Ibuprofen prevents synthetic smoke-induced pulmonary edema

Multiple potentially injurious agents are present in smoke but the importance of each of these agents in producing lung injury as well as the mechanisms by which the lung injury is produced are unknown. In order to study smoke inhalation injury, we developed a synthetic smoke composed of a carrier of hot carbon particles of known size to which a single known common toxic agent in smoke, in this case HCI, could be added. We then exposed rats to the smoke, assayed their blood for the metabolites of thromboxane and prostacyclin, and intervened shortly after smoke with the cyclooxygenase inhibitors indomethacin or ibuprofen to see if the resulting lung injury could be prevented. Smoke exposure produced mild pulmonary edema after 6 h with a wet-to-dry weight ratio of 5.6 +/- 0.2 SEM (n = 11) compared with the non-smoke-exposed control animals with a wet-to-dry weight ratio of 4.3 +/- 0.2 (n = 12), p less than 0.001. Thromboxane B, and 6-keto-prostaglandin F1 alpha rose to 1,660 +/- 250 pg/ml (p less than 0.01) and to 600 +/- 100 pg/ml (p greater than 0.1), respectively, in the smoke-injured animals compared with 770 +/- 150 pg/ml and 400 +/- 100 pg/ml in the non-smoke-exposed control animals. Indomethacin (n = 11) blocked the increase in both thromboxane and prostacyclin metabolites but failed to prevent lung edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

An evaluation of nebulized prostacyclin in patients with primary and secondary pulmonary hypertension

AIMS: To investigate the response to inhaled prostacyclin in patientswith primary and secondary pulmonary hypertension and to compareits effects to those of intravenous prostacyclin and inhalednitric oxide. METHODS AND RESULTS: Twelve patients with pulmonary hypertension (seven primary andfive secondary) were studied. All patients had a pulmonary arteryballoon flotation catheter inserted into the proximal pulmonaryartery and radial arterial line. Prostacyclin was nebulizedwith 81. min^–1 of oxygen and administered in doses increasingfrom 15 to 50 ng. kg^–1. min^–1 via a facemask. Eightof these patients also received intravenous prostacyclin indoses of 1 to 5 ng.kg^–1.min^–1 and nitric oxide indoses of 10 to 100 ppm via a facemask. Haemodynamic measurementswere taken during each treatment. In the 12 patients, nebulizedprostacyclin produced a significant reduction in mean pulmonaryartery pressure from 56±5 to 45±4 mmHg (P=0·0001).The pulmonary vascular resistance decreased by 38% from 964±169to 595±116 dyne s^–1.cm^–5 (P=0·0001).Direct comparison with inhaled nitric oxide and intravenousprostacyclin in eight patients demonstrated that nebulized prostacyclinproduced a greater fall in mean pulmonary artery pressure thanthe other two agents without any significant effect on systemicarterial pressure. CONCLUSION: Nebulized prostacyclin appears to be more effective at reducingpulmonary artery pressure in patients with pulmonary hypertensionwhen compared to intravenous prostacyclin and inhaled nitricoxide. This could have important clinical implications for themanagement of patients with pulmonary hypertension.     

Time course of cigarette smoke-induced pulmonary inflammation in mice.

Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease. In the present study a murine model of tobacco smoke-induced emphysema was used to investigate the time course of airway and pulmonary inflammatory response, with a special emphasis on pulmonary dendritic cell (DC) populations. Groups of mice were exposed to either cigarette smoke or to control air for up to 24 weeks. In response to cigarette smoke, inflammatory cells (i.e. neutrophils, macrophages and lymphocytes) progressively accumulated both in the airways and lung parenchyma of mice. Furthermore, a clear infiltration of DCs was observed in airways (10-fold increase) and lung parenchyma (1.5-fold increase) of cigarette-exposed mice at 24 weeks. Flow cytometric analysis of bronchoalveolar lavage (BAL) DCs of smoke-exposed mice showed upregulation of major histocompatability complex II molecules and costimulatory molecules CD40 and CD86, compared with BAL DCs of air-exposed mice. Morphometric analysis of lung histology demonstrated a significant increase in mean linear intercept and alveolar wall destruction after 24 weeks of smoke exposure. In conclusion, the time course of the changes in inflammatory and dendritic cells in both bronchoalveolar lavage and the pulmonary compartment of cigarette smoke-exposed mice was carefully characterised.     

