病毒感染后的肺指數(shù)，抑制病毒感染后的肺部炎性損害，抗甲型人流感病毒[15]。其主要成分為連翹、金銀花、麻黃、杏仁、石膏、板藍(lán)根、綿馬貫眾、魚腥草、廣藿香、大黃、紅景天、薄荷腦、甘草，從中藥組分來(lái)看符合中醫(yī)治療炎性疾病的特點(diǎn)，除了具有明確的抗病毒作用，對(duì)急性肺部感染效果顯著，還具有一定的免疫調(diào)節(jié)作用[16]。本研究結(jié)果顯示，高劑量連花清瘟組BALF及血清中促炎性細(xì)胞因子IL-1、IL-6、TNF-α水平較PM2.5染塵組均明顯下降，且病理結(jié)果提示，炎性反應(yīng)明顯減輕，表明連花清瘟對(duì)PM2.5急性暴露所致肺炎性損傷有拮抗作用。而夏敬文等[17]研究連花清瘟對(duì)COPD大鼠模型氣管炎癥的影響，染塵組血清、肺組織勻漿及BALF中IL-8和TNF-α水平較對(duì)照組明顯升高，而連花清瘟治療組血清及BALF中上述細(xì)胞因子水平顯著降低，也提示連花清瘟對(duì)氣管炎癥的抑制作用。

綜上所述，本實(shí)驗(yàn)證實(shí)PM2.5急性暴露可導(dǎo)致大鼠肺部炎性損傷，而中、高劑量連花清瘟對(duì)這種炎性損傷具有拮抗作用，但其具體調(diào)節(jié)機(jī)制還有待進(jìn)一步研究。

利益沖突聲明：本課題未涉及任何廠家及相關(guān)雇主或其他經(jīng)濟(jì)組織直接或間接的經(jīng)濟(jì)或利益的贊助。無(wú)利益沖突。

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(本文編輯：陳素芳)

Antagonistic Effects of Lianhuaqingwen on Rat′s Pulmonary Inflammatory Injury Induced by Airborne Fine Particulate Matters

XUNing,PINGFen,XUXin，etal.

DepartmentofEmergency，HebeiGeneralHospital,Shijiazhuang050051,China

Objective To investigate the pulmonary inflammatory injury in rats induced by acute exposure to PM2.5and to explore the antagonistic effect of low,medium,and high dose of Lianhuaqingwen to the inflammatory injury.Methods From June to December in 2013,selected 48 healthy adult Wistar rats.Using random number table method,divided them into control group,sodium chloride group,PM2.5group,low-dose group,medium-dose group and high-dose group,with 8 rats in each group.Airborne fine particulate matters were provided by Shijiazhuang Environmental Monitoring Center,and PM2.5suspension liquid was prepared.Control group was not given any intervention;sodium chloride group was given trachea instillation of 0.9% sodium chloride solution (1 ml/kg);PM2.5group was given trachea instillation of 1 ml/kg(7.5 mg/kg) PM2.5suspension liquid;low-dose,medium-dose and high-dose groups were respectively given gavage with 2 g/kg,4 g/kg and 8 g/kg Lianhuaqingwen solution of 10 ml/kg for 4 days,and the three groups were given trachea instillation of 1 ml/kg(7.5 mg/kg) PM2.5suspension liquid on the fourth day and were killed 24 hours later.Pathological morphologic changes were observed under light microscope,and ELISA was employed to examine the levels of IL-1,IL-6 and TNF-α in BALF and serum.Results In control group and sodium chloride group,no abnormal manifestations in pulmonary tissue slices were observed under light microscope;in PM2.5group,exudation of inflammatory cells,interstitial proliferation of fibrous tissue and interstitial edema were noted in pulmonary tissue slices under light microscope;in the three Lianhuaqingwen groups,we found the exudation of inflammatory cells in alveolar space reduced with the increase of the dosage of Lianhuaqingwen.Sodium chloride group and control group were not significantly different in the levels of IL-1,IL-6 and TNF-α in BALF and serum(P>0.05);PM2.5group was higher than sodium chloride group in the level of IL-1 in BALF,and PM2.5group was higher than control group and sodium chloride group in the level of IL-1 in serum and the levels of IL-6 and TNF-α in BALF and serum (P<0.05);high-dose group was lower than control group,sodium chloride group,PM2.5group,low-dose group and medium group in the level of IL-1 in BALF,lower than control group,sodium chloride group,PM2.5group and low-dose group in the level of IL-6 in BALF and serum,lower than PM2.5group,low-dose group and medium-dose group in the level of TNF-α in BALF and the level of IL-1 in serum,and lower than PM2.5group and low-dose group in the level of TNF-α in serum(P<0.05).Conclusion The acute exposure to PM2.5can induce pulmonary inflammatory injury in rats,Lianhuaqingwen could produce antagonistic effects to the inflammatory injury.

Pneumonia；Particulate matter；Bronchoalveolar lavage fluid；Interleukin；Tumor necrosis factor-alpha

050051河北省石家莊市，河北省人民醫(yī)院急診科(許寧，徐鑫，諸葛銘寧)，呼吸內(nèi)二科(平芬，張鳳蕊，韓書芝)

平芬，050051河北省石家莊市，河北省人民醫(yī)院呼吸內(nèi)二科；E-mail:pingfen2003@126.com

R 563.1

A

10.3969/j.issn.1007-9572.2015.27.021

2015-01-21；

2015-07-21)