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

Interferon gamma is a key cytokine in lung phase immunity to schistosomes but what is its precise role?

Vaccination of mice with radiation-attenuated cercariae of Schistosoma mansoni induces a high level of protection against challenge with normal larvae. The immune effector mechanism, which operates in the lungs, is a cell-mediated delayed-type hypersensitivity response and involves the formation of a tight focus of mononuclear cells around embolised larvae. CD4+ T cells with Th1 characteristics are a major component of the infiltrate. They secrete abundant interferon gamma (IFNg) upon antigen stimulation in vitro, whilst in vivo neutralisation of the cytokine results in 90% abrogation of immunity. IFNg can induce a large number of genes and an attempt has been made to identify the ones which are essential components of the effector mechanism. Inducible nitric oxide synthase (iNOS) is such a candidate and nitric oxide (NO) is produced by cultures of airway leucocytes from the lungs of vaccinated mice post-challenge. However, the continued resistance of mice with a disrupted iNOS gene indicates that NO has only a minor role in the protective response. Mice with a disrupted IFNg receptor gene have been used to dissect the role of the cytokine. After vaccination and challenge, CD4+ T cells from the pulmonary interstitium have reduced levels of ICAM-1 and LFA-1 expression, compared to wild-type animals, which coincides with a reduced cohesiveness of foci. However, immunity is not significantly impaired in mice with a disrupted ICAM-1 gene, and focus formation is normal. Similarly, a role has not been found for CD2/CD48 interactions in cell aggregation. Possible IFNg-inducible molecules yet to be fully investigated include other ligand-receptor pairs, chemokines, and tumour necrosis factor a.

Inspiratory flow-volume curve in snoring patients with and without obstructive sleep apnea

We analyzed the flow-volume curves of 50 patients with complaints of snoring and daytime sleepiness in treatment at the Pneumology Unit of the University Hospital of Brasília. The total group was divided into snorers without obstructive sleep apnea (OSA) (N = 19) and snorers with OSA (N = 31); the patients with OSA were subdivided into two groups according to the apnea/hypopnea index (AHI): AHI<20/h (N = 14) and AHI>20/h (N = 17). The control group (N = 10) consisted of nonsmoking subjects without complaints of snoring, daytime sleepiness or pulmonary diseases. The population studied (control and patients) consisted of males of similar age, height and body mass index (BMI); spirometric data were also similar in the four groups. There was no significative difference in the ratio of forced expiratory and inspiratory flows (FEF50%/FIF50%) in any group: control, 0.89; snorers, 1.11; snorers with OSA (AHI<20/h), 1.42, and snorers with OSA (AHI>20/h), 1.64. The FIF at 50% of vital capacity (FIF50%) of snoring patients with or without OSA was lower than the FIF50% of the control group (P<0.05): snorers 4.30 l/s; snorers with OSA (AHI<20/h) 3.69 l/s; snorers with OSA (AHI>20/h) 3.17 l/s and control group 5.48 l/s. The FIF50% of patients with severe OSA (AHI>20/h) was lower than the FIF50% of snorers without OSA (P<0.05): 3.17 l/s and 4.30 l/s, respectively. We conclude that 1) the FEF50%/FIF50% ratio is not useful for predicting OSA, and 2) FIF50% is decreased in snoring patients with and without OSA, suggesting that these patients have increased upper airway resistance (UAR).

The effects of positive end-expiratory pressure on respiratory system mechanics and hemodynamics in postoperative cardiac surgery patients

