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The stethoscope is used as first line diagnostic tool in assessment of patients with pulmonary symptoms. However, there is much debate about the diagnostic accuracy of this instrument. This meta-analysis aims to evaluate the diagnostic accuracy of lung auscultation for the most common respiratory pathologies. Studies concerning adult patients with respiratory symptoms are included. Main outcomes are pooled estimates of sensitivity and specificity with 95% confidence intervals, likelihood ratios (LRs), area under the curve (AUC) of lung auscultation for different pulmonary pathologies and breath sounds. A meta-regression analysis is performed to reduce observed heterogeneity. For 34 studies the overall pooled sensitivity for lung auscultation is 37% and specificity 89%. LRs and AUC of auscultation for congestive heart failure, pneumonia and obstructive lung diseases are low, LR- and specificity are acceptable. Abnormal breath sounds are highly specific for (hemato)pneumothorax in patients with trauma. Results are limited by significant heterogeneity. Lung auscultation has a low sensitivity in different clinical settings and patient populations, thereby hampering its clinical utility. When better diagnostic modalities are available, they should replace lung auscultation. Only in resource limited settings, with a high prevalence of disease and in experienced hands, lung auscultation has still a role.

Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL - SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL - SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) - SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL - SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA - SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To develop and test a method to noninvasively assess the functional lung microstructure., Materials and Methods: The Multiple exchange time Xenon polarization Transfer Contrast technique (MXTC) encodes xenon gas-exchange contrast at multiple delay times permitting two lung-function parameters to be derived: (i) MXTC-F, the long exchange-time depolarization value, which is proportional to the tissue to alveolar-volume ratio and (ii) MXTC-S, the square root of the xenon exchange-time constant, which characterizes thickness and composition of alveolar septa. Three healthy volunteers, one asthmatic, and two chronic obstructive pulmonary disease (COPD) (GOLD stage I and II) subjects were imaged with MXTC MRI. In a subset of subjects, hyperpolarized xenon-129 ADC MRI and CT imaging were also performed., Results: The MXTC-S parameter was found to be elevated in subjects with lung disease (P-value = 0.018). In the MXTC-F parameter map it was feasible to identify regional loss of functional tissue in a COPD patient. MXTC-F maps showed excellent regional correlation with CT and ADC (P ≥ 0.90) in one COPD subject., Conclusion: The functional tissue-density parameter MXTC-F showed regional agreement with other imaging techniques. The newly developed parameter MXTC-S, which characterizes the functional thickness of alveolar septa, has potential as a novel biomarker for regional parenchymal inflammation or thickening., (Copyright © 2011 Wiley-Liss, Inc.)

Objective: We prospectively examined the relationship between lung function and risk of type-2 diabetes and fatal and nonfatal coronary heart disease (CHD) events and investigated the hypothesis that inflammation may underlie these associations., Research Design and Methods: A prospective study of 4,434 men aged 40-59 years with no history of cardiovascular disease (CHD or stroke) or diabetes drawn from general practices in 24 British towns and followed up for 20 years., Results: There were 680 major CHD events (276 fatal, 404 nonfatal) and 256 incident type 2 diabetes during the 20 years follow-up. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) but not FEV(1)-to-FVC ratio were significantly and inversely associated with incident type 2 diabetes and fatal CHD events (not nonfatal events) after adjustment for age, potential confounders, and metabolic risk factors. The adjusted relative risk (RR) for type 2 diabetes (Quartile 1 vs. Quartile 4) were 1.59 (1.07-2.56) and 1.74 (1.16-2.61) for FVC and FEV(1), respectively (P = 0.03 and P = 0.04 for trend). The corresponding RR for fatal CHD were 1.48 (1.00-2.21) and 1.81 (1.19-2.76) (P = 0.002 and P = 0.0003 for trend). Lung function was significantly and inversely associated with C-reactive protein and interleukin-6; the inverse associations with type 2 diabetes for FVC and FEV(1) were attenuated after further adjustment for these factors (P = 0.14 and P = 0.11 for trend) but remained significant for fatal CHD (P = 0.03 and P = 0.01, respectively)., Conclusions: Restrictive rather than obstructive impairment of lung function is associated with incident type 2 diabetes (and fatal CHD) with both associations partially explained by traditional and metabolic risk factors and inflammation.