Treatment of diabetic perforating ulcers (mal perforant) with local dimethylsulfoxide

Perforating foot ulcers constitute a major problem in diabetics with peripheral neuropathy for which no specific therapy is available. Twenty patients with chronic, resistant mal perforant were treated by local application of dimethylsulfoxide (DMSO) solution. Complete healing of the ulcers was achieved in 14 patients following 4-15 weeks of daily treatment. Partial resolution was observed in another four patients, and in the remaining two there was no effect. A control group, equal in number, was treated conventionally. Complete healing of the ulcers took place in only two patients. The therapeutic effect of DMSO most probably results from an increase in tissue oxygen saturation via a combined mechanism of local vasodilatation, decreased thrombocyte aggregation, and increased oxygen diffusion. Local DMSO is effective, simple, devoid of systemic side effects, and inexpensive. It should be employed for diabetic foot ulcers prior to the consideration of surgical measures.     

Clinical evaluation of nebulized verapamil in out‐patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease

ObjectiveChronic obstructive pulmonary disease (COPD) is associated with many health complications, including pulmonary hypertension (PH). Although oral calcium channel blockers have shown promising results in managing COPD‐induced PH, significant systemic side effects may limit their use in this population. Administering verapamil through nebulization can be an alternative approach. We aim to assess the possible therapeutic effects of verapamil inhalation in out‐patients with pulmonary hypertension (PH) secondary to COPD.MethodsA double‐blind, randomized placebo‐controlled clinical trial was conducted. Patients with PH were randomly assigned to two groups of 15 participants. The intervention group received a short‐term single dose of 10 mg nebulized verapamil (4 ampoules of 2.5 mg/ml verapamil solutions). The control group received nebulized distilled water as a placebo in addition to their standard treatment throughout the study.ResultsSystolic pulmonary artery pressure (sPAP) did not improve as a primary outcome significantly in patients receiving nebulized verapamil compared with those on placebo (p = 0.89). Spirometry results showed a significant improvement in FVC in the intervention group from 1.72 ± 0.63 to 1.85 ± 0.58 L (p = 0.00), and FEV1/FVC ratio decreased significantly after verapamil administration (p = 0.027).ConclusionVerapamil did not improve any of the pulmonary artery or RV parameters in patients with COPD‐associated, but it did improve SpO₂ and increase FVC, which revealed us possibility of verapamil in treating V/Q mismatch. The improved gas exchange may have been due to improvements in FVC as reflected in the improved spirometry. Higher doses of verapamil may be more efficacious and can be the subject of future trials.     

The effects of physical exercise on the cigarette smoke-induced pulmonary oxidative response

Studies have shown that the oxidative power of cigarettes is related to the pathogenesis of several pulmonary diseases and that regular physical exercise contributes significantly to reducing the deleterious effects of cigarettes. The objective of the present study was to investigate the therapeutic effects of physical exercise on histological and oxidative stress markers in animals exposed to cigarette smoke. Thirty-six male, eight-week-old C57BL-6 mice were divided into four groups (n = 9 for each group): control, exercise, cigarette smoke, and cigarette smoke plus exercise. The cigarette smoke (CS) groups were exposed to cigarette smoke 3 times/day (4 cigarettes/session) for 60 consecutive days. The exercise groups were submitted to swimming physical training 5 days/week for eight weeks. Forty-eight hours after the last exercise and cigarette exposure, the animals were sacrificed using cervical traction. The right lung was removed, processed, and stored for future analysis. In addition to the analysis of collagen content (hydroxyproline), oxidant production (anion superoxide), antioxidant enzyme activity (SOD and CAT), and lipid and protein oxidative damage (TBARS and Carbonylation), histological and morphological studies were performed. The results revealed that the animals exposed to cigarette smoke showed enlargement and destruction of the alveolar septum and increases in the numbers of macrophages and neutrophils, as well as in the amount of collagen. Our results also showed a decrease in the volume density of elastic fibers and an increase in the volume density of airspaces. However, physical exercise partially improved these markers. Additionally, physical exercise decreased oxidant production and increased the activity of the enzymatic antioxidant defense system, but did not reverse lipid and protein oxidative damage induced by cigarette smoke. These results suggest that physical training partially improves histological and oxidative stress parameters in the lungs of animals chronically exposed to cigarette smoke and that other therapies can contribute to potentiate these effects.     

