Recombinant human soluble tumor necrosis factor-alpha receptor fusion protein partly attenuates ventilator-induced lung injury

Ventilator-induced lung injury is mediated, at least in part, by TNF-alpha. We determined the effect of a recombinant human soluble TNF receptor fusion protein (etanercept) on mechanical ventilation (MV)-induced changes in a murine ventilator-induced lung injury model. After pretreatment with etanercept or placebo, C57Bl/6 mice were anesthetized and randomized to MV with either low tidal volumes (VT, approximately 7.5 mL/kg) or high VT ( approximately 15 mL/kg) for 5 h. Instrumented but spontaneously breathing mice served as controls. End points were lung wet-to-dry ratios, lung histopathology scores, protein levels, neutrophil cell counts and thrombin-antithrombin complex levels in bronchoalveolar lavage fluid (BALF), and cytokine levels in lung homogenates. The number of caspase 3-positive cells was used as a measure for apoptosis. Etanercept treatment attenuated MV-induced changes, in particular, in MV with high VT. Compared with placebo, etanercept reduced the number of neutrophils in BALF and thrombin-antithrombin complex levels in BALF and cytokine levels in lung homogenates. Lung wet-to-dry ratios, histopathology scores, and local protein levels in BALF, however, were not influenced by etanercept treatment. The number of caspase 3-positive cells was significantly higher in etanercept-treated animals. Inhibition of TNF by etanercept attenuates, in part, MV-induced changes.     

Bench-to-bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury

Mechanical ventilation (MV) has the potential to worsen pre-existing lung injury or even to initiate lung injury. Moreover, it is thought that injurious MV contributes to the overwhelming inflammatory response seen in patients with acute lung injury or acute respiratory distress syndrome. Ventilator-induced lung injury (VILI) is characterized by increased endothelial and epithelial permeability and pulmonary inflammation, in which the innate immune system plays a key role. A growing body of evidence indicates that endogenous danger molecules, also termed damage-associated molecular patterns (DAMPs), are released upon tissue injury and modulate the inflammatory response. DAMPs activate pattern recognition receptors, may induce the release of proinflammatory cytokines and chemokines, and have been shown to initiate or propagate inflammation in non-infectious conditions. Experimental and clinical studies demonstrate the presence of DAMPs in bronchoalveolar lavage fluid in patients with VILI and the upregulation of pattern recognition receptors in lung tissue by MV. The objective of the present article is to review research in the area of DAMPs, their recognition by the innate immune system, their role in VILI, and the potential utility of blocking DAMP signaling pathways to reduce VILI in the critically ill.     

胸部撞击伤时游离Ca2+浓度与中性粒细胞凋亡及肺损伤的关系

目的 :动态观察兔胸部撞击伤时中性粒细胞 (PMN)凋亡的发生以及与肺损伤之间的关系。方法 :制备兔胸部撞击伤模型 ,分离纯化肺灌洗液中的 PMN,应用流式细胞术测定 PMN凋亡、坏死、存活细胞比例及呼吸爆发功能的变化 ,并且观察与乳酸脱氢酶 (L DH)和胞浆游离 Ca2 变化之间的关系。结果 :肺灌洗液中PMN的凋亡延迟持续至 12小时 ,在伤后各时间点活细胞增多 ;而肺灌洗液 PMN呼吸爆发从伤后 2小时即显著增强 ,8小时达到峰值 ;同时肺灌洗液 L DH的升高在伤后 4～ 2 4小时显著高于正常对照组 ;伤后 PMN胞浆游离 Ca2 有短暂升高。结论 :胸部撞击伤时 ,PMN在肺组织中大量扣押 ,且正常的凋亡途径发生障碍 ,造成PMN持续处于激活状态及毒性内容物的持续释放 ,与肺组织损伤有密切关系 ,并且 PMN凋亡延迟可能与胞浆游离 Ca2 的短暂升高有关     