We aimed to evaluate the effects of smoking on the histopathology and the oxidant-antioxidant status of lungs and to test the effects of N-acetylcysteine (NAC) on the induced changes. Rabbits were exposed to cigarette smoke (CS) in a glass chamber for one hour daily for one month. An NAC control group was given intraperitoneal NAC only. CS + NAC rats were exposed to smoke and given intraperitoneal NAC. A control group was exposed to clean air only. At the end of one month, animals were sacrificed and lung tissues were examined histopathologically. Blood levels of protein sulfhydryls, carbonyls, prostaglandin F(2alpha) (PGF(2alpha)) and malondialdehyde (MDA) were measured. Intraparenchymal vascular congestion and thrombosis, intraparenchymal hemorrhage, respiratory epithelial proliferation, number of macrophages in the alveolar and bronchial lumen, alveolar destruction, emphysematous changes and bronchoalveolar hemorrhage scores were significantly increased in rabbits exposed to CS compared with the control group. Protein sulfhydryls were significantly decreased; carbonyls, PGF(2alpha) and MDA levels were significantly increased in the smoke exposed rabbits. Administration of NAC to rabbits exposed to CS caused a reduction in the bronchoalveolar hemorrhage score and blood PGF(2alpha) levels. Other parameters were unaffected by NAC. Exposure to CS causes severe histopathological changes and negatively effects the oxidant-antioxidant status in the lungs of rabbits. A low daily dose of NAC has some ameliorative effects on histopathological changes and oxidant-antioxidant status of the lungs in smoke exposed rabbits.

Background/purpose: In the last decades, several studies regarding cardiopulmonary sequelae in survivors of congenital diaphragmatic hernia (CDH) have been published, but results often are conflicting, and controversies still exist. The aim of this study was to assess cardiopulmonary anatomic and functional outcome in a group of long-term survivors of CDH of mild to moderate degree., Methods: Twenty-four children aged 8.15 +/- 2.80 years underwent clinical examination with growth assessment, chest radiographs, echocardiography, pulmonary perfusion scintigraphy, static lung volumes measurement, and spirometry., Results: Mean Z scores of weight for age and height for age were within normal values. Echocardiography showed normal anatomy and function in all but 3 patients with isolated CDH, in whom minor alterations were detected. Mean perfusion to the affected side was significantly lower (45.16 +/- 5.30%; P <.0001) but still within normal range. Four children showed a substantial impairment of perfusion to the hernia side. The mean spirometric values and pulmonary volumes were normal. However, a mild restrictive pattern was evident in 6 children (27.3%), an obstructive pattern in 3 (13.6%), and a mixed obstructive and restrictive impairment in 1., Conclusions: Hypoplastic lungs of mild to moderate CDH survivors continue to cause pulmonary morbidity in some children many years after the correction of the defect. In particular, lung perfusion appears to be impaired in 20% of the patients and pulmonary function in 45%, without any significant cardiac or developmental sequelae. The negative correlation between FEV1 and duration of ventilation at presentation (r = -0.49; P =.026) may be caused by the consequences of lung hypoplasia, but initial ventilatory management may contribute to increased pulmonary morbidity. Relationship between perfusion and FEF25-75 (r = 0.61; p = 0.004) could reflect an equivalent degree of reduction in the caliber of distal airways and pulmonary vascular tree.

The preoperative preparation program based upon the experience of treating 465 patients with acute pyonecrotizing diseases of lungs was developed. This system takes into account the stage of the disease (I--septic, II--stabilization, III--remission), endotoxicosis intensity and non respiratory activity of the affected lung (NRAL). The patients of the first group (I stage of the disease) with long-term subclavian vein catheterization were on the special scheme of NRAL correction, their supurative focuses being treated with electrized hypochlorite sodium solution. The system appeared to be effective in managing patients, in the first group--254 patients of which 202 (79,9%) were successfully treated without operation, as for the second group, there were only 52 (40,6%), in the third--26 (31,3%). By limiting and stabilizing the process, the effect of this preoperative preparation program was also seen in other patients. It allowed to perform less traumatic operations (lung resection) in 109 patients of the 179 operated on, with 8,7% of postoperative complications in 8,7% in the first group vers. 18,4% and 24,6% in the second and third, respectively. Thus the above mentioned results show the proposed system to be effective.

