百草枯致急性肺损伤大鼠模型的建立

目的建立一种百草枯诱导的急性肺损伤（ALI）大鼠模型。方法将20只SD大鼠随机分为正常对照组10只、实验组10只。实验组一次性口服灌胃百草枯（PQ）80mg／kg,于给药后1天处死大鼠,观察光镜下肺组织病理改变、肺动脉血氧分压（PaO2）、支气管肺泡灌洗液（BALF）蛋白含量等。结果给予百草枯1天后肺形态学出现显著异常,PaO2及BALF蛋白含量出现显著改变。结论一次性灌胃百草枯80mg／kg成功建立急性肺损伤动物模型。     

Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension.

During the latter third of gestation, the number of resistance vessels in the lungs of the fetal sheep increases by 10-fold even after correction for lung growth. We measured pulmonary arterial pressure and blood flow directly and calculated total pulmonary resistance (pressure divided by flow) in intrauterine fetal lambs at 93-95 days and at 136 days of gestation (term is 145-148 days). In addition, we used a hyperbaric chamber to increase oxygen tension in the fetuses and measured the effect on the pulmonary circulation. When corrected for wet weight of the lungs, pulmonary blood flow did not change with advancing gestation (139 +/- 42 to 103 +/- 45 ml.100 g-1.min-1). Pulmonary arterial pressure increased (42 +/- 5 to 49 +/- 3 mmHg); thus total pulmonary resistance increased with advancing gestation from 0.32 +/- 0.12 to 0.55 +/- 0.21 mmHg.100 g.min.ml-1. If the blood flow is corrected for dry weight of the lungs, neither pulmonary blood flow nor total pulmonary resistance changed with advancing gestation. Increasing oxygen tension increased pulmonary blood flow 10-fold in the more mature fetuses but only 0.2-fold in the less mature fetuses. At the normal low oxygen tension of the fetus, pulmonary blood flow does not increase between these two points of gestation in the fetal lamb despite the increase in vessel density in the lungs. However, during elevated oxygen tension, pulmonary blood flow does increase in proportion to the increase in vessel density.     

Oxidative stress response of <Emphasis Type="Italic">Kluyveromyces marxianus</Emphasis> to hydrogen peroxide,paraquat and pressure

The aim of this work was to study the oxidative stress response of Kluyveromyces marxianus to hydrogen peroxide (50 mM), paraquat (1 mM), an increase in air pressure (120 kPa, 600 kPa) and pure oxygen pressure (120-600 kPa) in a pressurized bioreactor. The effect of these oxidants on metabolism and on the induction of antioxidant enzymes was investigated. The exposure for 1 h of K. marxianus at exponential growth phase with either H(2)O(2) or paraquat, under air pressure of 120 kPa or 600 kPa, induced an increase in both superoxide dismutase (SOD) and glutathione reductase (GR) content. SOD induction by the chemical oxidants was independent of the air pressure values used. A 2-fold increase in SOD activity was observed after 1 h of exposure to H(2)O(2) and a 3-fold increase was obtained by the presence of paraquat, with both air pressures studied. In contrast, GR activity was raised 1.7-fold by the exposure to both chemicals with 120 kPa, but a 2.4-fold GR induction was obtained with 600 kPa. As opposed to Saccharomyces cerevisiae, catalase was not induced and was even lower than the normal basal levels. This antioxidant enzyme seemed to be inhibited under increasing oxygen partial pressure. The cells showed a significant increase in SOD and GR activity levels, 4.7-fold and 4.4-fold, when exposed for 24 h to 120 kPa pure oxygen pressure. This behaviour was even more patent with 400 kPa. However, whenever cells were previously exposed to low air pressures, low enzymatic activity levels were measured after subsequent exposure to pure oxygen pressure.     

Acid-base balance and cardiac index in SO2-bronchitic, papaine-emphysematous and paraquat-fibrotic rats after isoproterenol treatment

SO2-bronchitis, papaine-emphysema and paraquat fibrosis were induced in Wistar rats. Blood pressure, cardiac index, total peripheral resistance, arterial blood gas values, parameters of acid-base balance were determined. Effects of 0.1 and 0.3 microgram.-1.min-1 isoproterenol iv. infusion were examined. Morphologic alterations of the lungs were verified by histopathological examinations. All the parameters investigated were found to be normal in the control rats. The treated groups differed from the normal ones: an increased blood pressure was observed in emphysema and fibrosis. A decreased cardiac index was characteristic of chronic bronchitis, high cardiac index of emphysema, high TPR of bronchitis and arterial hypoxaemy of fibrosis. The groups reacted differently to beta adrenergic stimulation: in bronchitic and fibrotic rats the cardiac index was augmented, whereas in emphysematous ones the increase proved to be smaller. The effects of isoproterenol infusion can be related to the altered beta-receptor function in the various experimental pulmonary diseases.     

