Azithromycin inhibits interleukin-6 but not fibrinogen production in hepatocytes infected with cytomegalovirus and chlamydia pneumoniae

Chlamydia pneumoniae and cytomegalovirus (CMV) have been associated with the development of atherosclerosis. Inflammatory stimuli initiate the biosynthesis of fibrinogen, interleukin (IL)-6 and plasminogen activator inhibitor (PAI)-1 in the liver. Chronic infection may perpetuate the inflammatory status. We hypothesized that infection of human hepatocytes with the intracellular pathogens C pnemoniae and CMV accelerates biosynthesis of fibrinogen, IL-6, and PAI-1 but that this biosynthesis can be reduced with the use of azithromycin. HepG2 human hepatocytes were infected with C pneumoniae and CMV in vitro in the presence of 0, 0.016, 0.125, or 1 μg/mL azithromycin. We measured IL-6, PAI-1, and fibrinogen after 24, 48, 72, and 96 hours. C pneumoniae-infected hepatocytes produce IL-6 (2667 ± 309 pg/mL vs 137 ± 120 pg/mL in uninfected cells after 96 hours. Incubation with 0.016 μg/mL azithromycin decreased IL-6 levels to a mean of 1516 ± 402 pg/mL, and incubation with 0.125 and 1 μg/mL azithromycin decreased IL-6 to 871 ± 364 and 752 ± 403 pg/mL, respectively. C pneumoniae-induced IL-6 production was time- and dose-dependent. The interaction of C pneumoniae with azithromycin treatment was significant, indicating an inhibitory effect of azithromycin on C pnemoniae-induced IL-6 production. CMV infection did not lead to IL-6 production by hepatocytes. C pneumoniae and CMV infection did not induce any changes in PAI-1 production. Fibrinogen production was increased by CMV infection after 72 hours (838 ± 88 ng/mL; P < .01) and after 96 hours by infection with both C pneumoniae and CMV (765 ± 100 and 846 ± 123 ng/mL, respectively; P < .05). Azithromycin did not suppress CMV- or C pneumoniae-induced fibrinogen production. Moreover, we could not confirm an antiinflammatory effect of azithromycin in experiments with cross-titrations of azithromycin against either IL-1 or IL-6 (P > .05). Azithromycin reduces C pneumoniae-induced IL-6 production, but not fibrinogen production, by human hepatocytes. This is a result of the antimicrobial properties of azithromycin and not a direct antiinflammatory effect.     

希舒美针剂治疗儿童肺炎支原体肺炎疗效观察

目的 观察希舒美针剂治疗肺炎支原体肺炎的临床疗效.方法 将44例肺炎支原体肺炎住院患儿分为2组,分别用希舒美针剂(阿奇霉素,辉瑞制药)和国产阿奇霉素治疗,观察比较2组的临床症状、体征的改善情况.结果 希舒美组25例,1周后治愈17例,显效2例,好转6例,有效率(有效为治愈+显效)76.00%(19/25).对照组19例,治愈5例,显效9例,好转4例,无变化1例,有效率73.68%(14/19).2组对肺炎支原体肺炎治疗均有效,2组有效率比较差异无统计学意义(x2=0.03,P>0.05).但比较2组1周治愈率(x2=7.50,P<0.05)、退热时间(t=34.05.P<0.05)和啰音消失时间(t=2.39,P<0.05),希舒美组均优于对照组,差异均有统计学意义(P均<0.05).结论 希舒美针剂治疗肺炎支原体肺炎疗效好,在改善临床症状上具有一定优越性.

Abstract：

Objective To observe the effect Azithromycin injection in the treatment of mycoplasma pneumoniae pneumonia ( MPP) in children. Methods Forty-four children of mycoplasma pneumoniae pneumonia were randomly divided into two groups, the Azithromycin group ( treat by Azithromycin, made by Pfizer) and the control group (treat by domestic Azithromycin) respectively. Improvement in symptoms and signs between the two groups were observed and compared. Results There were 25 cases in the Azithromycin group, of which,after a week, 17 cases cured,2 cases got better significantly and 6 cases got better. The effective ratio was 76. 00% ( 19/25 ). There were 19 cases in the control group, of which 5 cases cured, 9 cases got better significantly ,4 cases got better and 1 case no change. The effective ratio was 73. 68% (14/19). There was no statistical significance in the effective ratio between the two groups ( x2 = 0. 03, P > 0. 05). However, the Azithromycin group was superior to the control group both in the one week cure rate (t = 7.50,P< 0.05) and on defervescence time (t = 34. 05, P < 0. 05 ) and rales disappearance (t = 2. 39, P < 0. 05 ). Conclusion Azithromycin injection is more effective than domestic Azithromycin in the treatment of mycoplasma pneumoniae pneumonia,especially in the aspect of improving symptoms.     

Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae

Pathogen virulence factors and the host inflammatory response cause tissue injury associated with respiratory tract infections. The azalide azithromycin has demonstrated efficacy in the treatment of these infections. It has been demonstrated previously that induction of polymorphonuclear leucocyte (PMN) apoptosis is associated with minimization of tissue damage and inflammation in the lung. We hypothesized that, in addition to its antibacterial effects, azithromycin may promote apoptosis. The aim of the study was to determine the effects of azithromycin on PMN apoptosis, oxidative function and interleukin-8 (IL-8) production in the presence or absence of Streptococcus pneumoniae, in comparison with penicillin, erythromycin, dexamethasone or phosphate-buffered saline. Human circulating PMNs were assessed for apoptosis (by annexin V labelling and ELISA), oxidative function (by nitroblue tetrazolium reduction) and IL-8 production (by ELISA). Azithromycin significantly induced PMN apoptosis in the absence of S. pneumoniae after 1 h (10.27% +/- 1.48%, compared with 2.19% +/- 0.42% in controls) to levels similar to those after 3 h induction with tumour necrosis factor-alpha (8. 73% +/- 1.86%). This effect was abolished in the presence of S. pneumoniae. Apoptosis in PMNs exposed to the other drugs was not significantly different from that in controls. Azithromycin did not affect PMN oxidative metabolism or IL-8 production. In summary, azithromycin-induced PMN apoptosis may be detected in the absence of any effect on PMN function, and the pro-apoptotic properties of azithromycin are inhibited in the presence of S. pneumoniae.     

白细胞介素-6/糖蛋白130/转录激活因子3通路在百草枯诱导小鼠急性肺损伤中的作用机制

目的基于肺特异性白细胞介素-6(IL-6)敲除小鼠研究IL-6/糖蛋白130(gp130)/转录激活因子3(STAT3)通路在百草枯(PQ)诱导急性肺损伤(ALI)中的作用。方法野生型C57BL/6J小鼠分为IL-6野生型(IL-6 WT)组、IL-6 WT+PQ组,采用Sftpc(肺表面活性蛋白C基因)-Cre⁺小鼠与IL-6^FLOX/FLOX小鼠交配的方式得到肺特异性IL-6敲除小鼠并分为IL-6 KO组、IL-6 KO+PQ组,单次腹腔注射PQ诱导ALI,比较四组小鼠肺组织病理改变、肺泡动脉氧分压差(PA-aO₂)、肺组织湿/干质量比值(W/D)、IL-6/gp130/STAT3通路、核转录因子-κB(NF-κB) p65、肿瘤坏死因子-α(TNF-α)及白细胞介素-1β(IL-1β)的差异。结果与IL-6 WT组比较,IL-6 WT+PQ组小鼠肺组织出现了典型的ALI病理改变,肺组织胞浆蛋白中IL-6、gp130、p-STAT3、TNF-α、IL-1β表达水平及胞核蛋白中NF-κB p65的表达水平、PA-aO₂、W/D明显增加(P <0.05);与IL-6 WT+PQ组比较,IL-6 KO+PQ组小鼠肺组织病理改变明显改善,肺组织胞浆蛋白中IL-6、gp130、p-STAT3、TNF-α、IL-1β的表达水平及胞核蛋白中NF-κB p65的表达水平、PA-aO₂、W/D明显降低(P <0.05)。结论 IL-6/gp130/STAT3通路激活与PQ诱导ALI有关。     

Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response

Shiga toxin (Stx)-producing Escherichia coli (STEC) colonizes the human intestinal mucosa, produces Stx from phage, and causes the development of hemolytic-uremic syndrome via Stx-induced inflammatory cytokine production. Azithromycin exhibited strong in vitro activity against STEC without inducing Stx-converting phage, in marked contrast to norfloxacin. Azithromycin decreased the tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 production from Stx-treated human peripheral mononuclear cells or monocytes to a greater extent than did clarithromycin. In Stx-injected mice, azithromycin significantly suppressed Stx-induced TNF-alpha, IL-1beta, and IL-6 levels in serum and improved the outcome as assessed by survival rate. In the STEC oral infection experiment using immature mice immediately after weaning (weaned immature-mouse model), all mice died within 7 days postinfection. Azithromycin administration gave the mice 100% protection from killing, while ciprofloxacin administration gave them 67% protection. The data suggest that azithromycin (at least at higher concentrations) has a strong effect on Stx production by STEC and on the Stx-induced inflammatory host response and prevents death in mice. Azithromycin may have a beneficial effect on STEC-associated disease.     