Asthma and chronic obstructive lung disease (COPD) are both inflammatory conditions of the lung associated with structural "remodeling" inappropriate to the maintenance of normal lung function. The clinically observed distinctions between asthma and COPD are reflected by differences in the remodeling process, the patterns of inflammatory cells and cytokines, and also the predominant anatomic site at which these alterations occur. In asthma the epithelium appears to be more fragile than that of COPD, the epithelial reticular basement membrane (RBM) is significantly thicker, there is marked enlargement of the mass of bronchial smooth muscle, and emphysema does not occur in the asthmatic nonsmoker. In COPD, there is epithelial mucous metaplasia, airway wall fibrosis, and inflammation associated with loss of surrounding alveolar attachments to the outer wall of small airways: bronchiolar smooth muscle is increased also. Emphysema is a feature of severe COPD: in spite of the destructive process, alveolar wall thickening and focal fibrosis may be detected. The hypertrophy of submucosal mucus-secreting glands is similar in extent in asthma and COPD. The number of bronchial vessels and the area of the wall occupied by them increase in severe corticosteroid-dependent asthma: it is likely that these increases also occur in severe COPD as they do in bronchiectasis. Pulmonary vasculature is remodeled in COPD. In asthma several of these structural alterations begin early in the disease process, even in the child. In COPD the changes begin later in life and the associated inflammatory response differs from that in asthma. The following synopsis defines and compares the key remodeling processes and proposes several hypotheses.

Airway epithelium represents the first line of defense against toxic inhalants. In some subjects, cigarette smoking causes airway inflammation, hypersecretion of mucus, and poorly reversible airflow limitation through mechanisms that are still largely unknown. Likewise, it is unclear why only some smokers develop chronic obstructive pulmonary disease (COPD). Two cell types consistently result in relation to chronic airflow limitation in COPD: neutrophils and CD8(+) cells. Neutrophils are compartmentalized in the mucosal surface of the airways and air spaces, that is, the epithelium and lumen, whereas CD8(+) cells exhibit a more extensive distribution along the subepithelial zone of the airways and lung parenchyma, including alveolar walls and arteries. This pattern of inflammatory cell distribution is observed in mild or moderate COPD, and in patients who have developed COPD, it is not modified by smoking cessation. The number of neutrophils further increases in the submucosa of patients with severe COPD, suggesting a role for these cells in the progression of the disease. Hypersecretion of mucus is a major manifestation in COPD. Mucus is produced by bronchial glands and goblet cells lining the airway epithelium. Unlike mucous gland enlargement, greater mucosal inflammation is associated with sputum production. Whereas neutrophil infiltration of submucosal glands occurs only in smokers with COPD, goblet cell hyperplasia in peripheral airways occurs both in smokers with or without COPD, suggesting that the major determinant of goblet cell hyperplasia is cigarette smoke itself.

Oxidative stress results from an oxidant/antioxidant imbalance in favour of oxidants. A large number of studies have demonstrated that increased oxidative burden occurs in airways diseases, shown by increased marks of oxidative stress in the airspaces and systemically in these patients. There is now substantial evidence that oxidative stress plays an important role in the injurious and inflammatory responses in airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). In addition to these proinflammatory mechanisms resulting from oxidative stress, protective mechanisms such as the upregulation of protective antioxidant genes also occur. At present, effective antioxidant therapy that has good bioavailability and potency is not available. Such drugs are being developed and should in the future allow the hypothesis that oxidative stress is a fundamental factor in the inflammation, which occurs in these airways diseases to be tested.

