The ultrastructural effects of carbon monoxide inhalation on the rat lung

Summary The effects of carbon monoxide inhalation on the ultrastructure of rat lungs were investigated. Rats were exposed to 0.5% to 1.0% carbon monoxide for 13 to 137 min.The pulmonary ultrastructural alterations consisted of: 1. swelling of alveolar epithelial cell mitochondria and nucleoplasm, 2. capillary endothelial and alveolar epithelial swelling and 3. capillary platelet thrombosis. Due to the swelling of the epithelium defects are formed in the alveolar lining and the basement membranes of the capillaries are no longer covered with epithelium. As a result of the marked swelling of endothelium and epithelium the lumina of the capillaries and alveolar spaces appear to be narrow and slit-like.The concentration of inhaled carbon monoxide was more important than the level of blood CO Hb and the duration of exposure to carbon monoxide in producing these changes. The results suggest that carbon monoxide has a direct effect on pulmonary tissue.

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Die Wirkungen einer Kohlenmonoxyd-Atmung auf die Ultrastruktur der Rattenlunge

Zusammenfassung Die Wirkungen einer Kohlenmonoxyd-Atmung auf die Ultrastruktur der Rattenlunge wurden elektronenmikroskopisch untersucht. Mehrere Ratten atmeten 13–137 min 0,5–1,0% CO, vermischt mit Luft. Die wichtigsten Veränderungen des Lungengewebes bestehen in einer Schwellung der Mitochondrien der Alveolarepithelien, in einer deutlichen Schwellung des Capillarendothels und des Alveolarepithels sowie in einer capillaren Plättchenthrombose. Durch die Schwellung der Epithelien entstehen Defekte in der Auskleidung der Lungenalveolen. Durch die erhebliche Schwellung der Endothelien und Epithelien werden die Lichtungen der Capillaren und der Alveolen eng und spaltförmig.Für das Auftreten dieser Veränderungen ist die Konzentration des eingeatmeten CO wichtiger als die Konzentration des CO-Hb und als die Dauer der Gaseinwirkung. Die Ergebnisse lassen vermuten, daß CO unmittelbar auf das Lungengewebe einwirkt und Veränderungen am Lungengewebe hervorruft.

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Supported in part by a grant from the National Heart Institute (H-6918).     

Redox imbalance and ventilator-induced lung injury

Mechanical ventilation (MV) is an indispensable therapy in the care of critically ill patients with acute lung injury and the acute respiratory distress syndrome; however, it is also known to further lung injury in certain conditions of mechanical stress, leading to ventilator-induced lung injury (VILI). The mechanisms by which conventional MV exacerbates lung injury and inflammation are of considerable clinical significance. Redox imbalance has been postulated, among other mechanisms, to enhance/perpetuate susceptibility to VILI. A better understanding of these pathologic mechanisms will help not only in alleviating the side effects of mechanical forces but also in the development of new therapeutic strategies. Here, we review the relevance of oxidative stress in VILI from human studies as well as cellular and mouse models of mechanical stress. Potential therapeutic avenues for the treatment of VILI with exogenous administration of antioxidants also are discussed.     