Augmented lung injury due to interaction between hyperoxia and mechanical ventilation

OBJECTIVE: Mechanical overdistension and hyperoxia can independently cause lung injury, yet little is known about their combined effects. We hypothesized that hyperoxia exacerbates lung injury caused by large tidal volume ventilation. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: Anesthetized, paralyzed rabbits. INTERVENTIONS: In experiment 1, 12 rabbits were ventilated with 25 mL/kg tidal volumes at positive end-expiratory pressure of 0 cm H2O for 4 hrs with either hyperoxia (HO; FiO2 = 0.5) or normoxia (NO; FiO2 = 0.21). In experiment 2, a separate group of animals were randomized to one of four groups to assess the interaction of tidal volume and inspired oxygen concentration on potential mediators of injury after 2 hrs of ventilation, before significant injury occurs: a) NO+normal tidal volume (NV; VT = 10 mL/kg); b) HO+NV; c) NO+high tidal volume (HV; VT = 25 mL/kg); d) HO+HV (n = 3 per group). MEASUREMENTS AND MAIN RESULTS:: In the first study, HO compared with the NO group had significantly reduced PaO2/FiO2 ratio (320 +/- 110 vs. 498 +/- 98, p = .014) and increased lung injury scores at 4 hrs. Hyperoxia also significantly increased polymorphonuclear leukocytes, growth-related oncogene-alpha (2073 +/- 535 vs. 463 +/- 236 pg/mL, p = .02), and monocyte chemotactic protein-1 (7517 +/- 1612 vs. 2983 +/- 1289 pg/mL, p = .05) concentrations in bronchoalveolar lavage fluid. The second study showed increased alveolar-capillary permeability to a 70-kD fluorescent-labeled dextran only in response to the combination of both HO and HV. Chemokines and bronchoalveolar lavage fluid neutrophils were elevated in both HV groups; however, hyperoxia did not further increase chemokine or neutrophil counts over normoxia. No difference in lipid peroxidation was seen between groups. CONCLUSIONS: Moderate hyperoxia exacerbates lung injury in a large tidal volume model of ventilator-induced lung injury. The mechanism by which this occurs is not mediated by increased production of CXC chemokines or lipid peroxidation.     

高浓度氧对未成年大鼠肺部炎症反应的影响

目的 探讨高浓度氧对未成年大鼠肺部炎症反应的影响.方法 将40只出生21 d的SD大鼠按随机数字表法分为空气对照组及高氧暴露12、24、48、72 h组,每组8只,分别将大鼠置于空气和常压高氧箱(氧含量达92%～94%)中.于相应时间点采用放血法处死大鼠后取肺组织,并行支气管肺泡灌洗.采用硫代巴比妥酸法和比色法分别测定肺组织丙二醛(MDA)含量及髓过氧化物酶(MPO)活性;采用酶联免疫吸附法(ELISA)检测支气管肺泡灌洗液(BALF)中肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)和IL-10含量;观察肺组织病理改变,并进行肺损伤评分.结果 与空气对照组比较,高氧暴露12 h肺组织MDA含量(mmol/g)即显著升高(2.24±0.43比1.57±0.31),MPO活性(U/g)于高氧暴露24 h显著升高(1.24±0.25比0.69±0.22),并均随高氧暴露时间延长逐渐增加(P<0.05或P<0.01).BALF中TNF-α、IL-6和IL-10含量于高氧暴露24 h时较空气对照组显著增加[TNF-α(ng/L):135.2±44.0比94.5±22.3,IL-6(ng/L):73.1±14.2比55.7±17.3,IL-10(ng/L):67.9±21.7比48.2±7.6,P<0.05或P<0.01];但高氧暴露48 h时较24 h时显著降低(48 h时BALF中TNF-α、IL-6、IL-10分别为105.4±17.0,54.3±17.4,50.9±6.9,均P<0.05).高氧暴露12 h时肺损伤评分(分)即较空气对照组显著升高(4.5±1.4比1.3±0.5),并随高氧暴露时间延长进一步升高(P<0.05或P<0.01).结论 高浓度氧可引起未成年大鼠肺部炎症损伤;炎症细胞因子的出现高峰均在高氧暴露24 h.     