We prospectively evaluated the effects of positive end-expiratory pressure (PEEP) on the respiratory mechanical properties and hemodynamics of 10 postoperative adult cardiac patients undergoing mechanical ventilation while still anesthetized and paralyzed. The respiratory mechanics was evaluated by the inflation inspiratory occlusion method and hemodynamics by conventional methods. Each patient was randomized to a different level of PEEP (5, 10 and 15 cmH2O), while zero end-expiratory pressure (ZEEP) was established as control. PEEP of 15-min duration was applied at 20-min intervals. The frequency dependence of resistance and the viscoelastic properties and elastance of the respiratory system were evaluated together with hemodynamic and respiratory indexes. We observed a significant decrease in total airway resistance (13.12 ± 0.79 cmH2O l-1 s-1 at ZEEP, 11.94 ± 0.55 cmH2O l-1 s-1 (P<0.0197) at 5 cmH2O of PEEP, 11.42 ± 0.71 cmH2O l-1 s-1 (P<0.0255) at 10 cmH2O of PEEP, and 10.32 ± 0.57 cmH2O l-1 s-1 (P<0.0002) at 15 cmH2O of PEEP). The elastance (Ers; cmH2O/l) was not significantly modified by PEEP from zero (23.49 ± 1.21) to 5 cmH2O (21.89 ± 0.70). However, a significant decrease (P<0.0003) at 10 cmH2O PEEP (18.86 ± 1.13), as well as (P<0.0001) at 15 cmH2O (18.41 ± 0.82) was observed after PEEP application. Volume dependence of viscoelastic properties showed a slight but not significant tendency to increase with PEEP. The significant decreases in cardiac index (l min-1 m-2) due to PEEP increments (3.90 ± 0.22 at ZEEP, 3.43 ± 0.17 (P<0.0260) at 5 cmH2O of PEEP, 3.31 ± 0.22 (P<0.0260) at 10 cmH2O of PEEP, and 3.10 ± 0.22 (P<0.0113) at 15 cmH2O of PEEP) were compensated for by an increase in arterial oxygen content owing to shunt fraction reduction (%) from 22.26 ± 2.28 at ZEEP to 11.66 ± 1.24 at PEEP of 15 cmH2O (P<0.0007). We conclude that increments in PEEP resulted in a reduction of both airway resistance and respiratory elastance. These results could reflect improvement in respiratory mechanics. However, due to possible hemodynamic instability, PEEP should be carefully applied to postoperative cardiac patients.

Respiratory mechanics and morphometric changes during anesthesia with ketamine in normal rats

Ketamine is believed to reduce airway and pulmonary tissue resistance. The aim of the present study was to determine the effects of ketamine on the resistive, elastic and viscoelastic/inhomogeneous mechanical properties of the respiratory system, lungs and chest wall, and to relate the mechanical data to findings from histological lung analysis in normal animals. Fifteen adult male Wistar rats were assigned randomly to two groups: control (N = 7) and ketamine (N = 8). All animals were sedated (diazepam, 5 mg, ip) and anesthetized with pentobarbital sodium (20 mg/kg, ip) or ketamine (30 mg/kg, ip). The rats were paralyzed and ventilated mechanically. Ketamine increased lung viscoelastic/inhomogeneous pressure (26%) compared to the control group. Dynamic and static elastances were similar in both groups, but the difference was greater in the ketamine than in the control group. Lung morphometry demonstrated dilation of alveolar ducts and increased areas of alveolar collapse in the ketamine group. In conclusion, ketamine did not act at the airway level but acted at the lung periphery increasing mechanical inhomogeneities possibly resulting from dilation of distal airways and alveolar collapse.

Effect of asthma severity on symptom perception in childhood asthma

Individual ability to perceive airway obstruction varies substantially. The factors influencing the perception of asthma are probably numerous and not well established in children. The present study was designed to examine the influence of asthma severity, use of preventive medication, age and gender on the association between respiratory symptoms (RS) and peak expiratory flow (PEF) rates in asthmatic children. We followed 92 asthmatic children, aged 6 to 16 years, for five months. Symptom scores were recorded daily and PEF was measured twice a day. The correlations among variables at the within-person level over time were analyzed for each child and for the pooled data by multivariate analysis. After pooling the data, there was a significant (P<0.05) correlation between each symptom and PEF; 60% of the children were accurate perceivers (defined by a statistically significant correlation between symptoms and PEF across time) for diurnal symptoms and 37% for nocturnal symptoms. The accuracy of perception was independent of asthma severity, age, gender or the use of preventive medication. Symptom perception is inaccurate in a substantial number of asthmatic children, independently of clinical severity, age, gender or use of preventive medication. It is not clear why some asthmatic patients are capable of accurately perceiving the severity of airway obstruction while others are not.