辛伐他汀对烟雾吸入性损伤大鼠肺的保护作用

目的探讨辛伐他汀对烟雾吸入性损伤大鼠肺的保护作用。方法雄性SD大鼠24只,随机分为正常组、盐水组、辛伐他汀小剂量组、辛伐他汀大剂量组,每组6只。辛伐他汀大剂量组和小剂量组烟雾吸入致伤后,用灌胃器给予辛伐他汀大剂量组50mg/kg辛伐他汀,给予辛伐他汀小剂量组25mg/kg辛伐他汀。盐水组烟雾吸入致伤后灌入等体积的生理盐水,每日一次。正常组不做致伤及灌液处理。四组大鼠分别于48h后取左肺组织行病理切片光镜观察。腹主动脉取血2ml,离心后取血清检测肿瘤坏死因子-α、白细胞介素-6、白细胞介素-10含量,并取右肺组织匀浆取上清液检测髓过氧化物酶、脂质过氧化物酶和超氧化物歧化酶含量。结果光镜下正常组肺泡结构清晰完整,盐水组肺泡腔内可见大量粒细胞聚集、浸润,肺泡间隔增厚,而辛伐他汀大剂量和小剂量组上述病理表现明显减轻。与盐水组相比,辛伐他汀小剂量组肿瘤坏死因子水平降低(P<0.01),脂质过氧化物酶含量降低(P<0.05);辛伐他汀大剂量组肿瘤坏死因子、白细胞介素-6含量降低(P<0.01),白细胞介素-10含量升高(P<0.01),髓过氧化物酶、脂质过氧化物酶水平降低(P<0.05),超氧化物歧化酶水平升高(P<0.05)。结论辛伐他汀可减轻炎症及氧化应激,对烟雾所致吸入性损伤大鼠的肺起保护作用。     

呼吸机相关性肺损伤的炎症反应机制

机械通气是治疗急性呼吸窘迫综合征的主要手段，但呼吸机应用不当也可能加重原有的肺损伤，引起呼吸机相关性肺损伤。呼吸机相关性肺损伤本质上是生物伤，异常的机械力作用于细胞，激活细胞内信号转导通路，活化炎性细胞，产生大量炎症介质，加重炎症反应。探讨呼吸机相关性肺损伤的炎症反应机制，阻断机械力作用向细胞内的传导和细胞内信号转导途径的激活，减少炎症细胞的激活和炎症介质基因的表达，对于预防呼吸机相关性肺损伤发挥重要作用。     

丙泊酚对呼吸机所致肺损伤大鼠的保护作用及机制

目的探索丙泊酚对呼吸机所致肺损伤(VILI)模型大鼠的保护作用,并分析其调控机制。方法利用大潮气量通气建立肺损伤模型,将30只SD大鼠随机分为假手术组、模型组和丙泊酚组,每组10只。检测大鼠肺组织湿/干重比(W/D)、大鼠肺组织形态学变化情况、大鼠肺组织中TNF-α和IL-6含量以及JAK、STAT3 mRNA和蛋白水平,并比较3组大鼠肺组织中SOD、MDA的含量。结果与假手术组相比,模型组W/D明显较高,肺组织病理学形态较差,肺组织中TNF-α和IL-6含量明显较高,JAK、STAT3 mRNA水平较高,p-JAK、p-STAT3蛋白水平较高,MDA的含量较高,而SOD的含量较低,以上差异均有统计学意义(P<0.05);与模型组相比,丙泊酚组W/D明显较低,肺组织形态学得到改善,肺组织中TNF-α和IL-6含量明显较低,JAK、STAT3 mRNA水平较低,p-JAK、p-STAT3蛋白水平较低,MDA的含量较低,SOD的含量较高,以上差异均有统计学意义(P<0.05)。结论丙泊酚对VILI模型大鼠具有减弱炎症反应的作用,其机制可能与抑制JAK/STAT3信号通路有关。     

Distribution of peripheral blood flow in primary tissue hypoxia induced by inhalation of carbon monoxide

1. The effects of primary tissue hypoxia induced by the inhalation of small concentrations of carbon monoxide in air on the distribution of blood flow in the portal, renal, muscle and skin beds have been studied in normal unanaesthetized rabbits, in animals without functioning autonomic effectors (;de-efferented' rabbits) and in animals with section of the carotid sinus and aortic nerves (;de-afferented' rabbits).2. The pattern of blood flow distribution during CO hypoxia was similar in ;de-efferented' and ;de-afferented' animals, suggesting that the effects in the latter were determined by local mechanisms. The susceptibility of the various beds to the local dilator effects of CO hypoxia was markedly different, the greatest dilator effects being observed in the portal bed, followed by skin, kidney, and muscle. The pattern is somewhat different from that observed in arterial hypoxia.3. In this type of hypoxia the arterial baroreceptors are probably the main afferent source of reflex activity. In normal animals reflex constrictor effects affect the portal and renal beds most, ;moderating' the local dilator effects of hypoxia in these beds. In muscle there is vasodilatation, probably the result of adrenaline secretion, but the response in skin is largely determined by the local effects of hypoxia. The total orthosympathetic activity evoked in this type of hypoxia appears to be less than in severe arterial hypoxia.     