Effects of strain and treatment with inhaled aII-trans-retinoic acid on cigarette smoke-induced pulmonary emphysema in mice

Models of emphysema produced by exposing animals to cigarette smoke (CS) have potential for use in testing treatments of this disease. To better characterize development of emphysema in an animal model, male and female mice of the B6C3F1 and A/J strains were exposed to CS at 250 mg total particulate material (TPM)/m3 for 15 weeks. Emphysema was evident in both strains of mice to differing degrees of severity. The CS-induced increase in the mean linear intercept (normalized to BW) of A/J mice was 51% greater than the control value, while CS-exposed B6C3F1 had an increase of 38% in this morphometric measurement of alveolar air space enlargement. In separate experiments, female B6C3F1 mice and male A/J mice were exposed to CS for 32 weeks and 15 weeks, respectively, and were then used to test the efficacy of all trans-retinoic acid (ATRA) treatments to ameliorate emphysema lesions. Following CS exposure, the B6C3F1 mice were treated once daily for 14 days in a 3-week period by nose-only inhalation exposure to aerosols of 180 or 1,800 mg-minutes ATRA/m3. The A/J mice were treated once daily, 4 days/week, for three weeks by either intraperitoneal injection of ATRA (0.5 or 2.5 mg/kg) or inhalation exposure to ATRA (3,600 or 18,000 mg-minutes/m3). Neither the injections nor inhalation exposures of ATRA in either strain of mouse caused reversal of the emphysema. In summary, CS-induced emphysema was more severe in A/J mice than in B6C3F1 mice. Treatment with ATRA did not reverse emphysema in either strain of CS-exposed mice.     

Effectiveness of nebulized furosemide added to nebulized salbutamol in children with acute asthma

BackgroundNebulized furosemide has been shown to be protective against bronchoconstricting stimuli.MethodsTo investigate whether inhaled furosemide would exhibit an additional therapeutic effect in children with acute asthma we performed a double-blind, placebo-controlled study in which patients with acute asthma attack were randomized to receive either nebulized salbutamol (0.15 mg/kg) plus nebulized furosemide (10 mg/m2) or nebulized salbutamol (0.15 mg/kg) plus nebulized saline as placebo. In all patients, clinical asthma scores (CAS) were determined before and after drug administration. Peak expiratory flow rates (PEFR) were measured by a peak flow meter.ResultsCAS and PEFR improved in both groups with nebulized salbutamol treatment. The CAS changed from 3.56 ± 2.13 to 2.06 ± 1.84 (p = 0.0001) in the study group and from 4.44 ± 2.63 to 2.56 ± 1.86 (p = 0.0003) in the control group. PEFR increased from 177.50 ± 65.88 to 221.88 ± 66.05 L/min in the first group (p = 0.0001) and from 183.13 ± 51.73 to 218.13 ± 60.25 in the second group (p = 0.0001).ConclusionAdding nebulized furosemide to nebulized salbutamol in pediatric patients experiencing an acute asthma attack did not produce greater improvement in clinical (p = 0.3829) or spirometric (p = 0.3839) parameters than nebulized salbutamol alone.     

烟熏法建立的慢性阻塞性肺疾病鼠肺功能和病理的动态变化

目的 动态观察不同烟熏时间建立的慢性阻塞性肺疾病(COPD)大鼠肺功能和病理的改变,为成功建立COPD大鼠模型提供理论基础.方法 30只8周龄SD大鼠随机分为6周实验组(E1组)及6周对照组(C1组),12周实验组(E2组)及12周对照组(C2组),间隔实验组(烟熏12周后正常饲养6周,E3组).Buxco小动物肺功能仪检测肺功能、HE染色观察肺组织病理变化.结果 ①与C1组相比,E1组FRC、IC、VC和TLC增高(P＜0.05),FEV100/FVC和FEV200/FVC分别降低22％和11％(P＜0.01);②与C2组相比,E2组FRC增高,IC、VC和TLC降低(P＜0.05),FEV100/FVC和FEV200/FVC分别降低28％和21％(P＜0.01);③与C2组相比,E3组IC、VC和TLC升高(P＜0.05),FEV100/FVC和FEV200/FVC差异无统计学意义;④E1组肺泡间隔变窄,呈轻度肺气肿表现,局部可见炎症细胞浸润;E2组呈典型肺气肿表现,细支气管、血管周围有大量炎症细胞浸润;E3组肺气肿表现明显,但未见明显炎症;C1、C2组气道上皮结构完整,肺泡间隔完整.结论 烟熏时间对大鼠肺功能和病理改变的程度有显著影响,烟熏6周出现早期COPD表现,烟熏12周出现典型COPD表现.     

