一氧化氮及其合酶在哮喘发病机制中的作用

探讨一氧化氮及其合酶在哮喘发病机制中的作用。方法 采用哮喘豚鼠模型，将豚鼠分为４组；１．哮喘组，用１０％卵白蛋白腹腔注射１ｍｌ致敏，２周后用１％卵白蛋白超声雾化吸入致其哮喘发作．２；肾上腺皮质激素预防组；诱喘同哮喘组，在每次诱喘前腹腔滴注地塞米松０．５ｍｇ／ｋｇ。３．硝基精氨酸甲酯预防组；诱喘同哮喘组，每次诱喘产腹腔注射ＬＮＮＡ０．４ｍｇ／ｋｇ。４．正常对照组；用生理盐水代替诱喘剂。每组分别测定其     

过氧亚硝基阴离子在哮喘豚鼠气道高反应性中的作用

目的 探讨哮喘豚鼠内过氧亚硝基阴离子（ＯＮＮＯＯ＾－）的生成及其在哮喘气道高反应性形成中的作用。方法 １８只哮喘豚鼠模型随机分为３组：（１）哮喘组（６只）：用１０％卵蛋白１ｍｌ腹腔注射液致敏,２周后用１％卵蛋白超声雾化吸入复制豚鼠哮喘模型。（２）哮喘加氨基胍（ＡＧ）组（６只）：该喘同哮喘组,在每次诱喘前１ｈ腹腔注射ＡＧ１０ｍｇ／ｋｇ。（３）正常对照组（６只）：用生理盐水代替诱喘剂。每组哮喘豚鼠均用     

肾上腺髓质素对组胺诱发气道痉挛的作用

目的观察肾上腺髓质素（ＡＭ）对组胺诱发麻醉豚鼠气道痉挛的影响。方法实验分为生理盐水对照组、异丙肾上腺素０．０３μｇ／ｋｇ、０．３μｇ／ｋｇ、３μｇ／ｋｇ、３０μｇ／ｋｇ四个剂量组及ＡＭ０．０２μｇ／ｋｇ、０．２μｇ／ｋｇ、２μｇ／ｋｇ、２０μｇ／ｋｇ四个剂量组，每组豚鼠７只，戊巴比妥钠麻醉状态下，分别静脉注射生理盐水、不同剂量的异丙肾上腺素和ＡＭ，同时组胺（１０－４ｍｏｌ／Ｌ）雾化吸入，采用动物体描箱测定豚鼠气道阻力和肺顺应性。结果异丙肾上腺素０．３μｇ／ｋｇ、３μｇ／ｋｇ和３０μｇ／ｋｇ剂量下能明显拮抗组胺诱导的豚鼠气道阻力增加和肺顺应性降低（Ｐ＜０．０５）。ＡＭ２μｇ／ｋｇ、２０μｇ／ｋｇ剂量下能明显拮抗组胺诱导的气道阻力增加，０．２μｇ／ｋｇ、２μｇ／ｋｇ，２０μｇ／ｋｇ剂量下能明显拮抗组胺诱导的肺顺应性降低（Ｐ＜０．０５）。结论ＡＭ具有拮抗组胺诱发豚鼠气道痉挛的作用。     

两种一氧化氮合酶抑制剂在内毒素肝损伤中的作用

材料与方法：内毒素（ＬＰ）（Ｄｉｆｉｃｏ,美国）硝基左旋精氨酸（Ｌ－ＮＮＡ）（Ｓｉｇｍａ）,Ｓ－硫酸甲基异硫脲素（ＳＭＴ,Ｓｉｍａ）,丙氨酸转氨酶（ＡＬＴ）测定试剂盒（上海荣胜生物制剂厂）。Ｗｉｓｔａｒ大鼠（重庆医科大学实验动物中心）雄性,体重２００～３００ｇ。动物分为４组,第１组腹腔注射灭菌生理盐水１ｍｌ;第２组腹腔注射ＬＰＳ（４ｍｇ／ｋｇ）;第３组在腹腔注射ＬＰＳ（４ｍｇ／ｋｇ）前１小时,动物先腹腔注射Ｌ－ＮＮＡ（１００ｍｇ／ｋｇ）;第４组注射ＬＰＳ（４ｍｇ／ｋｇ）前２小时,腹腔注射ＳＭＴ（…     