水通道蛋白5在高氧肺损伤中的表达及调节机制

目的探讨水通道蛋白5(AQP5)在高氧肺损伤中的表达及其地塞米松对AQP5的调节作用。方法2周左右Wistar大鼠64只,按随机数字表法分为空气对照组、高氧暴露3、7、14d组和相应的地塞米松干预组。高氧暴露组置于常压氧仓中(O2体积分数≥95%);空气对照组置于同室常压空气中(O2体积分数为21%);各地塞米松干预组在暴露于空气或高氧的同时,经腹腔注射地塞米松5mg·kg-1·d-1,连续3d。采用逆转录聚合酶链反应(RT PCR)和免疫组化方法观察AQP5的mRNA表达和分布变化,并与地塞米松干预后进行比较分析。结果AQP5主要表达在肺泡型上皮细胞及气道分泌上皮顶质膜;与空气对照组相比,高氧暴露不同时间后,AQP5特异性表达部位保持不变,但随暴露时间延长,AQP5表达呈逐渐减弱趋势,高氧暴露3、7和14d,AQP5mRNA较空气对照组均降低(P均<0.05)。与同期高氧暴露组比较,地塞米松干预后不同时间点AQP5mRNA表达均无明显变化(P均>0.05)。结论高氧肺损伤时AQP5表达降低,可能是高氧肺损伤肺水肿形成的原因之一;而未见地塞米松对高氧肺损伤AQP5的表达有调节作用。     

阿奇霉素对特发性肺间质纤维化干预作用的临床研究

目的探讨阿奇霉素治疗特发性肺间质纤维化（IPF）的临床疗效。方法IPF患者34例，随机分为阿奇霉素组20例（阿奇霉素0．5g/次，1次／d，静脉滴注；症状好转后改为片剂，0125g／次，1次／d，口服）和泼尼松组14例（泼尼松30mg／次，1次／d，口服；4周后减为15mg／次，1次／d，口服；8周后改为隔日1次，口服）；两组疗程均为3个月。观察两组患者临床表现、肺功能改变情况及副作用。结果两组患者的临床表现、肺功能均有不同程度的改善，但差异无显著性（P〉0．05），阿奇霉素组副作用显著少于泼尼松组（P〈0．05）。结论阿奇霉素治疗IPF具有与口服泼尼松相当的疗效且副作用少．临床值得推广。     

阿奇霉素联合山莨菪碱治疗小儿支原体肺炎的临床疗效及免疫功能的影响

目的:探讨阿奇霉素联合山莨菪碱治疗小儿支原体肺炎的临床疗效及其对免疫功能的影响。方法:选取2014年5月~2016年4月我院收治的小儿支原体肺炎患儿共140例。随机分为观察组和对照组,每组70例,两组患者均予以化痰、止咳及对症支持治疗,同时予以阿奇霉素10 mg/(kg·d)静滴7 d。观察组在此基础上加用山莨菪碱注射液肺腧穴注射0.1~0.2 mg/(kg·d),持续治疗7 d。对比两组患儿临床症状消失时间及住院时间、治疗前和治疗14 d后的血浆免疫球蛋白和细胞炎症因子。结果:观察组的咳嗽缓解时间、退热时间、肺部罗音消失时间和住院天数显著低于对照组(P0.05)。两组患儿治疗后的中性粒细胞百分比、血沉及CRP显著低于治疗前(P0.05);观察组治疗后的中性粒细胞百分比、血沉及CRP显著低于对照组(P0.05)。经过治疗后,观察组患儿的血浆IgA、IgG、IgM较治疗前显著升高(P0.05),且观察组和对照组之间有显著统计学差异(P0.05)。结论:阿奇霉素联合山莨菪碱治疗小儿支原体肺炎可有效缩短病程,降低炎症反应,改善免疫功能,临床疗效可靠。     

Cytokine expression in severe pneumonia: a bronchoalveolar lavage study.