机械通气对急性肺损伤大鼠细胞凋亡的影响

目的 研究不同潮气量及不同呼气末正压(PEEP)水平对急性肺损伤(AU)大鼠支气管和肺组织细胞凋亡的影响,并初步探讨细胞凋亡在呼吸机相关性肺损伤(VILI)中的作用机制.方法 选用40只SD大鼠,制作ALI模型,随机(随机数字法)分为:(1)小潮气量组(LV组),潮气量8 mL/kg,不加PEEP;(2)大潮气量组,潮气量30 mL./kg,不加PEEP;(3)小潮气量+ 2PEEP组(LV2P组),潮气量8 mL/kg,同时给PEEP 2 cmH2O(1 crnH2O =0.098 kPa);(4)小潮气量+5PEEP组(LV5P组),潮气量8 mL/kg,同时给PEEP 5 cmH2O;(5)小潮气量+8PEEP组(LV8P组),潮气量8 mL/kg,同时给PEEP 8 cmH2O.通气2h后处死动物,留取肺标本.用脱氧核糖核苷酸末端转移酶介导的末端标记法(TUNEL)分析肺组织中的细胞凋亡情况,用免疫组化法检测肺组织中caspase-3蛋白的表达及分布.结果 大潮气量组支气管和肺组织细胞凋亡的明显增加(P＜0.01),caspase-3蛋白酶表达最强.采用PEEP后,支气管和肺组织细胞凋亡减少,capase-3蛋白酶表达弱阳性,以LV5P组最为显著(P＜0.01).结论 小潮气量对肺组织有保护作用,采用PEEP后保护作用更加明显,细胞凋亡在VILI的发生中有重要作用.     

中性粒细胞凋亡对急性胰腺炎相关性肺损伤的影响

目的 研究中性粒细胞（PMN）在急性胰腺炎相关性肺损伤（PALl）中自发性凋亡的变化及与肺损伤的相关性，探讨PMN凋亡在这一过程中的病理意义。方法 采用5％牛磺胆酸钠（TAC）逆行胆胰管注射造成大鼠急性出血坏死性胰腺炎（AHNP）模型。将36只实验动物随机分为AHNP组、假手术组及地塞米松（DXM）治疗组，3h后处死动物。从支气管肺泡灌洗液分离PMN，在体外分别孵育1、3、6h后，以Annexin V／PI双染色法测定其自发性凋亡率。取肺组织测定肺湿／干比值、髓过氧化物酶（MPO）含量及肺通透性指数，研究自发性凋亡率与肺损伤之间的相关性。结果 三组大鼠支气管肺泡灌洗液PMN的自发性凋亡率随体外孵育时间的延长而逐渐增加；在3、6h时，AHNP组均低于假手术组及DXM治疗组，而肺温／干比值、MPO含量及肺通透性指数则高于后两组。AHNP组3h凋亡率与肺温／干比值、MPO含量及肺通透性指数呈负相关。结论 肺PMN凋亡减低与PALI大鼠模型肺损伤成负相关，同时伴有活性增强，是PALI发生的重要原因；DXM可减轻PALI，与其促进PMN凋亡。     

急性肺损伤炎性细胞凋亡异常及粒细胞集落刺激因子调控的研究

目的 探讨急性肺损伤时支气管肺泡灌洗液(BALF)中的中性粒细胞(PMN)凋亡发生规律及其与粒细胞集落刺激因子调控关系.方法 豚鼠30只,分为3组:组1为生理盐水正常对照组,组2为油酸致病组,组3为油酸+粒细胞集落刺激因子组.组2、组3分别由尾静脉注射油酸(0.12 ml/kg)造成豚鼠急性肺损伤模型.组1则注入生理盐水.组3在实验造模前2 d由皮下注射粒细胞集落刺激因子1.0μg/kg,1次/d.组1、组2、组3分别于注射后2 h用生理盐水进行全肺支气管肺灌洗,收集BALF.用梯度密度法离心收集PMN.用原位末端标记法检测BALF中PMN凋亡.结果 组2、组3和组1BALF中PMN凋亡百分比分别为(2.500±1.080)%、(3.500±0.850)%、(6.400±1.505)%.组2、组3较组1 BALF中PMN凋亡均显著降低(均P＜0.01).结论 急性肺损伤炎性细胞PMN凋亡延迟,PMN持续激活和释放毒性内容物与肺损伤有密切关系.粒细胞集落刺激因子能调控干预急性肺损伤时PMN凋亡延迟.     

