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ELR+CXC趨化因子作為CXC趨化因子的一類。我們構(gòu)建的ELR+CXC趨化因子受體拮抗劑G31P能高親和力結(jié)合CXC趨化因子受體CXCR1/CXCR2，從而阻斷ELR+CXC趨化因子對中性粒細(xì)胞的趨化作用，進(jìn)而起到抗炎作用。本文研究G31P對C57BL/6鼠肺炎克雷伯桿菌肺炎的預(yù)防和抑制作用,并與頭孢他啶和地塞米松治療作用進(jìn)行比較。

目的：趨化因子是具有趨化作用的細(xì)胞因子, 能吸引免疫細(xì)胞到免疫應(yīng)答部位，參與免疫調(diào)節(jié)和免疫病理反應(yīng)。在維護(hù)免疫系統(tǒng)的自身穩(wěn)態(tài)和功能方面扮演著重要的角色。ELR+CXC趨化因子作為CXC趨化因子的一類，在中性粒細(xì)胞炎癥發(fā)生發(fā)展過程中起著重要的作用。我們構(gòu)建的ELR+CXC趨化因子受體拮抗劑G31P能高親和力結(jié)合CXC趨化因子受體CXCR1/CXCR2，從而阻斷ELR+CXC趨化因子對中性粒細(xì)胞的趨化作用，進(jìn)而起到抗炎作用。肺炎克雷伯桿菌（Kp）是目前較為常見的醫(yī)院內(nèi)機(jī)會致病菌。隨著耐藥株的增加，已成為防治的難點(diǎn)。本文研究G31P對C57BL/6鼠肺炎克雷伯桿菌肺炎的預(yù)防和抑制作用,并與頭孢他啶和地塞米松治療作用進(jìn)行比較。方法：致病菌株：肺炎克雷伯桿菌，取自臨床患者痰培養(yǎng)。LB培養(yǎng)取單菌落。根據(jù)細(xì)菌生長與OD值關(guān)系選擇12～14h為細(xì)菌活性最強(qiáng)時(shí)間。動物模型建立：肺炎克雷伯桿菌（Kp）氣管注射接種C57BL/6鼠激發(fā)肺炎，同時(shí)背部皮下注射G31P或生理鹽水作為實(shí)驗(yàn)組和陽性對照組，并設(shè)抗生素和激素治療對照組。檢測方法：24h后取肺組織病理學(xué)檢查，肺泡灌洗液（BALF）中性粒細(xì)胞計(jì)數(shù)，肺組織及肺泡灌洗液髓過氧化物酶（MPO）分析，肺組織RT-PCR檢測趨化因子基因表達(dá)水平。結(jié)果：與細(xì)菌陽性對照組相比，G31P治療組的中性粒細(xì)胞數(shù)量下降，髓過氧化物酶分泌減少，病理報(bào)告肺組織炎癥減輕，RT-PCR結(jié)果顯示ELR+CXC趨化因子表達(dá)量降低，與抗生素和激素治療組相比較也有一定的療效。結(jié)論：G31P可以明顯減輕C57BL/6鼠肺炎克雷伯桿菌肺炎的炎性中性粒細(xì)胞浸潤及肺組織損傷，對肺炎有一定的抑制作用 。 關(guān)鍵詞：CXCR1/CXCR2拮抗劑 趨化因子 肺炎克雷伯桿菌 中性粒細(xì)胞 The combined CXCR1/CXCR2 antagonist CXCL8(3–72)K11R/ G31P blocks neutrophil infiltration and pulmonary pathology in C57BL/6mouse challaged by Klebsiella pneumoniae Abstract Objective: ELR (Glu-Leu-Arg)-CXC chemokines are important in acute responses to bacterial infections, wherein neutrophils are often critical to pathogen clearance. However, excessive neutrophil recruitment augments the pathology of many diseases. ELR+ CXC chemokines bind CXCR1 and/or CXCR2 with a high affinity and have a potent chemotactic effect, particularly on neutrophils. CXCR1 and CXCR2 are coordinately expressed on the leukocytes. However, CXCR1 exhibits a slightly lower affinity for CXCL8 in vitro and requires more CXCL8 for internalization and recycling than CXCR2. Moreover, synthesis and release of CXCL8 can be induced by bacteria, bacterial products [e.g., lipopolysaccharide (LPS)]. We have developed a broad-spectrum ELR+CXC chemokine antagonist, CXCL8(3–72)K11R/G31P. In vitro, it effectively blocks neutrophil responses to CXCR1- and CXCR2-specific agonists, and ablates neutrophil responses to all mediators present in clinical bacterial pneumonia lesions. Klebsiella pneumoniae (Kp), accounts for a significant proportion of hospital-acquired urinary tract infections, pneumonia, septicemias, and soft tissue infections. Therefore, in this experiment we are trying to find out whether G31P also works very well in a C57BL/6mouse model of acute lung inflammation induced by the Klebsiella pneumoniae. Methods: For the preparation of the bacteria, we chose the optimal growth stage by drawing the time-growth curve of bacterium and diluted it with sterile saline. Then C57BL/6mouse were challenged with 0.2ml (10*9 cfu /ml) of Klebsiella pneumoniae through transtracheal injection. Meanwhile, administrated G31P(500ug/kg) or the same volume sterile saline as positive control by subcutaneously injection on the back. Also established antibiotic and hormones treated group. The C57BL/6mouse were sacrificed 24h later. Then count the number of neutrophils, assay the release of myeloperoxidase(MPO) in both lung tissue and the bronchoalveolar lavage fluid(BALF), observate the appearance of lung tissue and lung histopathology respectively. The RT-PCR was used to assay the expression of CXCL8 (IL-8), TNF and CXCL1 (IL-1) with a commercial one-step master mix kit. Results: The results show that, compared with the control group, the number of neutrophils decreased significantly, the secretion of MPO in both lung tissue and BALF dropped in G31P group, and there are a lot of differences in histopathology between G31P treated group and control. The mRNA level of inflammatory cytokines in G31P treated group were lower than that of control. The differences also happened between G31P treated group and antibiotic, hormones groups . Conclusion: The combined CXCR1/CXCR2 antagonism-G31P had a significant therapeutic effect on C57BL/6mouse pulmonary inflammation and hemorrhage induced by Kp. In a word, G31P can partly block netrophil influx and tissue hemorrhage so as to exert a certain effect on this pneumonia model. Compared with antibiotic and hormones group, G31P treated group showed more effective. Keyword: chemokine inflammation CXCR1/CXCR2 Kp (Klebsiella pneumoniae)

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