灵芝孢子对支气管哮喘豚鼠引喘潜伏期及类胰蛋白酶释放的影响

目的研究灵芝孢子对支气管哮喘（简称哮喘）豚鼠引喘潜伏期及肥大细胞类胰蛋白释放的影响。方法10％卵蛋白腹腔注射致敏,雾化吸入1％卵蛋白方式诱导复制哮喘动物模型。30只健康豚鼠随机分为对照组（A）、哮喘组（B）、灵芝组（C）3组,每组10只,分别用生理盐水,灵芝孢子灌胃15d。测定哮喘豚鼠的引喘潜伏期及呼气相气道阻力（Re）,计数支气管肺泡灌洗液（BALF）细胞总数及分类,肺组织HE染色和免疫组织化学观察肺组织病理变化及肥大细胞类胰蛋白酶分布情况。结果①灵芝组的引喘潜伏期明显较哮喘模型组延长,Re显著降低（P〈0．05）。②哮喘BALF白细胞总数及嗜酸粒细胞比例较生理盐水组增高（P〈0．05）,肺组织炎性病变明显;灵芝组BALF细胞总数、嗜酸粒细胞比例及肺组织炎性病变明显较哮喘组降低或减轻（P〈0．05）。③哮喘组类胰蛋白酶染色阳性的肥大细胞计数明显较生理盐水组增多（P〈0．05）,主要分布在气道黏膜下,肺泡间隔及血管周围;灵芝组类胰蛋白酶染色阳性的肥大细胞计数较哮喘组显著减少。结论灵芝孢子有延长哮喘豚鼠引喘潜伏期,降低气道阻力,减轻肺组织炎性病变,抑制肥大细胞释放类胰蛋白酶的作用。     

汉防己甲素对慢性缺氧大鼠肺胶原的影响

目的 探讨汉防己甲素（Ｔｅｔ）对慢性低氧性肺动脉高压大鼠肺组织胶原含量的影响。方法 雄性大鼠３０只，随机分为：（１）对照组１０只，不缺氧处理；（２）单纯缺氧组１０只，每只于低氧前后腹腔注射生理盐水１ｍｌ，共２１天，每天缺氧８小时；（３）汉防己甲素处理组１０只，于每天缺氧前后按７．５ｍｇ·ｋｇ＾－１腹腔注射汉防己甲素，共２１天。应用氯胺Ｔ氧化比色法测定肺组织和肺外肺动脉的羟脯氨酸（Ｈｙｐ）含量和马三     

吸入肝素对哮喘豚鼠气道炎症影响的研究

肝素在临床上作为抗凝剂而广泛使用。然而很多证据显示，肝素还有非抗凝血的生物学功能，包括抗炎、免疫调节、抑制过敏反应等。我们通过抗原激发形成哮喘豚鼠模型，以肝素雾化吸入治疗，研究肝素对哮喘豚鼠气道炎症的影响，探讨肝素抗哮喘的机制。材料与方法　健康豚鼠６０只。雌雄不限，体重３００～４５０ｇ，随机分为三组：哮喘模型组（Ａ组，２０只）：用５％卵蛋白生理盐水注射于豚鼠后腿肌肉，每侧０４ｍｌ，同时腹腔注射１ｍｌ。２周后将豚鼠置于面罩内，给与１％卵蛋白生理盐水雾化吸入２０秒；肝素治疗组（Ｂ组，２０只）：模型…     