A murine model of cigarette smoke-induced pulmonary inflammation using intranasally administered smoke-conditioned medium

To date, few animal models of chronic obstructive pulmonary disease (COPD) exist that are ideal for the evaluation of pathophysiology, as they typically require many months of cigarette smoke exposure in inhalation facilities. Here we show that pulmonary inflammation and some of the inflammatory hallmarks of COPD can be induced in mice by cigarette smoke-conditioned media (CS) administered by the intranasal route. Balb/c mice were challenged with CS for up to 40 days. At the end of smoke treatment, mice were sacrificed and bronchoalveolar lavage (BAL) fluid collected. Total cell counts and cell differentials were performed. Enzyme-linked immunosorbent assays (ELISAs) for KC and tumor necrosis factor alpha (TNF-alpha) were performed on BAL fluid. Lungs and nasal cavities were examined histologically. Intranasal CS treatment significantly increased BAL neutrophils, lymphocytes, KC, TNF-alpha, and mucin. Changes in pulmonary reactivity to methacholine were also observed in mice challenged with CS for 40 days. The model described above demonstrates that within 1 to 8 weeks of intranasal instillation of CS, mice develop pulmonary inflammation and cellular lung changes that are characteristic of human COPD and therefore may be a good short-term in vivo model that can be utilized to monitor intervention strategies targeted for COPD.     

布地奈德混悬液对慢性阻塞性肺疾病急性加重期的疗效观察

目的观察布地奈德混悬液（普米克令舒）雾化吸入治疗慢性阻塞性肺疾病急性加重期（AECOPD）的临床疗效与安全性。方法 70例AECOPD的患者随机分为两组,普米克令舒雾化吸入治疗组及全身激素组,对两组的临床症状及肺功能检查进行评价。结果两组都明显改善患者的临床症状及肺功能指标,观察组对血糖的影响更小。结论普米克令舒雾化吸入治疗AECOPD的疗效明显,不良反应少。     

Comparison of nebulized and intravenous terbutaline during exacerbations of pulmonary infection in patients with cystic fibrosis.

Twenty three patients completed a double-blind study, comparing intravenous and nebulized terbutaline, during the first four days of a pulmonary exacerbation of cystic fibrosis (CF), with follow-up to day 10. Routine treatment with chest physiotherapy and appropriate intravenous antibiotics was given to all patients. The best peak flow rate (PF), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), in the past year and at entry to the study, revealed no significant difference between the groups. However, on day 10, PF, FEV1 and FVC, of the nebulizer group remained significantly reduced compared to best values in the previous year, whereas the PF and FEV1 in the intravenous group were not significantly reduced compared to the best values in the previous year. Comparison of regression lines showing the overall rate of improvement of PF, FEV1 and FVC between the two groups showed that the rate of improvement of each parameter was more rapid in the group receiving intravenous terbutaline. This was statistically significant for PF. It is possible that during acute exacerbations of infection, sputum retention makes it more difficult for the inhaled bronchodilators to reach the airways and intravenous therapy is, therefore, more beneficial.     

高龄慢性阻塞性肺疾病患者长期雾化吸入布地奈德的疗效及安全性评估

目的 观察高龄慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)患者雾化吸入布地奈德混悬液的临床疗效及安全性评估.方法 25例高龄COPD稳定期患者随机分为两组,分别给予布地奈德1mg bid,2 mg bid雾化吸入1年.15例正常高龄老人为对照组.结果 雾化吸入布地奈德2mg bid明显改善COPD患者PaCO2(P＜0.01)、FEV1 (P＜0.05).治疗6m后两组CAT评分均较治疗前明显改善(P＜ 0.05,P＜0.01);较高剂量组治疗12 m后CAT评分较治疗6m后有进一步改善(P＜0.05),治疗6m后及12 m后的CAT改善率均优于较低剂量组(P＜0.05,P＜ 0.01).两组患者治疗期内慢性阻塞性肺疾病急性加重的发生率无明显差异.治疗组与正常对照组相比,糖代谢及血尿骨代谢均无明显影响.治疗期间两组患者肺炎的发生率无明显差异.结论 雾化吸入布地奈德1年可改善中重度COPD高龄患者肺功能和临床症状,未对糖代谢和骨代谢产生不良影响.较高剂量雾化吸入布地奈德1年未增加COPD患者的肺炎发生率.     