Objective: To evaluate the association among clinical signs, results of cytologic evaluation of bronchoalveolar lavage (BAL) fluid, and measures of pulmonary function in horses with inflammatory respiratory disease., Animals: 9 healthy horses, 5 horses with inflammatory airway disease (IAD), and 9 horses with chronic obstructive pulmonary disease (COPD)., Procedures: Clinical examination, lung function tests, and BAL were performed on each horse., Results: Standard lung mechanics of horses with exacerbated COPD differed significantly from those of healthy horses; however, there were few differences among horses with IAD, horses with COPD during remission, and healthy horses. Most variables for forced expiration (FE) in horses with COPD or IAD differed significantly from those for healthy horses. Results of clinical examination had low to moderate sensitivity and predictive values for a diagnosis of COPD (range, 67 to 80%). Results of FE tests had high sensitivity, specificity, and predictive values for a diagnosis of COPD (79 to 100%), and results of standard lung mechanics tests had low sensitivity and predictive values (22 to 69%). Percentage of neutrophils in BAL fluid was highly sensitive (100%) but moderately specific (64%) for a diagnosis of COPD., Conclusions and Clinical Relevance: Clinical examination is moderately accurate for establishing a diagnosis of COPD. Forced expiration tests can specifically detect early signs of airway obstruction in horses with COPD and IAD that may otherwise be inapparent. Cytologic evaluation of BAL fluid allows early detection of inflammatory respiratory disease, but it is not specific for COPD.

This paper reports a case of a 71-year-old pulmonary emphysema patient with neuropsychological impairments that were markedly improved 6 months after he underwent lung volume reduction surgery (LVRS). He also underwent pulmonary rehabilitation before and after surgery. He was suspected of having memory impairment and attention disorder when he was referred for rehabilitation. The neuropsychologic test showed a general cognitive impairment, attention disorder, and verbal memory impairment. Magnetic resonance imaging showed moderate atrophy of the left hippocampal area, cortex, and lacunae infarction in the periventricular area. Interestingly, scores of the neuropsychologic test, as well as severity of dyspnea and lung function, remarkably improved 6 months after LVRS. These results suggested that the neuropsychological impairments in pulmonary emphysema patients can be improved after lung reduction surgery.

It is not clear how airway pathology relates to the severity of airflow obstruction and increased bronchial responsiveness in cystic fibrosis (CF) patients. The aim of this study was to measure the airway dimensions of CF patients and to estimate the importance of these dimensions to airway resistance using a computational model. Airway dimensions were measured in lungs obtained from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1), or autopsy (n=4). These dimensions were compared to those of airways from lobectomy specimens from 72 patients with various degrees of chronic obstructive pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were introduced into a computational model to study their effect on airway resistance. The inner wall and smooth muscle areas of peripheral CF airways were increased 3.3- and 4.3-fold respectively compared to those of COPD airways. The epithelium was 53% greater in height in peripheral CF airways. The sensitivity and maximal plateau resistance of the computed dose/response curves were substantially increased in the CF patients compared to COPD patients. The changes in airway dimensions of cystic fibrosis patients probably contribute to the severe airflow obstruction, and to increased bronchial responsiveness, in these patients.

Background: A central feature in the pathogenesis of COPD is the inflammation coexisting with an abnormal protease/antiprotease balance. However, the possible role of different serine and metalloproteinases remains controversial., Patients and Measurements: We examined the expression of gelatinases A and B (matrix metalloproteinase [MMP]-2 and MMP-9); collagenases 1, 2, and 3 (MMP-1, MMP-8, and MMP-13); as well as the presence of apoptosis in lung tissues of 10 COPD patients and 5 control subjects. In addition, gelatinase-A and gelatinase-B activities were assessed in BAL obtained from eight COPD patients, and from six healthy nonsmokers and six healthy smoker control subjects., Setting: Tertiary referral center and university laboratories of biochemistry, and lung cell kinetics., Results: Immunohistochemical analysis of COPD lungs showed a markedly increased expression of collagenases 1 and 2, and gelatinases A and B, while collagenase 3 was not found. Neutrophils exhibited a positive signal for collagenase 2 and gelatinase B, whereas collagenase 1 and gelatinase A were revealed mainly in macrophages and epithelial cells. BAL gelatin zymography showed a moderate increase of progelatinase-A activity and intense bands corresponding to progelatinase B. In situ end labeling of fragmented DNA displayed foci of positive endothelial cells, although some alveolar epithelial, interstitial, and inflammatory cells also revealed intranuclear staining., Conclusion: These findings suggest that there is an upregulation of collagenase 1 and 2 and gelatinases A and B, and an increase in endothelial and epithelial cell death, which may contribute to the pathogenesis of COPD through the remodeling of airways and alveolar structures.