Acute effects of cigarette smoking and inhalation of carbon monoxide during maximal exercise

Summary The acute effect of inhaling the smoke of three cigarettes was compared to the effect of inhalation of an amount of carbon monoxide (CO), giving the same CO-saturation of the arterial blood as smoking during rest and during maximal exercise on a Krogh cycle ergometer. Sixteen male subjects were tested in the morning (1) after about 8 h without smoking (control), (2) after inhalation of the smoke of three cigarettes (smoke), and (3) after CO-inhalation (CO). It was found that the average maximal rate of O₂-uptake ( max) decreased during both smoke and CO by about 7%. Endurance time at max decreased 20% during smoke but only 10% during CO. A significant decrease in maximal heart rate (HR), and an increase in HR at rest, was demonstrated only during smoke. The peak lactate concentration (HLa) following maximal exercise was significantly decreased after smoke. The results suggest that the decrease in max during smoke is due to the CO-saturation of the blood, and hence to a decrease in the oxygen capacity of the blood, while the decrease in endurance time during smoke is a combined effect of the CO-saturation and an increased cost of breathing caused by the smoke particles. It is further suggested that nicotine, or possibly some other components of the smoke, have an enhancing effect on the heart at rest, while an inhibition is seen during maximal exercise. Finally it was found that the subjects who had a max above the average for all subjects investigated were less susceptible to the effects of smoking than subjects with a max below the average. Supported by a grant from The Danish Sports Research Council     

褪黑素对烟雾吸入所致大鼠急性肺损伤的保护作用

目的通过建立褪黑素干预大鼠烟雾吸入性损伤模型,探讨褪黑素对急性肺损伤的保护作用。方法成年清洁级雄性SD大鼠72只随机分为空白组、损伤组和褪黑素组。空白组不做任何处理,损伤组于吸入性损伤处理后腹腔注射1%乙醇生理盐水（10ml/kg）,褪黑素组于吸入性损伤处理后腹腔注射褪黑素（10mg/kg,1次/8h）。三组大鼠分别在3h、12h、24h三个时相腹主动脉取血2ml后处死,动脉血离心后检测肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）含量和白细胞介素10（IL-10）。肺组织匀浆测超氧化物歧化酶（SOD）、丙二醛（MDA）、髓过氧化物酶（MPO）的含量。取右下肺组织作病理切片,光镜下观察肺组织病理情况。结果光镜下见空白组大鼠肺泡腔结构完整,壁光滑;损伤组肺泡壁增厚,肺间质炎症细胞浸润;褪黑素组肺组织较损伤组病理表现有所减轻。褪黑素组各时相点血清TNF-α和IL-6含量高于空白组（P〈0.05）,低于损伤组（P〈0.05）。损伤组各时相点IL-10含量与空白组相比无统计学差异（P〉0.05）,而褪黑素组IL-10含量与空白组、损伤组相比均升高（P〈0.05）。褪黑素组各时相点肺组织SOD含量均高于损伤组（P〈0.05）,低于空白组（P〈0.05）。褪黑素组各时相肺组织MDA和MPO含量均高于空白组（P〈0.05）,低于损伤组（P〈0.05）。结论褪黑素可以减轻炎症及氧化应激,对烟雾吸入性损伤所致急性肺损伤发挥一定的保护作用。     