Derecruitment of filtration surface area in paraquat-injured isolated dog lungs

The capillary filtration coefficient (Kf,c) is a sensitive and specific index of vascular permeability if surface area remains constant, but derecruitment might affect Kf,c in severely damaged lungs with high vascular resistance. We studied the effect of high and low blood flow rates on Kf,c in papaverine-pretreated blood-perfused isolated dog lungs perfused under zone 3 conditions with and without paraquat (PQ, 10(-2) M). Three Kf,cs were measured successively at hourly intervals for 5 h. These progressed sequentially from isogravimetric blood flow with low vascular pressure (I/L) to high flow with low vascular pressure (H/L) to high flow with high vascular pressure (H/H). The blood flows of H/L and H/H were greater than or equal to 1.5 times that of I/L. There were no significant changes in Kf,c in lungs without paraquat over a 50-fold range of blood flow rates. At 3 h after PQ, I/L-Kf,c was significantly increased and both isogravimetric capillary pressure and total protein reflection coefficient were decreased from base line. At 4 and 5 h, H/L-Kf,c was significantly greater than the corresponding I/L-Kf,c (1.01 +/- 0.22 vs. 0.69 +/- 0.09 and 1.26 +/- 0.19 vs. 0.79 +/- 0.10 ml.min-1.cmH2O-1.100 g-1, respectively) and isogravimetric blood flow decreased to 32.0 and 12.0% of base line, respectively. Pulmonary vascular resistance increased to 12 times base line at 5 h after PQ. We conclude that Kf,c is independent of blood flow in uninjured lungs. However, Kf,c measured at isogravimetric blood flow underestimated the degree of increase in Kf,c in severely damaged and edematous lungs because of a high vascular resistance and derecruitment of filtering surface area.     

房水平单向活瓣式补片对老年先天性心脏病合并重度肺动脉高压 的临床效果分析

目的:探究房水平单向活瓣式补片对老年先天性心脏病伴重度肺动脉高压患者的作用疗效。方法:选取我院心血管科收治的先天性心脏病伴重度肺动脉高压患者80例,随机分为对照组和实验组。对照组40例,予以常规基础药物治疗(波生坦);实验组,在基础药物治疗两个疗程后,采用房水平单向活瓣式补片进行手术治疗。比较两组患者治疗前后的肺动脉压(PAP)、体动脉压(SAP)、肺动脉压/体动脉压(PAP/SAP)、动脉血氧分压(Pa O2)、二氧化碳分压(Pa CO2)及吸氧浓度、右室收缩末期内径变化情况。结果:治疗后,与对照组比较,实验组肺动脉压下降幅度较大(P0.05);与治疗前比较,实验组肺动脉压与体动脉压的比值显著下降,且优于对照组(P0.05);治疗后,实验组动脉血氧分压、二氧化碳分压以及吸氧浓度显著优于对照组(P0.05);治疗后,实验组患者右室收缩末期内径显著小于对照组(P0.05);随访结果:实验组死亡1例、术后活瓣坏死2例、其余37例病情均转好且无复发情况;对照组死亡4例、出现各项并发症16例、剩余20例病情转好。结论:房水平单向活瓣式补片法可有效改善患者的肺动脉压、体动脉压、动脉血氧分压、二氧化碳分压及吸氧浓度、右室收缩末期内径及6 min步行距离,对老年先天性心脏病伴重度肺动脉高压患者疗效显著。     

Protective effect of alpha-human atrial natriuretic polypeptide (alpha-hANP) on chemical-induced pulmonary edema