豚鼠中性粒细胞性哮喘模型的建立

目的建立豚鼠中性粒细胞性哮喘模型。方法 40只成年雄性豚鼠按随机数字表法分为对照组（A组）、嗜酸粒细胞性哮喘组（B组）、中性粒细胞性哮喘组（C组）、嗜酸粒细胞性哮喘治疗组（D组）和中性粒细胞性哮喘治疗组（E组）。用卵白蛋白（ovalbumin,OVA）和弗氏完全佐剂（Freund’s complete adjuvant,FCA）联合致敏或OVA单独致敏豚鼠后用OVA雾化吸入激发建立中性粒细胞性哮喘或嗜酸粒细胞性哮喘模型,治疗组在激发前腹腔注射地塞米松。观察各组豚鼠雾化激发后体征变化及支气管肺组织病理改变,并比较各组豚鼠气道阻力、血中白细胞分类计数、支气管肺泡灌洗液（brochial alveolar lavage fiuid,BALF）细胞总数及分类计数。结果 B、C组豚鼠激发后均出现典型哮喘症状,不同浓度乙酰甲胆碱激发后的气道阻力与A组相比均显著增高（P〈0.05）;B组豚鼠BALF总数、BALF及血中嗜酸粒细胞所占比例与A组比较显著增加（P〈0.05）;C组豚鼠BALF总数、BALF及血中中性粒细胞所占比例与A组比较均显著增加（P〈0.05）;C组豚鼠BALF中性粒细胞所占比例与B组相比显著增加（P〈0.05）;除B、D组血中性粒细胞外,D和E两组的上述其他各项指标分别与B组和C组相比明显降低（P〈0.05）,以上差异均有统计学意义。B、C两组豚鼠支气管肺组织病理均提示支气管管腔狭窄、黏膜上皮脱落、炎症细胞浸润等典型的哮喘病理学改变,其中B组以嗜酸粒细胞浸润为主,C组以中性粒细胞浸润为主,D、E组较之明显好转。结论本实验建立的豚鼠中性粒细胞性哮喘模型是成功的。     

溴环己胺醇对哮喘豚鼠肺表面活性物质的影响

材料与方法健康雄性豚鼠３０只，体重３００ｇ±５０ｇ，随机分成正常组（Ａ组，１０只）：用０．９％生理盐水替之，哮喘组（Ｂ组，１０只），哮喘＋溴环己胺醇组（Ｃ组，１０只）：即豚鼠致敏同时予溴环己胺醇（德国勃林格殷格翰公司）７．５ｍｇ·ｋｇ－１·ｄ－１，每...     

哮喘气道炎症粘附机制的实验研究

目的评价细胞间粘附分子１（ＩＣＡＭ１）、Ｐ选择素在哮喘气道炎症粘附机制中的作用,进一步阐明哮喘的发病机理。方法用酶联免疫吸附试验、肺组织免疫组化检查和呼吸生理学方法系统观察正常组和哮喘组豚鼠各项指标。结果（１）哮喘组豚鼠肺潮气量、动态肺顺应性（Ｃｄｙｎ）和肺气道阻力与对照组比较差异有显著性（Ｐ＜０．０１及Ｐ＜０．０５）。（２）哮喘组豚鼠血浆和肺泡灌洗液（ＢＡＬＦ）可溶性ＩＣＡＭ１（ｓＩＣＡＭ１）、可溶性Ｐ选择素、血清和ＢＡＬＦ嗜酸粒细胞阳离子蛋白（ＥＣＰ）与对照组比较,差异有显著性（Ｐ＜０．０１）;ＢＡＬＦ中白细胞介素８（ＩＬ８）与对照组比较差异也有显著性（Ｐ＜０．０１）。（３）哮喘组豚鼠肺组织（气道上皮和血管内皮）ＩＣＡＭ１和ＩＬ８表达与对照组比较,差异有显著性（Ｐ＜０．０１）。结论ＩＣＡＭ１、Ｐ选择素、ＩＬ８、ＥＣＰ参与介导了哮喘气道炎症的粘附过程     

Studies of an antiendotoxin antibody in preventing the physiologic changes of endotoxemia in awake sheep

In sheep, endotoxin (LPS) causes pulmonary hypertension, hypoxemia, leukopenia, exudation of protein-rich lung lymph, reduced dynamic compliance (Cdyn), and increased resistance to airflow (RL), changes similar to those seen in human sepsis and sepsis-induced ARDS. We used well-described methods in the awake sheep-endotoxin model to evaluate the effectiveness of a commercially manufactured antibody to prevent the physiologic changes of endotoxemia. In awake sheep with chronic lung lymph fistulas, we used a whole-body plethysmograph to measure Cdyn, RL, and FRC. Pulmonary artery, left atrial, and systemic arterial pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples were collected every 30 min. Animals received a 30-min (2 mg/kg) infusion of antiendotoxin antibody 4 h before LPS (0.75 micrograms/kg) challenge (n = 4), or were given a mixture of LPS (0.75 micrograms/kg) and antibody (2 mg/kg) that had been incubated in vitro at 37 degrees C for 30 min before infusion (n = 6). A control group given only 2 mg/kg of antibody (n = 4) showed no change in any measured parameter, whereas control animals receiving LPS alone (n = 6) exhibited a typical endotoxin response. In all animals receiving endotoxin, Cdyn declined by approximately 50% within 30 to 60 min, and RL increased approximately sixfold over a similar time course. Accompanying the abnormalities in lung mechanics were pulmonary hypertension, leukopenia, and widening of the AaPO2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Canine parainfluenza type 2 bronchiolitis increases histamine responsiveness in beagle puppies