OBJECTIVE: To assess the cytokine expression (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, and IL-6) in severe pneumonia, both locally (in the lungs) and systemically (in blood). DESIGN: Prospective sequential study with bronchoalveolar lavage (BAL) and blood sampling. SETTING: Six-bed respiratory intensive care unit of a 1,000-bed teaching hospital. PATIENTS: Thirty mechanically ventilated patients (>48 hrs) were allocated to either the pneumonia group (n = 20) or a control group (n = 10). INTERVENTIONS: Protected specimen brush and BAL samples for quantitative cultures, and serum and BAL fluid TNF-alpha, IL-1beta, and IL-6 levels were measured on days 1, 3, and 7. In the control group, the procedure was done on day 1 only. MEASUREMENTS AND MAIN RESULTS: Serum TNF-alpha levels were significantly higher in patients with pneumonia compared with controls (35 +/- 4 vs. 17 +/- 3 pg/mL, respectively, p = .001). IL-6 levels in serum and BAL fluid were higher in pneumonia than in control patients (serum, 837 +/- 260 vs. 94 +/- 35 pg/mL, respectively, p = .017; BAL fluid, 1176 +/- 468 vs. 234 +/- 83 pg/mL, respectively, p = .05). On days 1, 3, and 7 in patients with pneumonia, IL-1beta levels turned out to be higher in BAL fluid than in serum (71 +/- 17 vs. 2 +/-1 pg/mL on day 1; 49 +/- 8 vs. 6 +/- 2 pg/mL on day 3; and 47 +/- 16 vs. 3 +/- 2 pg/mL on day 7 for BAL fluid and serum, respectively, p < .05). No significant correlation between BAL fluid cytokine levels and lung bacterial burden was shown in presence of antibiotic treatment. Although no clear relationship was found between BAL fluid and serum cytokines and mortality, there was a trend toward higher serum IL-6 levels in nonsurvivors (1209 +/- 433 pg/mL) with pneumonia compared with survivors (464 +/- 260 pg/mL). In addition, serum TNF-alpha and IL-6 correlated with multiple organ failure score (r2 = .36, p = .004 for both) and with lung injury score (r2 = .30, p = .01, and r2 = .22, p = .03, for TNF-alpha and IL-6, respectively). CONCLUSIONS: The present study describes the lung and systemic inflammatory response in severe pneumonia. The lung cytokine expression seems to be independent from the lung bacterial burden in the presence of antibiotic treatment. Because of the limited sample size, we did not find a clear relationship between serum and BAL fluid cytokine levels and outcome.     

高氧致大鼠急性肺损伤Toll样受体2和4的变化及意义

目的 探讨Toll样受体(TLRs)在高氧致急性肺损伤(ALI)发病过程中的作用.方法 将32只SD大鼠按随机数字表法分为空气对照组和高氧暴露24、48、72 h组,每组8只.分别于相应时间点活杀8只大鼠,取肺组织标本,测定肺湿/干重(W/D)比值并行肺组织病理评分,用实时荧光定量逆转录-聚合酶链反应(RT-PCR)测定肺组织TLR2和TLR4的mRNA表达,用蛋白质免疫印迹法(Western blotting)测定肺组织TLR2和TLR4的蛋白表达,用酶联免疫吸附法(ELISA)测定肺组织匀浆中白细胞介素-6(IL-6)含量.结果 各高氧暴露组肺W/D比值均较空气对照组明显增高(P均<0.01).高氧暴露48 h、72 h肺组织病理评分[(2.69±0.53)分,(3.94±0.62)分]均明显高于空气对照组[(0.41±0.38)分,P均<0.01].RT-PCR结果显示,高氧暴露组肺组织TLR2和TLR4 mRNA表达均明显高于空气对照组(0.67±0.15和0.63±0.19),并均于24 h达高峰(1.82±0.33,1.35±0.26,P均<0.05).Western blotting结果显示,高氧暴露组TLR2和TLR4蛋白表达均较空气对照组[(7.20±0.51)%和(14.26±0.19)%]明显增高,分别于48 h、72 h达峰值[(28.12±0.24)%,(81.35±0.82)%,P均<0.05].ELISA结果显示,高氧暴露组肺组织匀浆IL-6含量较空气对照组[(639.38±95.24)pg/L]明显增高,于72 h达高峰[(1 300.58±442.24)pg/L,P<0.05].结论 在高氧引起的ALI中,TLR2和TLR4在肺组织炎症启动和维持中起重要作用.     