It has been established that alpha-hANP, the newly discovered peptide extracted from human cardiac atria, has potent natriuretic and hypotensive actions. Our present investigation is the first to demonstrate that alpha-hANP is capable of protecting against pulmonary edema caused by various chemicals, using isolated perfused guinea pig lung system. Lungs were perfused via pulmonary artery with Krebs-Ringer bicarbonate buffer at 5.0 ml/min, and wet weight of lungs and perfusion pressure of pulmonary artery (Pa) were monitored. Bolus injection of Triton-X or CHAPS into cannulated pulmonary artery produced edema as indicated by a massive increase in wet weight and a slight increase in Pa. Constant infusion of alpha-hANP through pulmonary artery at 200 ng/ml was effective in causing decrease in wet weight of lung. Perfusion of lung with paraquat or PGF2 alpha, and repeated bolus injection of arachidonic acid or PGE2 caused elevation in both wet weight of lung and Pa. The treatment with alpha-hANP similar to that described above also protected against edema caused by paraquat or arachidonic acid. Bolus administration of epinephrine induced a slight increase in wet weight and Pa, and alpha-hANP was effective in decreasing the elevated lung wet weight and Pa of lungs. Infusion or bolus administration of alpha-hANP into control lungs increased cGMP level in outflow perfusate as well as in lung tissue significantly. In lungs with edema which were induced by Triton-X or paraquat, there was a slight increase in cGMP level in Triton-X treated and no increase in paraquat treated lung tissues. In either cases, was there any increase in cGMP level in perfusate. The specific binding study of [125I]alpha-hANP revealed that the lack of increase in cGMP was not due to a loss of receptor in Triton-X or paraquat treated lungs. Thus our study demonstrated that alpha-hANP had a direct anti-edematic action(s) in lung which was not secondary to the systemic natriuretic and/or hypotensive action(s).     

Microvascular pressures measured by micropuncture in isolated perfused lamb lungs

To investigate the influence of vasomotor tone and vessel compliance on pulmonary segmental vascular resistance, we determined the longitudinal distribution of vascular pressures in 15 isolated blood perfused lungs of newborn lambs. We measured pulmonary arterial and left atrial pressures and by micropuncture the pressures in 20- to 80-micron-diam subpleural arterioles and venules, both before and after paralyzing the vasculature with papaverine hydrochloride. In five lungs we also determined the microvascular pressure profile during reverse perfusion. In lungs with baseline vasomotor tone, approximately 32% of the total pressure drop was in arteries, approximately 32% in microvessels, and approximately 36% in veins. With elimination of vasomotor tone, arterial and venous resistances decreased to one-fifth and one-half of base-line values, respectively, indicating that vasomotor tone contributed mainly toward arterial resistance. During reverse perfusion, the pressure drop in veins was similar to that in arteries during forward perfusion, suggesting that the compliance of arteries and veins is comparable. We conclude that vascular tone and compliance are important factors that determine the distribution of segmental vascular resistance in lungs of the newborn.     

Methylprednisolone Attenuates Airway and Vascular Responses Induced by Reactive Oxygen Species in Isolated, Plasma-Perfused Rat Lungs

The effects of methylprednisolone (MP) on the acute airway and pulmonary vascular responses induced by reactive oxygen species (ROS) were investigated in isolated, plasma-perfused rat lungs. ROS were generated by adding xanthine oxidase and hypoxan-thine to the perfusate. MP was administered in 3 different ways: 1. Added to the perfusate (1 mg*ml^-1) 5 min prior to xanthine oxidase and hypoxanthine, 2. Given as intraperitoneal injections (40 mg*kg^-1) to lung donor rats 12 and 2 hours prior to the experiments, or 3. Combining 1 and 2. The lungs were perfused at constant volume inflow (15 ml*min^-1). Pulmonary arterial pressure and transpulmonary pressure were followed for 30 min after addition of xanthine oxidase and hypoxanthine. ROS induced a powerful, acute broncho- and vasoconstriction, which was inhibited by addition of MP to the perfusate. Pretreatment with MP also inhibited the vascular and airway responses. Adding MP to the perfusate of pretreated lungs further reduced the ROS-induced smooth muscle constriction. In conclusion, MP inhibits vasoconstriction and bronchocon-striction induced by ROS in isolated rat lungs.     

Cardiorespiratory responses to prolonged normobaric inhalatory hypoxia in healthy men

Changes in the cardiorespiratory indicators due to the prolonged (25 min) inhalation of a respiratory mixture with an exponentially falling (from 20.9% to 10%) oxygen concentration were studied in healthy young men. The efficiency of oxygen uptake (as the ventilatory equivalent of O₂) in the lungs has been shown to fall particularly promptly (within the first 2–5 min). Individual manifestations of this fall were variable (ranging from 22 to 84% of the baseline data) and driven, to a considerable degree, by the subject’s current level of alveolar ventilation, mobilizing its urgent reserve to improve the ventilation-perfusion relations in the lungs. The subsequent response as a growth in the heart rate (HR) recorded in 100% of cases was delayed relative to the start of hypoxic exposure and combined with increased hypoxemia marked as a decrease in the blood oxygen saturation of hemoglobin. The individual HR growth in response to hypoxia ranged from 8 to 43% of the baseline level and was significantly related to the current level of diastolic arterial blood pressure. The hypoxic ventilatory response was expressed only in 71% of cases, including the 15% when it was reversed (decreased) against the background of a concomitant decrease in the respiratory frequency.     