Histamine hyperresponsiveness with viral bronchiolitis may depend on previous exposures to viruses or to other pathogens. We studied 32 outbred beagle puppies 80 to 155 days of age who were raised in isolation and who were specific pathogen-free. Puppies were inoculated with canine parainfluenza type 2 (CPI2, n = 8), Bordetella bronchiseptica (Bb, n = 7), or both CPI2 and Bb (CPI2-Bb, n = 9). Control puppies (C, n = 8) were not inoculated. The puppies were anesthetized with sodium thiopental (5 mg/kg) and chloralose (80 mg/kg) and were ventilated mechanically. Lung resistance (RL), dynamic lung compliance (Cdyn), functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured 3 days prior to inoculation (Day -3), on the day of inoculation (Day 0), and on Days 3-4, 6, 8-10, and 12-14 after inoculation. Histamine responsiveness was measured as: (1) the concentration of histamine base that increased RL to 150% (PC 150% RL) or decreased Cdyn to 75% (PC 75% Cdyn) of the response to saline (RL sal and Cdyn sal, respectively), and (2) the change in RL or Cdyn after inhalation of 11 mg/ml of histamine when compared with RL sal and Cdyn sal. On Day 0 there were no significant (p greater than 0.05) differences among groups with regard to age-corrected weights, FRC, RL, Cdyn, or histamine responsiveness. Control puppies remained healthy, and their pulmonary function and histamine responsiveness did not change. CPI2-Bb puppies increased RL and decreased FRC on Day 3-4, and were moderately ill and histamine-hyperresponsive on Day 3-4 and on Day 6.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo bronchodilator activity of nifedipine in the guinea pig

We administered histamine subcutaneously to anesthetized guinea pigs to induce prolonged bronchoconstriction and then tested the effect of intravenously administered nifedipine on pulmonary resistance (RL) and dynamic compliance (Cdyn). One mg of subcutaneously administered histamine caused RL to increase by an average of more than 250% and Cdyn to fall on average to 26% of baseline; mean RL remained more than twice baseline, and mean Cdyn remained less than half baseline for 80 min. Intravenously administered nifedipine 3 micrograms/kg and ethanol (diluent) administered 25 min after histamine had no effect on RL but caused a slightly greater fall in Cdyn than in the control animals treated with histamine alone. Nifedipine 30 micrograms/kg, however, exhibited significant bronchodilator activity: 35 min after nifedipine 30 micrograms/kg, RL decreased on average to 41 +/- 17% above baseline (p less than 0.02), and Cdyn increased to 49 +/- 5% below baseline (p less than 0.0001). By comparison, isoproterenol (0.3 to 3.0 micrograms/kg) caused bronchodilation of more rapid onset (within 1 min) and shorter duration of action (approximately 10 min). Thus, we were able to demonstrate bronchodilator activity of nifedipine in vivo, as had been predicted by in vitro studies of guinea pig and human tracheal strips. These results would appear to justify continued exploration of the potential role for calcium channel blockers in the treatment of obstructive lung disease.     

Airway responsiveness to intravenous and inhaled acetylcholine in the guinea pig after cigarette smoke exposure

Exposure of conscious guinea pigs to cigarette smoke results in bronchial hyperresponsiveness. To examine the mechanisms involved, we measured airway responses to increasing doses of intravenous or inhaled acetylcholine in guinea pigs exposed to cigarette smoke (n = 20) or to air (n = 20). After exposure the guinea pigs were anesthetized, paralyzed, and studied in a pressure-sensitive body plethysmograph while ventilated through a tracheostomy. Two and 6 puffs of an aerosol of increasing concentrations (0.05 to 500 micrograms/ml) of acetylcholine were delivered via the tracheostomy. Intravenous acetylcholine was delivered in boluses of 0.1 ml of increasing concentrations (0.5 to 50,000 micrograms/ml) via a catheter in an external jugular vein. Pulmonary resistance (RL), dynamic compliance (Cdyn), and heart rate (HR) were measured at baseline (after aerosolized or intravenous saline) and after each dose of acetylcholine. The peak responses to both inhaled and intravenous acetylcholine were rapid in onset (less than 15 s), short-lived (3 to 4 breaths), and were noncumulative. The baseline RL, Cdyn, and HR were not different in the smoke and air exposure groups. In the intravenous acetylcholine group, there were no differences in RL, Cdyn, and HR responses between the air and smoke exposure groups. In the inhaled acetylcholine group, the dose-response curve was shifted to the left (p less than 0.05) and reached a higher maximal response (p less than 0.01) after smoke exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute canine adenovirus 2 infection increases histamine airway reactivity in beagle puppies

