Osvaldo Shigueomi Beppu

Pulmonary emphysema induced by passive smoking: an experimental study in rats

We describe a short time model for inducing experimental emphysema in rats by chronic tobacco smoke inhalation. Three groups of male Wistar rats (6 months old) were studied: controls (N = 8), rats intoxicated for 45 days (s-45, N = 7) or for 90 days (s-90, N = 8). The exposed animals were intoxicated 3 times a day (10 cigarettes per exposure period), 5 days a week. Pulmonary damage was assessed by means of functional tests and quantitative pathological examination of the airways and lung parenchyma. The s-45 and s-90 animals were similar in terms of functional residual capacity (FRC) corrected for body weight (FRC/kg) but both groups of smoking rats exhibited significantly higher FRC/kg values than the controls (s-45 = 6.33; s-90 = 6.46; controls = 3.78; P < 0.05). When the two groups of smoking rats were pooled together and compared to controls, they showed decreased lung elastance (1.6 vs 2.19; P = 0.046) and increased mean linear intercept (Lm) (85.14 vs 66.44; P = 0.025). The s-90 animals presented higher inflammation and muscular hypertrophy at the level of the axial bronchus than the controls (P < 0.05). When smoking groups were pooled and compared to controls, they presented significantly higher inflammation at the lateral level (P = 0.028), as well as airway secretory hyperplasia (P = 0.024) and smooth muscle hypertrophy (P = 0.005) at the axial level. Due to its simplicity, low cost and short duration, this technique may be a useful model to obtain new information about airspace remodeling due to chronic tobacco consumption.

Pentoxifylline decreases tumor necrosis factor and interleukin-1 during high tidal volume.

Tumor necrosis factor-alpha (TNF-alpha) is one of the most important proinflammatory cytokines which plays a central role in host defense and in the acute inflammatory response related to tissue injury. The major source of TNF-alpha are immune cells such as neutrophils and macrophages. We tested the hypothesis that pentoxifylline, a methylxanthine derivative, down-regulates proinflammatory cytokine expression during acute lung injury in rats. Male Wistar rats weighing 250 to 450 g were anesthetized ip with 50 mg/kg sodium thiopental and randomly divided into three groups: group 1 (N = 7): tidal volume (V T) = 7 ml/kg, respiratory rate (RR) = 50 breaths/min and normal saline infusion; group 2 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and normal saline infusion; group 3 (N = 7): V T = 42 ml/kg, RR = 9 breaths/min and pentoxifylline infusion. The animals were ventilated with an inspired oxygen fraction of 1.0, a positive end-expiratory pressure of 3 cmH2O, and normal saline or pentoxifylline injected into the left femoral vein. The mRNA of TNF-alpha rapidly increased in the lung tissue within 180 min of ventilation with a higher V T with normal saline infusion. The concentrations of inflammatory mediators were decreased in plasma and bronchoalveolar lavage (BAL) in the presence of higher V T with pentoxifylline infusion (TNF-alpha: plasma, 102.2+/-90.9 and BAL, 118.2+/-82.1; IL-1 : plasma, 45.2+/-42.7 and BAL, 50.2+/-34.9, P < 0.05). We conclude that TNF-alpha produced by neutrophil influx may function as an alert signal in host defense to induce production of other inflammatory mediators.