一氧化碳吸入装置的设计与实现

目的一氧化碳(carbon monoxide,CO)是一种重要的内源性介质,可用于治疗新生儿持续肺动脉高压、急性肺损伤等严重疾病。但目前有关一氧化碳吸入装置的报道较少,因此本文设计并实现了一种与呼吸机联用的一氧化碳吸入装置以满足临床需求。方法通过气体稀释公式计算出在治疗条件下CO标气的流量,并由转子流量计控制CO标气送入呼吸回路,采用CO电化学传感器对进入患者前的治疗气中CO浓度进行检测,具有实时监测、显示浓度、超标声光报警等功能,并与呼吸机联用后检验了该装置的示值误差和响应时间。结果该装置的示值误差为2.2%,响应时间平均为23.5 s,能满足临床实验的需求。结论本文所研发的与呼吸机联用吸入装置的浓度监测范围、输出流量、响应时间及显示精度等技术参数满足预期的设计要求。     

丙泊酚对呼吸机所致肺损伤大鼠的保护作用及其机制

目的探讨p38信号通路在丙泊酚抑制呼吸机所致肺损伤（VILI）大鼠肺组织表达高迁移率族蛋白B1（HMGB1）中的作用。方法将32只健康SD大鼠随机分为4组,每组8只。对照组（A组）不行机械通气,保留自主呼吸;常规通气组（B组）潮气量（VT）为8ml/kg;大潮气量通气组（C组）VT为30ml/kg;大潮气量通气＋丙泊酚组（D组）VT为30ml/kg,同时静脉注射丙泊酚8mg/（kg.h）。机械通气4h后处死动物,测定支气管肺泡灌洗液（BALF）中总蛋白水平、白细胞计数以及肺湿干重比值（W/D）和中性粒细胞髓过氧化物酶（MPO）活性。采用Western blot方法检测肺组织HMGB1蛋白含量以及p38的激酶活性,采用RT-PCR方法检测HMGB1 mRNA的表达。应用单因素方差分析进行不同组别间的比较。结果通气4h后,与A组相比,C组总蛋白水平（1.58±0.46）g/L、白细胞计数（112.05±21.33）×107/L、肺W/D比值（8.25±0.92）、MPO活性（3.08±0.85）U/g、HMGB1蛋白（0.43±0.13）和mRNA（0.30±0.08）表达以及p38激酶活性（0.52±0.11）均明显增加（P〈0.05）;与C组相比,D组上述各项指标的变化均明显降低（P〈0.05）。结论丙泊酚可改善VILI肺内炎症反应,可能与通过p38信号通路抑制HMGB1蛋白和mRNA的表达有关。     

肺缺血-再灌注损伤时HO-1/CO系统的变化及葛根素对其的影响

目的：探讨兔肺缺血-再灌注损伤时血红素加氧酶－1（HO-1）/一氧化碳（CO）的变化及葛根素对其的影响。方法:复制在体兔原位单肺缺血－再灌注模型，随机分：假手术对照（control）组、肺缺血－再灌注（I-R）组与肺缺血－再灌注加葛根素（puerarin）组，每组10只。各组在缺血前、缺血1h、再灌注1 h、3 h和5 h分别抽血，检测一氧化碳血红蛋白(COHb)浓度、环磷酸鸟苷(cGMP)含量。实验结束时取肺组织检测湿干重比(W/D)、 肺泡损伤率(IAR)，观察肺组织超微结构的改变、HO-1的活力、表达部位及强度。结果:血浆COHb浓度、cGMP 含量I-R组、puerarin组明显高于control组，以puerarin组为著（P<0.01）。肺组织HO-1活性，I-R组较control组明显增加，puerarin组增加更加显著（P<0.01）。I-R组、puerarin组HO-1在肺血管内皮、部分血管平滑肌、外膜层及部分气道上皮呈阳性表达，明显高于control组，尤以puerarin组最为明显（P<0.01）。W/D、IAR，I-R组明显高于control组（P<0.01），puerarin组虽较control组为高，但显著低于I-R组（P< 0.01）。I-R组有明显的肺超微结构损伤，而puerarin组损伤较轻。结论:葛根素可通过上调HO-1表达，增加HO-1活性，对缺血再灌注肺发挥明显的保护作用。     