Exhaled nitric oxide collected with two different mouthpieces: a study in asthmatic patients

Techniques for collecting exhaled nitric oxide (ENO) recommend the use of antibacterial filters of 0.3 µm. The aim of the present study was to compare the measurements of ENO obtained with two different filtering devices. Air samples from 17 asthmatic and 17 non-asthmatic subjects were collected by a recommended off-line technique using two different mouthpieces: 1) the Sievers disposable tool (A) under a breathing pressure of 18 cmH2O, and 2) a mouthpiece containing a HEPA filter (B) under a breathing pressure of 12 cmH2O. The nitric oxide samples were collected into an impermeable reservoir bag. Values for ENO were compared using two-way repeated measures ANOVA followed by the Tukey test. Agreement was assessed by Bland-Altman analysis. ENO values obtained with mouthpieces A and B were comparable for asthmatic (mean ± SEM, 42.9 ± 6.9 vs 43.3 ± 6.6 ppb) and non-asthmatic (13.3 ± 1.3 vs 13.7 ± 1.1 ppb) subjects. There was a significant difference in ENO between asthmatics and non-asthmatics using either mouthpiece A (P<0.001) or B (P<0.001). There was a positive correlation between mouthpiece A and mouthpiece B for both groups. The Bland-Altman limits of agreement were considered to be acceptable. Mouthpiece B was less expensive than A, and these data show that it can be used without compromising the result. Our data confirm reports of higher ENO values in the presence of airway inflammation.

Pulmonary function, cholinergic bronchomotor tone, and cardiac autonomic abnormalities in type 2 diabetic patients

This prospective study analyzed the involvement of the autonomic nervous system in pulmonary and cardiac function by evaluating cardiovascular reflex and its correlation with pulmonary function abnormalities of type 2 diabetic patients. Diabetic patients (N = 17) and healthy subjects (N = 17) were evaluated by 1) pulmonary function tests including spirometry, He-dilution method, N2 washout test, and specific airway conductance (SGaw) determined by plethysmography before and after aerosol administration of atropine sulfate, and 2) autonomic cardiovascular activity by the passive tilting test and the magnitude of respiratory sinus arrhythmia (RSA). Basal heart rate was higher in the diabetic group (87.8 ± 11.2 bpm; mean ± SD) than in the control group (72.9 ± 7.8 bpm, P<0.05). The increase of heart rate at 5 s of tilting was 11.8 ± 6.5 bpm in diabetic patients and 17.6 ± 6.2 bpm in the control group (P<0.05). Systemic arterial pressure and RSA analysis did not reveal significant differences between groups. Diabetes intragroup analysis revealed two behaviors: 10 patients with close to normal findings and 7 with significant abnormalities in terms of RSA, with the latter subgroup presenting one or more abnormalities in other tests and clear evidence of cardiovascular autonomic dysfunction. End-expiratory flows were significantly lower in diabetic patients than in the control group (P<0.05). Pulmonary function tests before and after atropine administration demonstrated comparable responses by both groups. Type 2 diabetic patients have cardiac autonomic dysfunction that is not associated with bronchomotor tone alterations, probably reflecting a less severe impairment than that of type 1 diabetes mellitus. Yet, a reduction of end-expiratory flow was detected.

Factors associated with penicillin-nonsusceptible pneumococcal infections in Brazil

Resistance of Streptococcus pneumoniae is a worldwide, growing problem. Studies of factors associated with resistance to penicillin have not been conducted in Brazil. The objective of the present study was to evaluate factors associated with infection by S. pneumoniae not susceptible to penicillin. A prevalence study was conducted including all patients with a positive culture for S. pneumoniae in a hospital from July 1991 to December 1992 and the year 1994. Of 165 patients identified, 139 were considered to have clinically relevant infections and 88% of them had invasive infections. All infections were community acquired and consisted of pneumonia (44%) and of central nervous system (19%), pelvic or abdominal (12%), upper airway or ocular (12%), primary bloodstream (9%) and skin and soft tissue (5%) infections. Mortality was 25%. Susceptibility to penicillin was present in 77.6% of the isolates; 21.8% were relatively resistant, and one isolate was resistant (minimal inhibitory concentration = 4 µg/ml). Multivariate analysis showed that age below 4 years (odds ratio (OR): 3.53, 95% confidence interval (95%CI): 1.39-8.96) and renal failure (OR: 5.50, 95%CI: 1.07-28.36) were associated with lack of susceptibility to penicillin. Bacteremia occurred significantly less frequently in penicillin-nonsusceptible infections (OR: 0.34, 95%CI: 0.14-0.84), possibly suggesting that lack of penicillin susceptibility is associated with lower virulence in S. pneumoniae.