Ventilation with high tidal volume induces inflammatory lung injury

Mechanical ventilation with high tidal volumes (V(T)) has been shown to induce lung injury. We examined the hypothesis that this procedure induces lung injury with inflammatory features. Anesthetized male Wistar rats were randomized into three groups: group 1 (N = 12): V(T) = 7 ml/kg, respiratory rate (RR) = 50 breaths/min; group 2 (N = 10): V(T) = 21 ml/kg, RR = 16 breaths/min; group 3 (N = 11): V(T) = 42 ml/kg, RR = 8 breaths/min. The animals were ventilated with fraction of inspired oxygen of 1 and positive end-expiratory pressure of 2 cmH2O. After 4 h of ventilation, group 3, compared to groups 1 and 2, had lower PaO2 [280 (range 73-458) vs 517 (range 307-596), and 547 mmHg (range 330-662), respectively, P<0.05], higher wet lung weight [3.62 +/- 0.91 vs 1.69 +/- 0.48 and 1.44 +/- 0.20 g, respectively, P<0.05], and higher wet lung weight/dry lung weight ratio [18.14 (range 11.55-26.31) vs 7.80 (range 4.79-12.18), and 6.34 (range 5.92-7.04), respectively, P<0.05]. Total cell and neutrophil counts were higher in group 3 compared to groups 1 and 2 (P<0.05), as were baseline TNF-alpha concentrations [134 (range <10-386) vs 16 (range <10-24), and 17 pg/ml (range <10-23), respectively, P<0.05]. Serum TNF-alpha concentrations reached a higher level in group 3, but without statistical significance. These results suggest that mechanical ventilation with high V T induces lung injury with inflammatory characteristics. This ventilatory strategy can affect the release of TNF-alpha in the lungs and can reach the systemic circulation, a finding that may have relevance for the development of a systemic inflammatory response.

High-dose inhaled beclomethasone treatment in patients with chronic cough: a randomized placebo-controlled study

BACKGROUND It is important to determine whether chronic cough is associated with asthma and can be helped by treatment with inhaled corticosteroids. OBJECTIVE To compare the effects of beclomethasone and placebo in patients with chronic cough for at least 8 weeks after excluding those with cough due to postnasal drip and gastroesophageal reflux disease. METHODS A prospective, randomized, double-blind, placebo-controlled study comprising 64 patients was performed for 2 weeks. The active group received metered-dose inhaler chlorofluorocarbon-beclomethasone (1,500 microg/d), and the placebo group received identical-appearing placebo inhalers. All the participants completed a respiratory questionnaire and underwent bronchoprovocation testing (BPT) with methacholine and allergy skin testing. The primary outcome measure was a decrease in daily cough scores (symptom diary and visual analog scale) during the 2-week treatment period. RESULTS The active group comprised 44 patients and the placebo group 20 patients. Cough duration averaged 20 weeks. At the end of treatment 82% of the active group and 15% of the placebo group had complete resolution of cough. In the active group 22 patients (50%) had positive BPT results, and in the placebo group 10 patients (50%) had positive results. There was no correlation between treatment response and responses on the respiratory questionnaire, allergy skin testing, or BPT. CONCLUSION Therapy with high-dose inhaled beclomethasone provided an excellent response in a subgroup of patients with chronic cough that did not correlate with atopy or airway hyperresponsiveness.

A prospective longitudinal study of clinical characteristics, laboratory findings, diagnostic spectrum and outcomes of specific therapy in adult patients with chronic cough in a general respiratory clinic

Chronic cough with established diagnostic protocols has been well described in secondary and tertiary centres. Little information is available about adult patients to a general respiratory clinic where no such protocols exist.

Protective effect of aminoguanidine in a murine model of pulmonary fibrosis induced by bleomycin

Abstract— Aminoguanidine is a drug known for more than a century, which has been attracting increasing interest in recent years due to the discovery of new pharmacological properties. This study investigated the effects of aminoguanidine on the fibrotic response induced by intratracheal administration of bleomycin to rats. Three groups of animals were studied: Group A (n = 19) corresponded to the control group. Group B (n = 20) received 10 IU/kg bleomycin intratracheal, and Group C (n = 12) received the same amount of bleomycin as Group B followed by 50 mg/kg/day aminoguanidine bicarbonate for 4 weeks. Aminoguanidine led to significant reductions in total hydroxyproline content of the lungs in Group C compared to Group B (Group A: 1.83 ± 0.14 mg ± Group B: 3.46 ± 0.36 mg ± Group C: 2.09 ± 0.22 mg). Morphometric collagen studies carried out on histological sections stained with Sirius red F3BA showed that aminoguanidine promoted a significant reduction of the area occupied by collagen in the axial and septal zones of the lungs (Axial region = Group A: 4.29 ± 1.31% × Group B: 19.30 ± 4.86% × Group C: 8.52 ± 1.96%; Septal region = Group A: 0.15 ± 0.06% × Group B: 0.61 ± 0.21% × Group C: 0.15 ± 0.06%). These results suggest that aminoguanidine is a potential therapeutic agent for the treatment and prevention of pulmonary fibrosis which is associated with different clinical conditions.