肺缺血-再灌注损伤时HO-I／CO系统的变化及葛根素对其的影响

目的:探讨兔肺缺血-再灌注损伤时血红素加氧酶-1(HO-1)/一氧化碳(CO)的变化及葛根素对其的影响.方法:复制在体兔原位单肺缺血-再灌注模型,随机分:假手术对照(control)组、肺缺血-再灌注(I-R)组与肺缺血-再灌注加葛根素(puerarin)组,每组lO只.各组在缺血前、缺血1h、再灌注1 h、3 h和5 h分别抽血,检测一氧化碳血红蛋白(COHb)浓度、环磷酸鸟苷(cGMP)含量.实验结束时取肺组织检测湿干重比(W/D)、肺泡损伤率(IAR),观察肺组织超微结构的改变、HO-1的活力、表达部位及强度.结果:血浆COHb浓度、cGMP含量I-R组、puerarin组明显高于control组,以puerarin组为著(P<0.01).肺组织HO-1活性,I-R组较control组明显增加,puerarin组增加更加显著(P<0.01).I-R组、puerarin组HO-1在肺血管内皮、部分血管平滑肌、外膜层及部分气道上皮呈阳性表达,明显高于control组,尤以puerarin组最为明显(P<0.01).W/D、IAR,I-R组明显高于control组(P<0.01),puerarin组虽较control组为高,但显著低于I-R组(P<0.01).I-R组有明显的肺超微结构损伤,而puerarin组损伤较轻.结论:葛根素可通过上调HO-1表达,增加HO-1活性,对缺血再灌注肺发挥明显的保护作用.     

雾化吸入米力农对烟雾吸入性损伤大鼠肺的保护作用

目的探讨米力农对大鼠烟雾吸入性损伤肺保护作用。方法雄性Sprague-Dawley大鼠32只,随机分为正常组（Ⅰ组）、生理盐水组（Ⅱ组）、低剂量米力农组（Ⅲ组）、高剂量米力农组（Ⅳ组）,每组8只。Ⅱ、Ⅲ、Ⅳ组建立吸入性损伤模型,伤后30min开始分别给予雾化生理盐水、0.4mg/ml米力农、1mg/ml米力农,每次10min,间隔50min,共4次,Ⅰ组不予处理。最后一次雾化治疗结束后30min后,检测4组大鼠血清白细胞介素-6（IL-6）、白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）含量,以及肺组织匀浆中丙二醛（MDA）含量、髓过氧化物酶（MPO）和超氧化物歧化酶（SOD）活性,取左肺组织经做病理HE染色切片光镜观察。结果Ⅲ组以及Ⅳ组的IL-6、TNF-α、MDA、MPO均比Ⅱ组降低,IL-10、SOD活性增高;Ⅳ组相对于Ⅲ组IL-6、MDA、MPO降低,SOD活性增高（P〈0.05）。光镜下Ⅲ组和Ⅳ组较生理盐水组肺组织炎细胞浸润减少,肺水肿减轻。结论吸入性损伤后,早期雾化吸入米力农可以调节炎症/抗炎症以及氧化/抗氧化的平衡,对肺损伤早期起到肺组织保护作用。     

一氧化碳保护机制的研究进展

多年来,一氧化碳(carbon monoxide,CO)被认为是一种可以致命的毒性气体.1968年时,已认识到机体可以产生内源性的CO,血红素氧合酶是内源性CO产生的限速酶.上个世纪九十年代,随着一氧化氮(NO)作为一种气体信使分子的作用被逐渐了解,同为气体小分子的CO,在体内的生理作用也逐渐得到重视,CO成为第二种被发现有病理生理作用的气体信使分子.     