Role of immunoglobulin E and mast cells in murine models of asthma

Immunoglobulin E (IgE) and mast cells are believed to play important roles in allergic inflammation. However, their contributions to the pathogenesis of human asthma have not been clearly established. Significant progress has been made recently in our understanding of airway inflammation and airway hyperresponsiveness through studies of murine models of asthma and genetically engineered mice. Some of the studies have provided significant insights into the role of IgE and mast cells in the allergic airway response. In these models mice are immunized systemically with soluble protein antigens and then receive an antigen challenge through the airways. Bronchoalveolar lavage fluid from mice with allergic airway inflammation contains significant amounts of IgE. The IgE can capture the antigen presented to the airways and the immune complexes so formed can augment allergic airway response in a high-affinity IgE receptor (FcepsilonRI)-dependent manner. Previously, there were conflicting reports regarding the role of mast cells in murine models of asthma, based on studies of mast cell-deficient mice. More recent studies have suggested that the extent to which mast cells contribute to murine models of asthma depends on the experimental conditions employed to generate the airway response. This conclusion was further supported by studies using FcepsilonRI-deficient mice. Therefore, IgE-dependent activation of mast cells plays an important role in the development of allergic airway inflammation and airway hyperresponsiveness in mice under specific conditions. The murine models used should be of value for testing inhibitors of IgE or mast cells for the development of therapeutic agents for human asthma.

The role of chemokines and chemokine receptors in eosinophil activation during inflammatory allergic reactions

Chemokines are important chemotactic cytokines that play a fundamental role in the trafficking of leukocytes to sites of inflammation. They are also potent cell-activating factors, inducing cytokine and histamine release and free radical production, a fact that makes them particularly important in the pathogenesis of allergic inflammation. The action of chemokines is regulated at the level of agonist production and processing as well as at the level of receptor expression and coupling. Therefore, an analysis of the ligands must necessarily consider receptors. Eosinophils are target cells involved in the allergic inflammatory response since they are able to release a wide variety of mediators including CC and CXC chemokines and express their receptors. These mediators could damage the airway epithelial cells and might be important to stimulate other cells inducing an amplification of the allergic response. This review focuses on recently emerging data pertaining to the importance of chemokines and chemokine receptors in promoting eosinophil activation and migration during the allergic inflammatory process. The analysis of the function of eosinophils and their chemokine receptors during allergic inflammation might be a good approach to understanding the determinants of asthma severity and to developing novel therapies.

A comparison of public and private obstructive sleep apnea clinics

The aim of the present study was to compare the clinical findings and polysomnography results obtained at public and private clinics in Brazil, the follow-up after diagnosis, and the therapeutic aspects related to continuous positive airway pressure. Patients who snore and who have obstructive sleep apnea were retrospectively divided into two groups, i.e., public clinic (N = 307) and private clinic (N = 317). Data concerning age, sex, body mass index (BMI), neck circumference, medical history, sleepiness scale, follow-up after diagnosis, and acceptance of continuous positive airway pressure therapy were collected. Mean age was 50 ± 12 (range: 15-80) for public patients and 48 ± 12 years (range: 19-91) for private patients. Mean BMI was 30 ± 6 (range: 19-67) for public patients and 31 ± 6 kg/m² (range: 21-59) for private patients. The public clinic had a significantly higher frequency of women than the private clinic (M:F ratio of 2.0:1 and 6.9:1, respectively). The condition of private patients (apnea-hypopnea index = 31 ± 25) was more severe than that of public patients (apnea-hypopnea index = 25 ± 24 events/h; P = 0.0004). In the public and private clinics, 19 and 15% of patients were snorers, respectively, and 81 and 85% of them had sleep apnea. After diagnosis, follow-up was longer in the private group. The continuous positive airway pressure acceptance was similar for both groups (32 vs 35%), but patients from the public clinic abandoned treatment more than private ones (65 vs 13%). Social status was significant in terms of the severity of obstructive sleep apnea age and gender distribution. Private patients look for a diagnosis earlier in the course of the disease than public patients, adhere more to follow-up, and abandon continuous positive airway pressure treatment less than public patients do.