ACE及ACE2在慢性香烟烟雾诱导的大鼠肺动脉高压对血管紧张素Ⅱ的调控作用

目的 探讨慢性香烟暴露诱导的肺动脉高压形成过程中ACE、ACE2和血管紧张素Ⅱ（AngⅡ）的调控作用及特异性血管紧张素Ⅱ受体拮抗剂氯沙坦的治疗作用.方法 健康雄性SD大鼠60只,随机分为A组：对照组（Con）;B组：30 mg/kg单纯氯沙坦组（30 mg/kg Los）;C组：香烟诱导组（SM）;D组：香烟诱导＋10 mg/kg氯沙坦组（SM＋10 mg/kg Los）;E组：香烟诱导＋30 mg/kg氯沙坦组（SM＋30 mg/kg Los）.香烟暴露组和香烟暴露＋氯沙坦组在标准毒理香烟暴露箱中接受被动吸烟;对照组同时在同种毒理箱中暴露于新鲜空气;氯沙坦给药采用每天腹腔内注射;正常对照组给予等量生理盐水注射.建立香烟诱导的肺动脉高压大鼠模型后,用插入导管法检测右室收缩压（RVSP）;Western blotting法分析ACE2和ACE的蛋白表达量;放射免疫分析试剂药盒测定肺组织中的AngⅡ表达水平.结果 香烟暴露6个月后,慢性香烟暴露组大鼠RVSP较对照组明显升高,大鼠肺组织中AngⅡ表达水平显著增高.Western blotting结果显示,ACE表达水平增高,香烟暴露组大鼠肺组织ACE2蛋白表达水平降低,而ACE蛋白表达水平较对照组升高.氯沙坦干预治疗后,香烟暴露＋氯沙坦组大鼠RVSP和AngⅡ较香烟暴露组降低（P＜0.05）,肺组织ACE2蛋白表达水平较香烟暴露组增强,ACE蛋白表达水平较香烟暴露组减少（P＜0.05）.结论 慢性香烟暴露可导致肺动脉高压,还可刺激肺组织ACE2和ACE的蛋白表达变化,提示ACE2和ACE在慢性香烟暴露诱导的肺动脉高压中起一定作用.     

Efficacy of nebulized flunisolide combined with salbutamol and ipratropium bromide in stable patients with moderate-to-severe chronic obstructive pulmonary disease

BACKGROUND: The efficacy of nebulized corticosteroids in the prevention of exacerbation of chronic obstructive pulmonary disease (COPD) has been poorly studied. OBJECTIVE: To evaluate the efficacy and tolerability of nebulized flunisolide (1 mg) + salbutamol/ipratropium bromide (1,875/375 microg) b.i.d. in comparison with placebo + salbutamol/ipratropium bromide. METHODS: This was a randomized, parallel-group, double-blind study on 114 patients with COPD of moderate-to-severe degree. The main outcome was the frequency of severe exacerbations over a 6-month period. Before and after treatment, respiratory symptoms, forced expiratory volume in 1 s (FEV(1)), shuttle walking test distance and St. George's Respiratory Questionnaire scores were evaluated. RESULTS: The total number of exacerbations was slightly lower in the flunisolide group compared to the placebo group (19 vs. 34, p = 0.054); the number of patients experiencing at least one exacerbation during the study was also decreased (16 vs. 26, p = 0.059). In particular, type 3 Anthonisens's exacerbations were significantly reduced by flunisolide (p = 0.044). In the placebo group, scores were higher than in the flunisolide group but nonsignificant for dyspnea, cough, sputum amount and purulence. FEV(1) was significantly increased compared to baseline in both groups, and the area under the FEV(1)-time curve during the 6-month period was significantly greater in the flunisolide group (5.2 +/- 10.6 vs. 2.1 +/- 5.0, flunisolide vs. placebo, respectively; p = 0.047). For shuttle walking test distance and scores of the St. George's Respiratory Questionnaire, no significant difference between the baseline evaluation and the end of the study was observed in both groups. CONCLUSIONS: Nebulized flunisolide is a good alternative to other inhaled corticosteroids when added to nebulized salbutamol/ipratropium bromide in the long-term treatment of moderate-to-severe COPD patients.     

Aerosolized hyaluronan limits airspace enlargement in a mouse model of cigarette smoke-induced pulmonary emphysema

This study was designed to determine if aerosolized hyaluronan (HA) could prevent airspace enlargement and elastic fiber injury in a mouse model of cigarette smoke-induced pulmonary emphysema. Compared to untreated/smoked controls, HA-treated animals showed statistically significant reductions in mean linear intercept (54 versus 65 microm; P < .001) and elastic fiber breakdown products (desmosine and isodesmosine) in bronchoalveolar lavage fluid (0.3 versus 7.0 ng/mL; P < .05). As in previous studies, the aerosolized HA showed preferential binding to elastic fibers, suggesting that it may protect them from injury. These findings support further investigation of the potential use of HA as a treatment for pulmonary emphysema.