阿奇霉素联合乙酰半胱氨酸对COPD稳定期患者肺功能及炎症因子水平的影响

目的研究阿奇霉素联合乙酰半胱氨酸对慢性阻塞性肺疾病(COPD)稳定期患者肺功能及炎症因子水平的影响。方法将2017年7月至2019年6月我院收治的90例COPD稳定期患者按照随机数字法分为对照组和联合组,各45例。对照组在常规治疗基础上给予阿奇霉素,联合组在对照组基础上给予乙酰半胱氨酸。比较两组的肺功能指标、炎症指标及不良反应发生情况。结果治疗后,两组FEV1、FEV1%pred和FEV1/FVC均明显升高,TNF-α、IL-10和GRO-α水平均明显降低,且联合组优于对照组(P<0.05)。两组不良反应总发生率比较,差异无统计学意义(P>0.05)。结论阿奇霉素联合乙酰半胱氨酸能够有效减轻COPD稳定期患者的炎症反应,改善其肺功能,安全性好。     

Solitary erythema migrans in children: comparison of treatment with azithromycin and phenoxymethylpenicillin

OBJECTIVE: To compare clinical effectiveness and side effects of treatment with azithromycin or phenoxymethylpenicillin in children with solitary erythema migrans. METHODS: Consecutive patients younger than 15 years, referred to our institution in 1998 and 1999 with previously untreated typical solitary erythema migrans, were included in this prospective study. Basic demographic features and clinical data were collected by means of a questionnaire. The efficiency of treatment of acute disease, development of later major and/or minor manifestations of Lyme borreliosis and side effects of treatment were surveyed by follow-up visits during the first year. RESULTS: Forty-two patients received azithromycin 20 mg/kg/day for the first day followed by 10 mg/kg/day for a further four days and phenoxymethylpenicillin 100,000 IU/kg/day for 14 days. No differences in demographic and clinical pre-treatment characteristics were present in the two groups, with the exception of the duration of erythema migrans before treatment (3 days in the azithromycin group versus 4 days in the phenoxymethylpenicillin group; p = 0.0320). The clinical course during the post-treatment period revealed no significant differences between the two groups in the duration of EM (3 days versus 4 days; p = 0.2471), the appearance of minor manifestations of Lyme borreliosis (17.5% in the azithromycin group versus 24.4% in the phenoxymethyl-penicillin group; p = 0.6252), or in the emergence of major manifestations of Lyme borreliosis (one patient in each treatment group). One year after antibiotic treatment all patients were asymptomatic. Side effects of treatment were observed in 5.3% of patients treated with azithromycin and in 6% treated with phenoxymethylpenicillin. The appearance of "Herxheimer's reaction" at the beginning of treatment was recorded in 7 out of 42 patients (6%) in each treatment group. CONCLUSIONS: Azithromycin and phenoxymethylpenicillin are equally effective in treatment of children with solitary erythema migrans and have comparable side effects.     

红霉素在早产鼠高氧肺损伤中对白细胞介素6、8及γ-谷氨酰半胱氨酸合成酶表达的影响

目的 探讨红霉素在早产鼠高氧肺损伤中对白细胞介素6 （IL-6）,IL-8及γ-谷氨酰半胱氨酸合成酶（γ-GCS）的干预作用.方法 96只早产新生SD大鼠生后1d分为四组：Ⅰ组空气暴露＋生理盐水、Ⅱ组空气暴露＋红霉素、Ⅲ组高氧暴露＋生理盐水、Ⅳ组高氧暴露＋红霉素,每组各24只.四组分别于高氧或空气暴露后1、7、14d处死取肺组织做病理学检查.采取双抗体夹心酶联免疫吸附试验分析肺组织匀浆细胞因子IL-6、IL-8和γ-GCS的水平,并采取半定量逆转录聚合酶链反应测定γ-GCS mRNA的表达.结果 Ⅰ、Ⅱ组肺组织无明显病理改变,Ⅲ组肺泡炎性改变及水肿较Ⅳ组更为明显.Ⅳ组γ-GCS水平在7、14 d较Ⅲ组降低,但是γ-GCS mRNA表达较γ-GCS mRNA均明显增强（P均＜0.05）.Ⅲ组1、7、14 d IL-6及IL-8水平较Ⅰ组均显著增强（P均＜0.05）.Ⅳ组IL-6水平在1、7、14d与Ⅲ组比较,差异均有统计学意义（P均＜0.05）,而IL-8水平仅在7、14d较Ⅲ组明显下降（P均＜0.05）.结论 氧化爆发诱导的炎症介质IL-6及IL-8参与高氧肺损伤发病过程,红霉素可抑制其释放,影响γ-GCS活性从而提高谷胱甘肽抗氧化能力.     