Patient and physician evaluation of the severity of acute asthma exacerbations

We studied the ability of patients not experienced in the use of peak expiratory flow meters to assess the severity of their asthma exacerbations and compared it to the assessment of experienced clinicians. We also evaluated which data of physical examination and medical history are used by physicians to subjectively evaluate the severity of asthma attacks. Fifty-seven adult patients (15 men and 42 women, with a mean (± SD) age of 37.3 ± 14.5 years and 24.0 ± 17.9 years of asthma symptoms) with asthma exacerbations were evaluated in a University Hospital Emergency Department. Patients and physicians independently evaluated the severity of the asthma attack using a linear scale. Patient score, physician score and forced expiratory volume at the first second (FEV1) were correlated with history and physical examination variables, and were also considered as dependent variables in multiple linear regression models. FEV1 correlated significantly with the physician score (rho = 0.42, P = 0.001), but not with patient score (rho = 0.03; P = 0.77). Use of neck accessory muscles, expiratory time and wheezing intensity were the explanatory variables in the FEV1 regression model and were also present in the physician score model. We conclude that physicians evaluate asthma exacerbation severity better than patients and that physician's scoring of asthma severity correlated significantly with objective measures of airway obstruction (FEV1). Some variables (the use of neck accessory muscles, expiratory time and wheezing intensity) persisted as explanatory variables in physician score and FEV1 regression models, and should be emphasized in medical schools and emergency settings.

Effect of salbutamol on pulmonary responsiveness in chronic pulmonary allergic inflammation in guinea pigs

Beta-2-agonists have been widely used by asthmatic subjects to relieve their obstructive symptoms. However, there are reports that continuous use could lead to loss of bronchial protection and exacerbation of asthma symptoms. We evaluated the effect of two regimens of salbutamol administration (twice and five times a week) in a model of chronic airway inflammation in male Hartley guinea pigs (protocol starting weight: 286 ± 30 g) induced by repeated exposures to aerosols of ovalbumin (OVA). After sensitization, guinea pigs were exposed to aerosols of 0.1 mg/ml salbutamol solution twice a week (OVA + S2x, N = 7) or five times a week (OVA + S5x, N = 8). We studied allergen-specific (OVA inhalation time) and -nonspecific (response to methacholine) respiratory system responsiveness. Seventy-two hours after the last OVA challenge, guinea pigs were anesthetized and tracheostomized, respiratory system resistance and elastance were measured and a dose-response curve to inhaled methacholine chloride was obtained. Specific IgG1 was also quantified by the passive cutaneous anaphylactic technique. OVA-sensitized guinea pigs (N = 8) showed reduction of the time of OVA exposure before the onset of respiratory distress, at the 5th, 6th and 7th exposures (P < 0.001). The OVA + S2x group (but not the OVA + S5x group) showed a significant increase in OVA inhalation time. There were no significant differences in pulmonary responsiveness to methacholine among the experimental groups. OVA + S2x (but not OVA + S5x) animals showed a decrease in the levels of IgG1-specific anaphylactic antibodies compared to the OVA group (P < 0.05). Our results suggest that, in this experimental model, frequent administration of ß2-agonists results in a loss of some of their protective effects against the allergen.

Heterotopic transplantation of glycerin-preserved trachea: effect of respiratory epithelium desquamation on acute rejection

An effective preservation method and decreased rejection are essential for tracheal transplantation in the reconstruction of large airway defects. Our objective in the present study was to evaluate the antigenic properties of glycerin-preserved tracheal segments. Sixty-one tracheal segments (2.4 to 3.1 cm) were divided into three groups: autograft (N = 21), fresh allograft (N = 18) and glycerin-preserved allograft (N = 22). Two segments from different groups were implanted into the greater omentum of dogs (N = 31). After 28 days, the segments were harvested and analyzed for mononuclear infiltration score and for the presence of respiratory epithelium. The fresh allograft group presented the highest score for mononuclear infiltration (1.78 ± 0.43, P <= 0.001) when compared to the autograft and glycerin-preserved allograft groups. In contrast to the regenerated epithelium observed in autograft segments, all fresh allografts and glycerin-preserved allografts had desquamation of the respiratory mucosa. The low antigenicity observed in glycerin segments was probably the result of denudation of the respiratory epithelium and perhaps due to the decrease of major histocompatibility complex class II antigens.