内源性CO在CCK-8减轻脂多糖所致的急性肺损伤中的作用

目的：探讨内源性一氧化碳（CO）在八肽胆囊收缩素（CCK-8）减轻LPS所致急性肺损伤（ALI）中的作用。 方法： 将56只大鼠随机分为正常对照组、LPS组、LPS+ZnPP（HO-1特异性阻断剂）组、LPS+Hm（CO供体）组、CCK-8+LPS组、CCK-8+LPS+ZnPP组、CCK-8组7组，每组8只。各组给药后2 h，6 h，12 h行支气管肺泡灌洗、检测支气管肺泡灌洗液（BALF）中中性粒细胞（PMN）数目，并进行肺组织的形态学观察；计算大鼠死亡率；测定肺组织中MDA、CO含量。 结果： 给药2 h和6 h后，各组大鼠死亡率均为0，LPS 注入12 h后大鼠死亡率高于相应对照组，LPS+Hm和CCK-8+LPS组大鼠死亡率均低于LPS组，LPS+ZnPP和CCK-8+LPS+ZnPP组大鼠死亡率分别高于LPS和CCK-8+LPS组；LPS组肺组织均出现损伤变化，同时BALF中PMN数目和肺组织中MDA和CO含量高于相应对照组；LPS+Hm和CCK-8+LPS组肺组织损伤程度、BALF中PMN数目和肺组织中MDA含量低于相应LPS组，但肺组织中CO含量高于相应LPS组；LPS+ZnPP和CCK-8+LPS+ZnPP组肺组织损伤程度、BALF中PMN数目和肺组织中MDA含量分别高于相应LPS和CCK-8+LPS组，而肺组织中CO含量分别低于相应LPS组和CCK-8+LPS组。 结论： CCK-8可通过内源性CO介导的抗氧化、抑制PMN聚集等效应来发挥改善LPS所致的肺损伤作用。     

Cerebrovascular effects of carbon monoxide

This review examines the influence of endogenous and exogenous carbon monoxide (CO) on the cerebral circulation. Although CO generated from neuronal heme oxygenase can modulate neurotransmission, evidence supporting its role in cerebral vasodilation is limited. In newborn piglets, heme oxygenase is enriched in microvessels and contributes to hypoxic vasodilation. Low CO concentrations dilate piglet arterioles by opening calcium-activated potassium channels. With inhalation of CO and formation of carboxyhemoglobin, cerebral vasodilation can be greater than that occurring with hypoxic hypoxia at equivalent reductions of arterial oxygen content. This additional vasodilation is probably attributable to additional release of hypoxic vasodilators secondary to increased oxyhemoglobin affinity, although direct effects of CO on cerebral arterioles may also occur. When CO exposure is prolonged, cerebral endothelium undergoes oxidant stress as evident by nitrotyrosine formation. As CO levels increase, modest decreases in oxygen consumption are detectable, which may reflect CO or nitric oxide interactions with cytochrome oxidase in regions with very low oxygen availability. If subsequent CO concentration increases sufficiently to depress cardiac function and limit cerebral perfusion, cerebral oxygen consumption becomes further reduced, and oxidant stress becomes amplified by leukocyte sequestration and xanthine oxidase activity with consequent lipid peroxidation. Specific regions of the brain, such as central white matter, globus pallidus, and hippocampus, are selectively vulnerable to CO toxicity, but whether the mechanisms involved in selective injury differ from other forms of hypoxia-ischemia needs to be clarified.     