Protective effects of a selective neutrophil elastase inhibitor (sivelestat) on lipopolysaccharide-induced acute dysfunction of the pulmonary microcirculation

OBJECTIVE: The purpose of this study was to evaluate the effect of a neutrophil elastase inhibitor, sivelestat, on lipopolysaccharide-induced acute lung injury through analysis of hemodynamic changes in the pulmonary microcirculation. DESIGN: Randomized animal study. SETTING: Medical school laboratory. SUBJECTS: Twenty-seven Wistar rats (15 rats for microspectroscopic observations, 12 rats for measurements of neutrophil elastase activity and wet-to-dry ratio). INTERVENTIONS: Thoracosternotomy was performed on male Wistar rats under continuous anesthesia and mechanical ventilation. Rats were divided into three groups (n = 5 each groups) on the basis of the reagent used: lipopolysaccharide group (100 microg/kg lipopolysaccharide intravenously), sivelestat group (10 mg/kg sivelestat; 100 microg/kg lipopolysaccharide intravenously), and control group (saline only, intravenously). MEASUREMENTS AND MAIN RESULTS: We measured morphologic changes and hemodynamic variables, including tissue blood flow, erythrocyte velocity, erythrocyte count, thickness of interalveolar septa, and leukocyte adhesion in the pulmonary microcirculation, with a video-rate (33 msec/frame) dual-spot microspectroscopy system (DSMSS) and a laser-Doppler flowmeter. Blood-free wet-to-dry ratio and neutrophil elastase activity in bronchoalveolar lavage fluid, serum, and supernatant of lung homogenate were measured in another set of experiments (n = 4 for each group). Sixty minutes after lipopolysaccharide administration, severe thickening of the interalveolar septa was observed in the lipopolysaccharide but not the sivelestat group. In the lipopolysaccharide group, DSMSS measurements of erythrocyte velocity and hemoglobin oxygenation in single capillaries were decreased significantly (vs. control p < .05, vs. sivelestat p < .01), whereas tissue blood flow and erythrocyte velocity measurements from laser-Doppler flowmeter were increased significantly (vs. control p < .05, vs. sivelestat p < .01). The number of adherent leukocytes was increased significantly in the lipopolysaccharide group at 30, 45, and 60 mins after lipopolysaccharide administration (vs. control p < .01, vs. sivelestat p < .05). The number of adherent leukocytes did not increase in the sivelestat group. The wet-to-dry ratio was significantly higher in the lipopolysaccharide group than in control (p < .05) and sivelestat (p < .05) groups. Neutrophil elastase activities in the bronchoalveolar lavage fluid, serum, and lung tissue were all significantly lower in the sivelestat group than in the lipopolysaccharide group (p < .05). CONCLUSIONS: Lipopolysaccharide induces leukocyte adhesion in the pulmonary microcirculation, resulting in decreased tissue hemoglobin oxygen and alveolar and interstitial edema. The selective neutrophil elastase inhibitor sivelestat reduces neutrophil elastase activity and attenuates acute changes in the pulmonary microcirculation.     

阿奇霉素联合布地奈德混悬液雾化吸入治疗小儿支原体肺炎的临床效果

目的探讨阿奇霉素联合布地奈德混悬液雾化吸入治疗小儿支原体肺炎的临床效果。方法将2015年10月至2019年1月我院收治的300例小儿支原体肺炎患儿按照随机数表法分为对照组与观察组,各150例。对照组采用阿奇霉素序贯疗法,观察组在对照组基础上给予布地奈德混悬液雾化吸入治疗。比较两组患儿治疗前、后的肺功能情况、血清IgE、外周血嗜酸性粒细胞(EOS)、炎症因子水平及临床疗效。结果治疗后,两组的FVC%、FEV1%、PEF%、MEF25%、MEF50%均有所提高,且观察组显著高于对照组(P<0.05)。治疗后,两组的IgE及EOS水平均有所下降,且观察组显著低于对照组(P<0.05)。治疗后,两组的IL-4水平均下降,IL-12、IFN-γ水平均升高,且观察组优于对照组(P<0.05)。观察组的治疗总有效率为91.33%,显著高于对照组的80.67%(P<0.05)。结论阿奇霉素联合布地奈德混悬液雾化吸入在小儿支原体肺炎的治疗中具有良好的效果,可降低炎症因子水平,有效改善患儿的肺功能,值得临床推广。     