一种猪模型的体外肺灌注系统的建立

目的:体外肺灌注技术(Ex vivo lung perfusion, EVLP)对于肺移植的实施意义重大,但成本昂贵。本文采用国产经济材料建立猪模型的EVLP系统,以探索保证系统性能的同时降低移植费用。方法:我们首先依据国产材料配置肺灌注液,并组装管道、连接仪器以建立EVLP系统;之后通过外科手段获得3头家猪的肺脏,并灌注肺灌注液,低温保存6小时;最后我们将肺脏连接到EVLP系统,通过血气分析和肺功能检查来评估肺脏随时间变化的状况。结果:离体并在低温保存6小时的猪肺脏,通过我们建立的相对经济的EVLP系统,可以在2小时内维持良好的氧合功能和肺生理指标:肺动脉压、气道峰压、平台压力、肺动脉氧气分压和二氧化碳分压和左心房的氧气分压和二氧化碳分压都保持稳定,同时肺脏具有正常的颜色和弹性,没有明显水肿和功能损害。结论:我们建立的EVLP系统可以有效地维护离体猪肺的生理功能,且降低了成本,从而为肺移植体外肺灌注技术的优化应用提供了研究基础。     

Lung protection against paraquat is calcium dependent.

Isolated, perfused, and ventilated rat lungs were challenged by paraquat (0.01 M) in the presence of 2.5 mM Ca2+, 2.5 mM Ca2+ with trifluoperazine (100 microM), 0.025 mM Ca2+, or 0.025 mM Ca2+ with sodium metavanadate (10 microM) to establish the effect of varying calcium concentration or calcium-dependent enzyme activities on injury induced by paraquat. Segmental vascular resistances, microvascular permeability (as assessed by the capillary filtration coefficient), lung tissue oxidized glutathione, and lung paraquat accumulation were measured. Exposure to paraquat for 2.5 h did not increase microvascular permeability or pulmonary vascular resistance in the presence of either normal extracellular calcium or low extracellular calcium and sodium metavanadate. Lungs exposed to paraquat were injured (as assessed by increased filtration coefficient) only in the presence of low extracellular calcium or after trifluoperazine was added. This injury was associated with decreased levels of oxidized glutathione and increased paraquat accumulation, suggesting that calcium's protective effect was both by inhibition of paraquat accumulation and maintenance of NADPH. Pulmonary vascular resistance was not increased with paraquat challenge.     

Effect of paraquat-induced lung damage on permeability of rat lung to drugs.

To investigate the effect of paraquat-induced lung damage on pulmonary absorption of drugs, rats were given a single oral dose of paraquat (250 mg/kg), and rates of drug absorption from damaged and control lungs were compared after various times. To measure absorption rates of drugs, 0.1 ml of 10 mM drug solution was administered through a tracheal cannula to anesthetized animals and, after various times, lungs were assayed for unabsorbed compound. Drugs investigated were procaine amide ethobromide, p-aminohippuric acid, and procaine amide. Rates of drug absorption increased 1.4-2.8-fold at 3.5 days after paraquat administration and returned to near control values by the 15th day. The results suggest that paraquat-induced lung damage increases the porosity of the pulmonary epithelium.     

Pulmonary vascular reactivity and hemodynamic changes in elastase-induced emphysema in hamsters.

Changes in pulmonary hemodynamics and vascular reactivity in emphysematous hamsters were studied in an isolated lung preparation perfused at constant flow with blood and 3% dextran. Hamsters were treated with intratracheal porcine pancreatic elastase at 70 days of age, and experimental studies were conducted at 1, 3, and 8 mo after treatment. Baseline pulmonary arterial pressure in elastase-treated lungs was increased compared with saline-treated control lungs 1 mo after treatment, but this increase did not progress at 3 and 8 mo. Increases in pulmonary arterial pressure in elastase-treated lungs were temporally correlated with the morphological development of emphysema and right ventricular hypertrophy; both of these were evident at 1 mo after treatment and showed little change thereafter. Pressor responses to hypoxia and angiotensin II were not different between elastase-treated and control lungs at 1 and 3 mo. At 8 mo, however, pressor responses in emphysematous lungs to 0% O2 (but not to angiotensin II) were significantly increased. This was the result of a lack of the normal age-related fall in the hypoxic pressor response. Our results suggest that the right ventricular hypertrophy found in these emphysematous animals results from a chronically increased pulmonary vascular resistance. Furthermore, increases in pulmonary vascular resistance in the early development of emphysema are likely a result of the loss of vascular beds and supporting connective tissue.     