曲尼司特减轻松木屑烟雾吸入性损伤大鼠肺组织胶原沉积的研究

目的观察曲尼司特对松木屑烟雾致大鼠肺组织损伤后胶原蛋白合成的影响,为曲尼司特防治松木屑烟雾吸入性损伤致肺组织胶原沉积乃至纤维化提供可行性。 方法将72只雄性SD大鼠按照随机数字表法分为正常组、对照组、治疗组、盐水组,每组18只。对照组、治疗组和盐水组大鼠吸入松木屑烟雾共15 min(每间隔5 min吸烟1次,每次5 min,共吸烟雾3次),对照组不给予任何治疗,治疗组和盐水组于吸入烟雾后6 h,分别每天经腹腔注射1次曲尼司特(200 mg·kg^-1)和0.9%氯化钠溶液0.5 mL,正常组大鼠不予致伤、治疗。伤后7、14、28 d,各组取肺组织行苏木精-伊红、Masson染色,并行组织病理评分和计算胶原沉积率(CVF),碱水解法测定肺组织中羟脯氨酸(HYP)含量,对数据行单因素方差分析、t检验。 结果(1)苏木精-伊红染色：松木屑烟致伤后7 d,对照组和盐水组大鼠肺组织中均可见不同程度炎性细胞浸润、充血、肺间质水肿,随着观察时间的延长,肺组织炎性细胞浸润增加、出血增多,肺间隔逐渐增宽。伤后7、14、28 d,治疗组肺组织病理评分[(2.60±0.63)、(4.05±0.20)、(3.80±0.23)分]分别低于对照组[(3.20±0.28)、(5.00±0.40)、(8.48±0.51)分]和盐水组[(3.20±0.16)、(5.20±0.33)、(8.20±0.52)分],差异均有统计学意义(t＝-1.732、-1.837、-4.025、-5.745、-16.673、-15.556, P<0.05),除伤后7 d,治疗组与正常组[(2.20±0.23)分]比较差异无统计学意义(t＝1.188, P>0.05),伤后14、28 d,治疗组均高于正常组,差异有统计学意义(t＝12.438、9.798, P<0.05);(2)胶原沉积：伤后7 d,对照组和盐水组大鼠小气道周围胶原纤维沉积增加,随着观察时间的延长,肺间质逐渐出现大面积的胶原沉积。伤后7、14、28 d,治疗组的CVF[(5.22±0.26)%、(6.66±0.59)%、(4.86±0.44)%]均低于对照组[(6.21±0.31)%、(11.64±0.39)%、(36.17±2.24)%]和盐水组[(6.20±0.56)%、(11.11±1.01)%、(33.72±4.41)%],差异均有统计学意义(t＝-4.893、-3.170、-8.476、-10.184、-27.491、-13.014,P<0.05),且除伤后28 d,治疗组CVF与正常组[(4.54±0.23)%]差异无统计学意义(t＝3.860, P>0.05),伤后7、14 d的治疗组均高于正常组[(4.54±0.23)%、(4.54±0.23)%],差异均有统计学意义(t＝1.275、6.646, P<0.05);(3)HYP表达：伤后7、14 d,治疗组[(0.77±0.01)、(0.97±0.01) μg/mL]、对照组[(0.93±0.01)、(1.27±0.18) μg/mL]和盐水组[(0.92±0.01)、(1.23±0.16) μg/mL]大鼠肺组织中HYP表达均高于正常组[(0.66±0.06)、(0.66±0.06)μg/mL],差异均有统计学意义(t＝3.619、9.134、8.918、10.739、6.309、6.652,P<0.05),且伤后14、28 d治疗组[(0.97±0.01)、(0.83±0.02) μg/mL]显著低于对照组[(1.27±0.18)、(1.43±0.16) μg/mL]和盐水组[(1.23±0.16)、(1.42±0.15) μg/mL],差异均有统计学意义(t＝-3.232、-3.230、-7.699、-7.913,P<0.05),伤后28 d,治疗组[(0.83±0.02) μg/mL]与正常组[(0.66±0.06) μg/mL]低于对照组[(1.43±0.16) μg/mL]和盐水组[(1.42±0.15) μg/mL],差异均有统计学意义[(t＝-7.699、-7.913、-9.326、-9.564, P<0.05),且治疗组与正常组间比较差异无统计学意义(t＝5.720, P>0.05)。 结论曲尼司特减轻了松木屑烟雾吸入性大鼠肺组织病理损伤程度,减少胶原沉积和HYP的表达。     

Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice

Both hyperoxia and mechanical ventilation can independently cause lung injury. In combination, these insults produce accelerated and severe lung injury. We recently reported that pre-exposure to hyperoxia for 12 hours, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone. We also reported that such injury and apoptosis are inhibited by antioxidant treatment. In this study, we hypothesized that apoptosis signal-regulating kinase-1 (ASK-1), a redox-sensitive, mitogen-activated protein kinase kinase kinase, plays a role in lung injury and apoptosis in this model. To determine the role of ASK-1 in lung injury, the release of inflammatory mediators and apoptosis, attributable to 12 hours of hyperoxia, were followed by large tidal volume mechanical ventilation with hyperoxia. Wild-type and ASK-1 knockout mice were subjected to hyperoxia (Fi(O(2)) = 0.9) for 12 hours before 4 hours of large tidal mechanical ventilation (tidal volume = 25 μl/g) with hyperoxia, and were compared with nonventilated control mice. Lung injury, apoptosis, and cytokine release were measured. The deletion of ASK-1 significantly inhibited lung injury and apoptosis, but did not affect the release of inflammatory mediators, compared with the wild-type mice. ASK-1 is an important regulator of lung injury and apoptosis in this model. Further study is needed to determine the mechanism of lung injury and apoptosis by ASK-1 and its downstream mediators in the lung.     

Interaction and pH dependence of effects of nicotine and carbon monoxide in cigarette smoke inhalation experiments with rats

In view of subacute inhalation studies with cigarette smoke at high concentrations, the toxic properties of combinations of carbon monoxide and nicotine were investigated. Treating rats with fresh diluted cigarette smoke in an inhalation chamber, we established a smoking schedule that resulted in a certain death rate after 13 days. The mortality under the experimental conditions was taken as a measure for the toxicity of different combinations of carbon monoxide and nicotine. Since the absorption and therefore the toxicity of nicotine is pH dependent, the factorial experiments were performed under two pH conditions. The first experiments were conducted between pH 6.5 and 6.9 and then between pH 6.6 and 7.8 where the higher pH is due to the addition of nicotine base to the cigarette filler. After extensive mathematical treatment of the data, the following results were established:

1. Equations for the dose-response surface of CO and nicotine were computed.
2. R ² values (square of the multiple correlation coefficient) for the respective dose-response surfaces were between 87% and 94%.
3. From the respective equations the dose-response surfaces were drawn in the form of several computer plots.

From the equations it becomes evident that, under the experimental conditions, there are no synergistic effects between carbon monoxide and nicotine. A simple additivity of the toxic effects was therefore postulated. On the other hand, it has been demonstrated that smoke pH plays an important role, because only from alkaline smoke does the absorption of nicotine seem sufficiently rapid for it to add to the acute toxicity of CO. The total particulate matter apparently does not contribute significantly to the toxicity of the smoke aerosol.     

外源性一氧化碳抗大鼠肢体缺血再灌注所致肺损伤的实验研究

目的：观察外源性一氧化碳（CO）对大鼠肢体缺血再灌注（IR）所致肺损伤的作用及机制。 方法： 32只SD大鼠，随机分为4组(每组n=8)：对照组（control）、control+CO、IR和IR+CO组。复制大鼠双后肢缺血及再灌注后肺损伤模型。IR+CO和control+CO组在再灌注前1 h或相应时点置含2.5×10-8 CO的空气中，其余两组呼吸正常空气。观察大鼠肺组织学、肺组织中中性粒细胞（PMN）数目、丙二醛(MDA)含量、肺组织湿重和干重之比(W/D)以及动物生存情况等。应用一氧化碳血氧分析仪监测动脉血中碳氧血红蛋白(COHb)水平的变化；应用Western blotting检测肺组织中细胞间粘附分子-1（ICAM-1）表达的变化。 结果： IR组动物死亡率、肺组织中PMN数目、W/D、MDA含量和ICAM-1表达均显著高于control组；IR+CO组血内COHb水平显著高于IR组，而上述指标则均显著低于IR组、肺损伤减轻。 结论： 外源性CO可减轻肢体IR所致肺损伤，其机制可能与下调ICAM-1表达、抑制PMN在肺内聚集有关。