急性肺损伤病人中性粒细胞凋亡变化的研究

目的　观察急性肺损伤 (ALI)病人中性粒细胞 (PMN)凋亡的发生以及与肺损伤的关系 ,并探讨其临床意义。方法　对 37例符合ALI诊断标准的病人 ,分离纯化肺灌洗液中的PMN ,应用流式细胞术测定PMN凋亡、坏死、存活细胞比例及呼吸瀑发功能的变化 ,设健康对照组 ,并观察与乳酸脱氢酶 (LDH)和胞浆游离Ca2 变化之间的关系。结果　ALI病人肺灌洗液中PMN凋亡比例显著降低 ,2 4h持续在低水平 (P <0 0 5 ,P <0 0 1) ;各检测点活细胞增多 (P <0 0 5 ,P <0 0 1) ;而灌洗液PMN的呼吸瀑发明显升高 ,8h达峰值 ,并持续升高 (P <0 0 1)。灌洗液中LDH水平 2～ 2 4h明显高于正常对照组 (P <0 0 5 ,P<0 0 1) ;PMN胞浆游离Ca2 各检测点显著增高 (P <0 0 5 ,P <0 0 1)。PMN凋亡与LDH水平呈显著相关性 (r =- 0 715 1,P <0 0 1) ;PMN凋亡与胞浆游离Ca2 的浓度有显著的相关性 ( r=- 0 6 0 39,P <0 0 1)。结论　ALI时PMN在肺组织中大量扣押 ,且正常的凋亡途径发生障碍 ,造成PMN持续处于激活状态及毒性内容物的持续释放 ,与肺组织的损伤有密切关系 ,并且PMN凋亡延迟可能与LDH、胞浆游离Ca2 的升高有关     

急性肺损伤患者中性粒细胞凋亡变化的研究

目的观察急性肺损伤(ALI)患者中性粒细胞(PMN)凋亡的发生以及与肺损伤的关系,并探讨其临床意义。方法对37例符合ALI诊断标准的患者,分离纯化肺灌洗液中的PMN,应用流式细胞术测定PMN凋亡、坏死、存活细胞比例及呼吸瀑发功能的变化,设健康对照组,并观察与乳酸脱氢酶(LDH)和胞浆游离Ca2 变化之间的关系。结果灌洗液中PMN凋亡比例显著降低,24h持续在低水平(P<0.05或P<0.01);各检测点活细胞增多(P<0.05或P<0.01);而灌洗液PMN的呼吸瀑发明显升高,8h达峰值,并持续升高(P<0.01)。灌洗液中LDH水平2～24h明显高于正常对照组(P<0.05或P<0.01);PMN胞浆游离Ca2 各检测点显著增高(P<0.05或P<0.01)。PMN凋亡与LDH水平有相关性(r=-0.7151,P<0.01),PMN凋亡与胞浆游离Ca2 水平有相关性(r=-0.6039,P<0.01)。结论ALI时PMN在肺组织中大量扣押,且正常的凋亡途径发生障碍,造成PMN持续处于激活状态及毒性内容物持续释放,与肺组织的损伤有密切关系,并且PMN凋亡延迟可能与LDH、胞浆游离Ca2 的升高有关。     

Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice

Introduction  

Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis.     

不同潮气量联合呼气末正压通气对急性肺损伤犬小肠的影响

目的 比较大、小潮气量(VT)机械通气(MV)对急性肺损伤(ALI)犬小肠组织的影响.方法 用静脉注射油酸法制备犬ALI模型,制模成功后随机分为两组,分别接受不同VT的MV,通气时间均为6 h.小VT MV组(LV组,n=6):VT 6 ml/kg,呼气末正压(PEEP)10 cm H2O(1 cm H2O=0.098 kPa);大VT MV组(HV组,n=6):VT 20 ml/kg,PEEP 10 cm H2O.通气6 h后放血处死动物,开腹取小肠组织,用苏木素-伊红(HE)染色,观察组织病理学改变;用原位末端缺刻标记法(TUNEL)观察小肠组织细胞凋亡情况.结果 机械通气6 h后HV组ALI犬小肠胀气明显;而LV组无此表现;LV组小肠损伤评分低于HV组[(3.17±0.75)分比(2.00±0.89)分],差异有统计学意义(P<0.01);但各组犬小肠组织细胞凋亡均罕见.结论 大VT通气可诱导小肠功能不全;小VT通气在一定程度上可避免出现小肠功能障碍.     

Tumor necrosis factor-alpha blockade prevents neutrophil CD18 receptor upregulation and attenuates acute lung injury in porcine sepsis without inhibition of neutrophil oxygen radical generation.