Change in the concentration of vitamins C and E in rat tissues by paraquat administration

Paraquat causes lung injury by oxidative stress. After 48 h of intraperitoneal administration of paraquat (50 mg/kg of body weight) to rats, the vitamin C concentration in the lungs was significantly decreased, while lung vitamin E content was increased after 12 h. These results indicate that vitamin C directly reflected the oxidative stress in the lungs.     

Role of substance P in hypersensitivity reactions induced by paclitaxel, an anticancer agent

The role of substance P in adverse pulmonary reactions induced by an anticancer agent paclitaxel was investigated in rats and humans who undertook post-operative chemotherapy for ovarian cancer. In rats, paclitaxel caused a marked plasma extravasation and edema in lungs with a concomitant decrease in arterial partial oxygen pressure, which were reversed by an NK1 antagonist LY303870. Substance P level in rat plasma and bronchoalveolar lavage fluid increased after paclitaxel injection. In 13 patients, plasma level of substance P but not histamine significantly (P < 0.05) increased during paclitaxel infusion. Therefore, substance P rather than histamine may be involved in paclitaxel hypersensitivity.     

7-Hydroperoxycholesterol as a marker of oxidative stress in rat kidney induced by paraquat

The in vivo paraquat-induced oxidative stress in rat tissue was studied by analyzing cholesterol-derived hydroperoxide as an index of lipid peroxidation. Paraquat (10 mg/kg) was administered i.p. to rats. Rats were sacrificed and lung, liver, and kidney were collected 2, 24 h, and 5 d after paraquat injection. Lipids were extracted and analyzed by HPLC with post-column chemiluminescence. We found that two cholesterol-derived hydroperoxides, 7alpha-hydroperoxycholest-5-en-3beta-ol (7alpha-OOH) and 7beta-hydroperoxycholest-5-en-3beta-ol (7beta-OOH) were present in lungs of control animals (0.06 and 0.06 nmol/g, respectively), in livers (6.5 and 15.8 nmol/g, respectively) and in kidneys (3.7 and 8.9 nmol/g, respectively). In liver paraquat increased lipid peroxidation approximately by 60% over the levels of control animals only at 2 h after paraquat treatment. In kidney, augmented lipid peroxidation, 7alpha-OOH and 7beta-OOH (by 70% and 147%, respectively) above levels was found at 2 h after paraquat treatment. Interestingly, these increase remained in kidney of rats 5 d after a single dose of paraquat. In contrast, cholesterol-derived hydroperoxides were not affected in lung of paraquat dosed rats. This is the first report on 7alpha-OOH and 7beta-OOH accumulations in rat liver and kidney, and it seems to reflect greater oxidative stress in the pathology of kidney of rats treated with acute paraquat at low dose.     

Pharmacological Inhibition of CXCR2 Chemokine Receptors Modulates Paraquat-Induced Intoxication in Rats

Paraquat (PQ) is an agrochemical agent commonly used worldwide, which is allied to potential risks of intoxication. This herbicide induces the formation of reactive oxygen species (ROS) that ends up compromising various organs, particularly the lungs and the brain. This study evaluated the deleterious effects of paraquat on the central nervous system (CNS) and peripherally, with special attempts to assess the putative protective effects of the selective CXCR2 receptor antagonist SB225002 on these parameters. PQ-toxicity was induced in male Wistar rats, in a total dose of 50 mg/kg, and control animals received saline solution at the same schedule of administration. Separate groups of animals were treated with the selective CXCR2 antagonist SB225002 (1 or 3 mg/kg), administered 30 min before each paraquat injection. The major changes found in paraquat-treated animals were: decreased body weight and hypothermia, nociception behavior, impairment of locomotor and gait capabilities, enhanced TNF-α and IL-1β expression in the striatum, and cell migration to the lungs and blood. Some of these parameters were reversed when the antagonist SB225002 was administered, including recovery of physiological parameters, decreased nociception, improvement of gait abnormalities, modulation of striatal TNF-α and IL-1β expression, and decrease of neutrophil migration to the lungs and blood. Taken together, our results demonstrate that damage to the central and peripheral systems elicited by paraquat can be prevented by the pharmacological inhibition of CXCR2 chemokine receptors. The experimental evidence presented herein extends the comprehension on the toxicodynamic aspects of paraquat, and opens new avenues to treat intoxication induced by this herbicide.