Acute infection with canine adenovirus was studied in 23 specific pathogen-free outbred beagle puppies (median age = 78 days, range = 67 to 86 days) to determine its effects on pulmonary function and airway responsiveness to aerosolized histamine. The following groups were studied: uninoculated (n = 6, Control); inoculated with canine adenovirus type 2 (CAV2) (n = 11, Infected); and subclinical spontaneous infection with CAV2 (n = 6, Subclinical). While anesthetized with chloralose and mechanically ventilated, lung function and responsiveness to aerosolized histamine were measured 3 days before inoculation (Day -3), the day of inoculation (Day 0), and 3 to 4 (Day 3-4), 6 (Day 6), 8 to 10 (Day 8-10), and 12 to 14 (Day 12-14) days after inoculation. Histamine responsiveness was assessed by calculating the provocation concentration of histamine diphosphate to increase lung resistance (RL) to 150% (PC 150% RL), or decrease dynamic lung compliance (Cdyn) to 75% (PC 75% Cdyn) of the response to saline [RL(sal) and Cdyn(sal), respectively]. Arterial blood gases, functional residual capacity (FRC), specific static lung compliance (spCst), RL, Cdyn, and histamine responsiveness were not significantly different on Day 0 among the groups (p greater than 0.05). Control and Subclinical puppies remained healthy, had a mean weight gain of 0.7 kg, and did not change their histamine responsiveness during the study period. Infected puppies developed moderate to severe clinical illnesses, had poor weight gain, and were histamine hyperresponsive on Days 3-4 and 6. One infected puppy died on Day 3-4, and two died on Day 6 of their illness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of verapamil and metoprolol on recovery from atrial electrical remodeling after cardioversion of long-lasting atrial fibrillation

The aim of this prospective, randomized study was to investigate the effect of pretreatment with two different intracellular calcium-lowering drugs (verapamil and metoprolol) on recovery from atrial effective refractory period (AERP) shortening after internal electrical cardioversion (EC) of persistent atrial fibrillation (AF) in patients on amiodarone. Twenty-one patients on amiodarone for at least 30 days were referred to our hospital for internal EC of a persistent AF refractory to external EC. They were randomized to receive only amiodarone (group AMI, n=7), or amiodarone and verapamil 240 mg/day (group VER, n=7), or amiodarone and metoprolol 100 mg/day (group MET, n=7). Left AERP was measured 10 min and 24 h after EC. AERP was also determined in 13 controls. The AERP after 10 min was significantly shorter in group AMI (201 (31) ms, P<0.02) and group MET (203 (34) ms, P<0.03) than in controls (249 (45) ms), but not in group VER (237 (51) ms, P=NS). The AERP after 24 h was still significantly shorter in group AMI (204 (38) ms, P<0.04) than in controls, but not in group MET (225 (52) ms, P=NS) or in group VER (290 (36) ms, P=NS). Pretreatment with amiodarone and verapamil prevents AERP shortening, while pretreatment with amiodarone and metoprolol only accelerated AERP recovery.     

Variability of pulmonary responsiveness to aerosolized histamine in normal rabbits

Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of GdCl3 and Angelica sinensis polysaccharides on differentially expressed genes in liver of hepatic immunological injury mice by cDNA microarray