Tumor necrosis factor (TNF alpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis. We examined the effects of pretreatment with a monoclonal antibody to TNF alpha on PMN function, hemodynamic derangements, and alveolar capillary membrane damage in a septic porcine model. Anti-TNF alpha profoundly improved hemodynamic consequences in this model. Reduction in PMN CD11/18 receptor expression, lung myeloperoxidase activity, and attenuation of peripheral neutropenia (all P < 0.05) indicate that pretreatment significantly reduced lung sequestration of PMNs seen in septic controls. In contrast, PMN oxygen radical (O2-) generation was not significantly different from unprotected septic animals. Despite the presence of circulating PMNs primed for O2- burst, alveolar capillary membrane damage, assessed by bronchoalveolar lavage protein content and arterial PO2 was markedly attenuated in the treatment group (P < 0.05). We conclude that anti-TNF alpha suppresses systemic hemodynamic actions of TNF alpha. Further, it prevents upregulation of PMN adhesion receptors inhibiting PMN/endothelial cell interaction. This prevents formation of a "microenvironment," protected from circulating oxidant scavengers, into which sepsis-activated PMNs release their toxic products. Pretreatment with anti-TNF alpha monoclonal antibody thus affords global protection in porcine Gram-negative sepsis.     

Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung

In models of acute lung injury, CXC chemokine receptor 2 (CXCR2) mediates migration of polymorphonuclear leukocytes (PMNs) into the lung. Since CXCR2 ligands, including CXCL1 and CXCL2/3, are chemotactic for PMNs, CXCR2 is thought to recruit PMNs by inducing chemotactic migration. In a model of PMN recruitment to the lung, aerosolized bacterial LPS inhalation induced PMN recruitment to the lung in wild-type mice, but not in littermate CXCR2-/- mice. Surprisingly, lethally irradiated wild-type mice reconstituted with CXCR2-/- BM still showed about 50% PMN recruitment into bronchoalveolar lavage fluid and into lung interstitium, but CXCR2-/- mice reconstituted with CXCR2-/- BM showed no PMN recruitment. Conversely, CXCR2-/- mice reconstituted with wild-type BM showed a surprisingly large defect in PMN recruitment, inconsistent with a role of CXCR2 on PMNs alone. Cell culture, immunohistochemistry, flow cytometry, and real-time RT-PCR were used to show expression of CXCR2 on pulmonary endothelial and bronchial epithelial cells. The LPS-induced increase in lung microvascular permeability as measured by Evans blue extravasation required CXCR2 on nonhematopoietic cells. Our data revealed what we believe to be a previously unrecognized role of endothelial and epithelial CXCR2 in LPS-induced PMN recruitment and lung injury.     

Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin

Introduction

Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia.

Methods

We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation.

Results

In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1–3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p < 0.01; prevention of pulmonary restriction) and against VILI-induced liver and gut injury in pneumonia (91% reduction of AST levels p < 0.05, 96% reduction of alanine aminotransaminase (ALT) levels p < 0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut).

Conclusions

MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically ventilated individuals with severe pneumonia.     

肺复张后不同潮气量对急性肺损伤大鼠肺血管内皮舒张功能的影响

目的 观察肺复张与肺复张后不同潮气量对ALI大鼠肺内皮舒张功能的影响.方法 内毒素(LPS)静脉注射复制大鼠ALI模型.25只清洁级SD大鼠随机(随机数字法)分成5组,每组5只:对照组、ALI组、小潮气量(VT)组(LV组,VT 6 mL/kg)、SI+小VT组(SI+LV组,VT 6 mL/kg)、SI+常规VT组(SI+MV组,VT12mL/kg),SI(30 cmH2O)维持30 s,进行肺复张.应用不同潮气量联合肺复张监测呼吸功能和血流动力学,实验5 h后放血处死动物.观察肺组织病理形态改变和湿/干重比(W/D);放射免疫法检测肺组织中ET-1;免疫组织化学法半定量分析肺动脉内皮细胞内皮型一氧化氮合酶(eNOS)蛋白表达水平;血管张力实验检测离体肺动脉环对乙酰胆碱(Ach)和硝普钠(SNP)介导的舒张功能的影响;ELISA检测肿瘤坏死因子-α(TNF-α)炎症反应指标.结果 与CON组比较,LPS增加各组内肺水肿,加重肺损伤,增加TNF-α含量,增加ET-1含量,减少肺动脉内皮细胞eNOS蛋白表达,减弱Ach介导的内皮依赖的舒张功能,最终影响内皮功能.SI+LV组ET-1含量为(109.18±15.62)pg/mL,SI+MV组和LV组肺组织ET-1含量分别为(158.78±30.40)pg/mL和(152.35±8.21)pr/mL,较SI+LV组升高(P＜0.05);SI+LV组肺组织eNOS蛋白表达的iOD值为(12663.83±1348.93),SI+MV组和LV组肺组织eNOS蛋白表达的iOD值分别为(9208.12±2773.68)和(9339.53±3366.40),较SI+LV组无统计学差异,但有降低趋势(P＞0.05);与SI+LV组比较,ALI组和SI+MV组在不同浓度Ach作用下内皮依赖的舒张功能降低(P＜0.05),LV组虽然与SI+LV组比较差异无统计学意义,但Ach介导舒张功能有下降的趋势;SI+LV组肺组织TNF-α含量(2374.53±410.60)ng/L,较SI+MV组(3468.86±659.25)ng/L和LV组(3370.75±314.17)ng/L降低(P＜0.05).结论 肺复张联合大潮气量和小潮气量机械通气能够改善ALI大鼠肺血管内皮舒张功能,肺复张联合小潮气量可进一步减轻ALI大鼠肺血管内皮舒张功能的损伤.     