Methacholine vs adenosine on intra and extrathoracic airway hyperresponsiveness in patients with cough variant asthma

Background:  Airway hyperresponsiveness (AHR) can be studied by bronchoprovocation test (BPT) using direct (methacholine – MCh) or indirect (adenosine 5′‐monophosphate – AMP) stimuli. These two substances have not been compared in cough variant asthma (CVA).

Effect of saline infusion for the maintenance of blood volume on pulmonary gas exchange during temporary abdominal aortic occlusion

We analyzed the effects of saline infusion for the maintenance of blood volume on pulmonary gas exchange in ischemia-reperfusion syndrome during temporary abdominal aortic occlusion in dogs. We studied 20 adult mongrel dogs weighing 12 to 23 kg divided into two groups: ischemia-reperfusion group (IRG, N = 10) and IRG submitted to saline infusion for the maintenance of mean pulmonary arterial wedge pressure between 10 and 20 mmHg (IRG-SS, N = 10). All animals were anesthetized and maintained on spontaneous ventilation. After obtaining baseline measurements, occlusion of the supraceliac aorta was performed by the inflation of a Fogarty catheter. After 60 min of ischemia, the balloon was deflated and the animals were observed for another 60 min of reperfusion. The measurements were made at 10 and 45 min of ischemia, and 5, 30, and 60 min of reperfusion. Pulmonary gas exchange was impaired in the IRG-SS group as demonstrated by the increase of the alveolar-arterial oxygen difference (21 +/- 14 in IRG-SS vs 11 +/- 8 in IRG after 60 min of reperfusion, P = 0.004 in IRG-SS in relation to baseline values) and the decrease of oxygen partial pressure in arterial blood (58 +/- 15 in IRG-SS vs 76 +/- 15 in IRG after 60 min of reperfusion, P = 0.001 in IRG-SS in relation to baseline values), which was correlated with the highest degree of pulmonary edema in morphometric analysis (0.16 +/- 0.06 in IRG-SS vs 0.09 +/- 0.04 in IRG, P = 0.03 between groups). There was also a smaller ventilatory compensation of metabolic acidosis after the reperfusion. We conclude that infusion of normal saline worsened the gas exchange induced by pulmonary reperfusion injury in this experimental model.

Variable positive end-expiratory pressure can maintain oxygenation in experimental acute respiratory distress syndrome induced by oleic acid in dogs

The use of positive end-expiratory pressure (PEEP) or lung recruitment maneuvers (RM) to improve oxygenation in acute respiratory distress syndrome (ARDS) is used but it may reduce cardiac output (CO). Intermittent PEEP may avoid these complications. Our objective was to determine if variable PEEP compared with constant PEEP is capable of maintaining arterial oxygenation and minimizing hemodynamic alterations with or without RM. Eighteen dogs with ARDS induced by oleic acid were randomized into three equal groups: group 1, low variable PEEP; group 2, high variable PEEP, and group 3, RM + high variable PEEP. All groups were submitted to constant PEEP, followed by variable PEEP (PEEP was increased from 5 to 10 cmH(2)O in group 1, and from 5 to 18 cmH(2)O in the other two groups). PaO(2) was higher in group 3 (356.2 +/- 65.4 mmHg) than in group 1 (92.7 +/- 29.7 mmHg) and group 2 (228.5 +/- 72.4 mmHg), P < 0.05. PaO(2) was maintained during variable PEEP except in group 2 (318.5 +/- 82.9 at constant PEEP to 228.5 +/- 72.4 at variable PEEP). There was a reduction in CO in group 3 after RM (3.9 +/- 1.1 before to 2.7 +/- 0.5 L*min(-1)*(m(2))(-1) after; P < 0.05), but there was not any difference between constant and variable PEEP periods (2.7 +/- 0.5 and 2.4 +/- 0.7 L*min(-1)*(m(2))(-1); P > 0.05. Variable PEEP is able to maintain PaO(2) when performed in combination with RM in dogs with ARDS. After RM, CO was reduced and there was no relevant difference between the variable and constant PEEP periods.