阿奇霉素治疗小儿支原体肺炎的效果及对乳酸脱氢酶、炎症因子、免疫功能的影响

目的探讨阿奇霉素治疗小儿支原体肺炎的效果及对乳酸脱氢酶、炎症因子、免疫功能的影响。方法将我院收治的212例支原体肺炎患儿随机分为观察组(n=106,阿奇霉素治疗)与对照组(n=106,红霉素治疗),比较两组的疗效。结果治疗2周后,两组患儿的乳酸脱氢酶、IL-12、IFN-γ水平、CD4^+/CD8^+均有所改善,且观察组优于对照组(P<0.05)。观察组的治疗总有效率高于对照组(P<0.05)。观察组不良反应总发生率低于对照组(P<0.05)。结论阿奇霉素治疗小儿支原体肺炎可有效降低炎症因子和乳酸脱氢酶水平,增强细胞免疫功能,改善预后,提高临床疗效。     

Azithromycin pharmacokinetics and intracellular concentrations in Legionella pneumophila-infected and uninfected guinea pigs and their alveolar macrophages.

Azithromycin pharmacokinetics in Legionella pneumophila-infected and uninfected guinea pigs were assessed by measuring the drug concentration in whole lungs or the drug content in bronchoalveolar lavage (BAL) fluid in separate experiments. Azithromycin concentrations were measured by using a bioassay. The mean azithromycin content in the BAL fluid of infected guinea pigs was higher than that in controls at 10 h (0.87 versus 0.39 microgram; P = 0.05), 24 h (1.10 versus 0.37 microgram; P = 0.003), and 48 h (1.21 versus 0.28 microgram; P = 0.05) after a single intraperitoneal injection of drug (15 mg/kg). The mean peak lung azithromycin concentration was higher in control animals than in infected animals (15.8 versus 13.4 micrograms/ml). The mean lung azithromycin concentration in infected animals was significantly higher than that in controls 48 h after dosing (12.7 versus 10.4 micrograms/g; P = 0.04). There were no significant differences between infected and uninfected animals in serum azithromycin levels. Complementary experiments assessed intracellular/extracellular concentration ratios of azithromycin and erythromycin in L. pneumophila-infected and control guinea pig alveolar macrophages. Azithromycin was highly concentrated in alveolar macrophages, and the intracellular/extracellular concentration ratios for infected cells were significantly higher (P < 0.0001) than those observed in controls after 4 h (127 versus 119), 24 h (481 versus 361), and 48 h (582 versus 520) of incubation. Erythromycin was also preferentially concentrated in infected cells (P < 0.0001). AZ intracellular concentrations were at least fivefold higher than those measured for erythromycin, and this differential increased with incubation time. Thus, azithromycin recovery from BAL fluid, and from guinea pig lungs at the 48-h time point, was higher in the presence of experimental Legionnaires' disease. This likely results from recruitment of phagocytes, including macrophages, that have an enhanced capacity to highly concentrate the drug.     

血必净对急性肺损伤兔核因子-κB活性变化的研究

目的观察血必净注射液对脂质糖(LPS)诱导的急性肺损伤(ALI)兔肺组织炎症相关细胞因子的影响,探讨其发挥抗炎作用的细胞信号调控转导机制。方法新西兰兔80只随机分为第一组(空白对照组)、第二组(单纯急性肺损伤组,股静脉注射LPS)、第三组(单纯股静脉注射血必净)、第四组(血必净联合LPS治疗)。观察病理形态和ALI生物标志物变化,并用放射免疫法(RIA)测定肺组织白细胞介素(IL)-6、IL-8、肿瘤坏死因子(TNF-α)水平,凝脉电泳迁延率法(EMSA)加计算机图象分析技术测白细胞兔核因子-κB(NF-κB)活性。结果与单纯急性肺损伤组比较,血必净可减轻兔肺组织的炎性病变,显著降低IL-6、IL-8、TNF-α、NF-κB含量,组间比较差异具有统计学意义(P<0.01)。结论中药制剂血必净注射液通过抑制核因子-κB活性而阻断炎症因子IL-6、IL-8、TNF-α的合成和释放。