大鼠内毒素血症时外周血及肺泡内中性粒细胞死亡方式及呼吸爆发

本研究观察大鼠内毒素血症时肺组织中及外周血多形核中性粒细胞（PMN）凋亡，坏死及功能改变的差异。采用Wistar大鼠20只。腹腔注射LPS（O55B5，5mg/kg)造成内毒素血症，给予LPS后2，4，8，12小时（每组5只动物）取血及支气管肺泡灌洗，密度梯度法分离PMN，用流式细胞仪测定凋亡和坏死比例以及呼吸爆发功能的改变，同时采用5只大鼠作为正常对照。结果显示，内毒素血症时外周血和支气管肺泡灌洗液中PMN凋亡细胞比例相似。但与对照相比，外周血PMN坏死比例明显增加，呼吸爆发能力明显受抑，而支气管肺泡灌洗液PMN坏死比例显减少，呼吸爆发能力显增强。结论：在内毒素血症时，扣押于肺组织中的PMN在凋亡和坏死上表现出与比例显减少，呼吸爆发能力显增强，结论：在内毒素血症时，扣押于肺组织中的PMN在凋亡和坏死上表现出与外周血PMN不同的改变，其结果是组织中PMN存活增加，并持续处于活化状态，这与PMN造成组织损伤有关。     

Effect of post recruitment maneuver ventilation by different tidal volume on lung vascular endothelial diastole function in rats with acute lung injury

BACKGROUND: This study aimed to observe the effect of recruitment maneuver (RM) and post-RM ventilation at different tidal volume on lung vascular diastole endothelial function in rats with acute lung injury (ALI).METHODS: A ALI rat model was produced by intravenous infusion of lipopolysaccharide (6 mg/kg). Twenty-five rats were randomly divided into five groups: control group (n=5), ALI group (n=5), low tidal volume group (LV group, VT 6 mL/kg, n=5), sustained inflation (SI) with low tidal volume group (SI+LV group, VT 6 mL/kg, n=5), and SI with moderate tidal volume group (SI+MV group, VT 12 mL/kg, n=5). RM was performed with SI, airway pressure 30 cmH₂O for 30 seconds, and positive end-expiratory pressure (PEEP) was set to 5 cmH₂O. Lung tissue was taken after 5 hours of mechanical ventilation. Mean arterial blood pressure (MAP) was monitored during the experiment. Endothelin-1 (ET-1), endothelial nitricoxide synthase (eNOS), Ach-induced endothelium-dependent relaxation response of isolated pulmonary artery rings were determined at 5 hours.RESULTS: LPS increased ET-1 level, decreased the expression of eNOS in lung tissue, impaired the Ach-induced endothelium-dependent relaxation response in the pulmonary artery, without obvious effect on systemic hemodynamics. SI+LV significantly reduced LPS-induced elevation of ET-1 level, increased the expression of eNOS, significantly improved endothelial dysfunction, and improved the dysfunction of endothelium-dependent relaxation in the pulmonary artery.CONCLUSIONS: RM with a high or low tidal volume ventilation could improve the lung vascular endothelial function of rats with acute lung injury, and RM with low tidal volume ventilation could lower significantly the injury of lung vascular endothelial diastole function in rats with acute lung injury.     

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.     

Reducing ventilator-induced lung injury and other organ injury by the prone position

Mechanical ventilation can cause structural and functional disturbances in the lung, as well as other vital organ dysfunctions. Apoptosis is thought to be a histological sign of distant organ damage in ventilator-induced lung injury (VILI). Nakos and colleagues observed a protective effect of prone positioning against VILI in normal sheep. Less alteration in the lung architecture and function and in liver transaminases, and lower indices for apoptosis in the liver, the diaphragm and the lung were noted in the prone position compared with the supine position. If confirmed, these data open a new hypothesis for pathogenesis and prevention of VILI and its extrapulmonary complications.     

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.