Efeito da posição prona sem PEEP na oxigenação e complacência em modelo experimental com lesão pulmonar

OBJECTIVE To observe the effects of the prone position and the need for positive end-expiratory pressure (PEEP) to improve oxygenation. METHOD Sixteen rats were anesthetized and ventilated at a tidal volume of 8 mL/kg, respiratory rate of 60 rpm and PEEP = 0 cmH(2)O (ZEEP), in the supine position for 30 minutes. Lung injury was then induced by means of intratracheal instillation of hydrochloric acid. Once the injury was established, rats were placed in the prone position for a further 30 minutes and randomized into two groups: in group 1 PEEP = 5 cmH(2)O was added; while group 2 was kept on ZEEP. Measurements of pulmonary mechanics, arterial blood gas analysis and mean arterial pressure were taken at the end of each phase. RESULTS In group 1, oxygen partial pressure increased significantly from 98.7+/-26.5 to 173.9+/-58.4 mmHg between injury and prone phases; in group 2 it was unchanged, varying from 99.6+/-15.4 to 100.5+/-24.5 mmHg. Group 1 also exhibited significant improvement in complacency, from 0.20+/-0.01 to 0.23+/-0.02 mL/cmH(2)O, while, once more, group 2 did not exhibit improvement, going from 0.21+/-0.02 to 0.22+/-0.01 mL/cmH(2)O. Mean arterial blood pressure measurements did not change significantly in either group at any point during the experiment. CONCLUSIONS The prone position only resulted in improved oxygenation and respiratory mechanics when combined with PEEP = 5 cmH(2)O. The prone position did not cause hemodynamic compromise with or without PEEP = 5 cmH(2)O.OBJECTIVE: To observe the effects of the prone position and the need for positive end-expiratory pressure (PEEP) to improve oxygenation. METHODS: Sixteen rats were anesthetized and ventilated at a tidal volume of 8 mL/kg, respiratory rate of 60 rpm and PEEP = 0 cmH2O (ZEEP), in the supine position for 30 minutes. Lung injury was then induced by means of intratracheal instillation of hydrochloric acid. Once the injury was established, rats were placed in the prone position for a further 30 minutes and randomized into two groups: in group 1 PEEP = 5 cmH2O was added; while group 2 was kept on ZEEP. Measurements of pulmonary mechanics, arterial blood gas analysis and mean arterial pressure were taken at the end of each phase. RESULTS: In group 1, oxygen partial pressure increased significantly from 98.7±26.5 to 173.9±58.4 mmHg between injury and prone phases; in group 2 it was unchanged, varying from 99.6±15.4 to 100.5±24.5 mmHg. Group 1 also exhibited significant improvement in complacency, from 0.20±0.01 to 0.23±0.02 mL/cmH2O, while, once more, group 2 did not exhibit improvement, going from 0.21±0.02 to 0.22±0.01 mL/cmH2O. Mean arterial blood pressure measurements did not change significantly in either group at any point during the experiment. CONCLUSIONS: The prone position only resulted in improved oxygenation and respiratory mechanics when combined with PEEP = 5 cmH2O. The prone position did not cause hemodynamic compromise with or without PEEP = 5 cmH2O.