AIM: To study the modulating effect of GdCl(3) and Angelica Sinensis polysaccharides (ASP) on differentially expressed genes in liver of hepatic immunological mice by cDNA microarray. METHODS: Hepatic immunological injury was induced by lipopolysaccharide (LPS ip, 0.2 mg/kg(-1)) in bacillus calmetteguerin (BCG ip, 1 mg/kg(-1)) primed mice; A single dose of 20 mg/kg(-1) GdCl(3) was simultaneously pretreated and 30 mg/kg(-1) ASP (ig, qdX7 d) was administrated when the BCG+LPS was primed. The mice were sacrificed at the end of the 7(th) day after ip LPS for 6 h and the liver was removed quickly. The PCR products of 512 genes were spotted onto a chemical material-coated glass plate in array. The DNAs were fixed to the glass plate after series of treatments. The total RNAs were isolated from the liver tissue, and were purified to mRNAs by Oligotex. Both mRNAs from the normal liver tissue and the liver tissue from the mice with hepatic immunological injury or that pretreated with GdCl(3) or ASP were reversely transcribed to cDNAs with the incorporation of fluorescent dUTP to prepare the hybridization probes. The mixed probes were hybridized to the cDNA microarray. After high-stringent washing, the cDNA microarray was scanned for fluorescent signals and showed differences between the two tissues. RESULTS: Among the 512 target genes, 18 differed in liver tissue of hepatic immunological injury mice, and 6 differed in those pretreated by ASP, 7 differed in those pretreated by GdCl(3). CONCLUSION: cDNA microarray technique is effective in screening the differentially expressed genes between two different kinds of tissue. Further analysis of those obtained genes will be helpful to understand the molecular mechanism of hepatic immunological injury and to study the intervention of drug. Both ASP and GdCl(3) can decrease the number of the differentially expressed genes in liver tissue of mice with hepatic immunological injury.     

Therapeutic intervention in a rat model of adult respiratory distress syndrome: II. Lipoxygenase pathway inhibition

The present study was designed to investigate the role of 5-lipoxygenase (5LO) metabolites in an endotoxin (LPS)-induced model of the adult respiratory distress syndrome (ARDS) in the rat. The therapeutic value of two 5LO inhibitors and a specific LTB4 and a LTD4 receptor antagonist were examined. Rats were treated 1 hr prior to administration of aerosolized LPS. Rats were either unexposed (n = 11), or pretreated with vehicle sham (n = 63), 50 mg/kg phenidone t.i.d. (n = 7, n = 10 for assessment of mortality), 30 mg/kg SK&F 103842 b.i.d. (n = 6), 50 mg/kg SK&F 106203 t.i.d. (n = 11), or 5 mg/kg SK&F 107324 b.i.d. (n = 6) 1 hr prior to the administration of aerosolized endotoxin (LPS, 7 mg/kg) or phosphate-buffered saline (PBS, n = 22). Twenty-four hours later, blood samples were collected for hematologic evaluation and after wet lung weight was determined, broncho-alveolar lavage (BAL) was performed to measure cells counts and total protein (TP). 5LO inhibition and LTD4 receptor antagonism reduced LPS-induced mortality to zero compared to 35% in rats pretreated with vehicle sham. Pretreatment with the LTD4 receptor antagonist attenuated the LPS-induced increased in wet/dry lung weight (W/D) whereas 5LO inhibition reduced TP increases. Both 5LO inhibition and LTD4 receptor antagonism attenuated the LPS-induced BAL erythrocyte increase. The LPS-induced thrombocytopenia was attenuated by phenidone, the 5LO receptor antagonist. We conclude that the increased microvascular permeability was associated with the formation of 5LO products since 5LO inhibition lessened the severity of the LPS-induced increase in W/D and TP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Roflumilast Inhibition of Pulmonary Leukotriene Production and Bronchoconstriction in Ovalbumin-Sensitized and -Challenged Guinea Pigs

This study investigated the effects of roflumilast, a PDE4 inhibitor, on slow-reacting substance of anaphylaxis (SRS-A)-mediated bronchoconstriction and pulmonary leukotriene (LT) release in ovalbumin (OVA)-sensitized and -challenged guinea pigs. Animals were treated with roflumilast orally (0.04, 0.12, 0.4, or 4 mg/kg) or placebo 1 hour before OVA challenge. Bronchoconstriction was quantified by measuring airway conductance (Gaw) and dynamic lung compliance (Cdyn). Roflumilast significantly attenuated the decrease in Gaw (50% inhibitory dose [ID₅₀] = 0.33 mg/kg) and Cdyn (ID₅₀ = 0.25 mg/kg) in a dose-dependent manner and significantly inhibited Cys-LT (ID₅₀ = 0.06 mg/kg) and LTB4 (ID₅₀ = 0.05 mg/kg) release versus placebo-treated animals. Roflumilast did not affect LTD4-induced bronchoconstriction. These findings support the role of roflumilast as an anti-inflammatory treatment for asthma.