Objective: To correlate clinical score, intrapleural pressure, cytologic findings of bronchoalveolar lavage fluid (BALF), and histologic lesions of pulmonary tissue in horses affected with summer pasture-associated obstructive pulmonary disease (SPAOPD)., Animals: 8 adult horses affected with SPAOPD and 6 adult horses without evidence of respiratory tract disease., Procedure: Clinical score, change in intrapleural pressure (deltaPpl) during tidal breathing, results of cytologic examination and bacteriologic culture of BALF, and results of histologic examination of pulmonary parenchyma were evaluated., Results: Clinical scores for SPAOPD-affected horses (median, 5.75; range, 4.0 to 7.5) were significantly greater, compared with clinically normal horses (median, 2.0; range, 2.0 to 3.0). Cytologic examination of BALF from SPAOPD-affected horses revealed predominantly nondegenerate neutrophils. Histologic lesions were identified throughout pulmonary tissue and included severe accumulation of mucus and neutrophils within the small airways, metaplasia of bronchiolar goblet cells, and mild peribronchial infiltrate. Histologic examination of specimens collected via percutaneous biopsy was predictive of disease and corresponded to findings at postmortem examination. Clinical score and deltaPpl were highly correlated with mucus accumulation in the airways of affected horses. Peribronchial inflammatory infiltrate correlated with percentage of neutrophils in BALF of affected horses., Conclusions and Clinical Relevance: Clinical scoring and deltaPpl provided valid estimates of disease severity. Findings from cytologic examination of BALF of SPAOPD-affected horses varied, although, in most instances, it was diagnostically useful. Severe mucus accumulation in the airways was the most remarkable histopathologic finding in SPAOPD-affected horses. Examination of biopsy specimens collected from pulmonary parenchyma was consistently useful in diagnosing SPAOPD.

Background and Objectives: We evaluated the size and configuration of the trachea in patients with chronic obstructive pulmonary disease (COPD; n = 35) on high-resolution computed tomography (HRCT) images and compared them with those of healthy volunteers (n = 24)., Methods: Using a newly developed computed method for analyzing the digital data of HRCT, the size and configuration of the trachea were automatically evaluated., Results: The size of the trachea of the COPD subjects was the same as that of the control subjects; however, the configuration was more distorted in the COPD patients. There was no difference in the tracheal index (TI), which is the ratio of the coronal to the sagittal length, between these two groups; however, the ratio of the short to the long radius (SR/LR) was significantly smaller in the COPD group than in the control group. There was a significant correlation between SR/LR and airflow limitation as assessed by pulmonary function tests in the COPD group., Conclusions: The SR/LR is a better index of tracheal deformity than the classical TI. This deformity is not a consequence secondary to hyperinflation or emphysematous change of the lung, because the low attenuation area of the lung was not correlated with SR/LR., (Copyright 2000 S. Karger AG, Basel)

The present study was designed to evaluate the bronchodilating role of zafirlukast, a CysLT(1)receptor antagonist, at the standard dosage currently recommended in the marketing of this agent in smokers with COPD. The study was performed using a double-blind, cross-over, randomized design and was conducted on 2 non-consecutive days. Sixteen outpatients suffering from stable COPD received 40 mg oral zafirlukast, or placebo. Lung function was controlled before drug administration and 30, 60, 120, 180, 240 min thereafter. At the end of the 4-h period, each patient received 400 microg inhaled salbutamol and spirometric testing was performed 30 min later. Zafirlukast, but not placebo, produced a significant (P<0.05) bronchodilation between 30 min and 4 h following administration, with a maximum mean increase in FEV(1)of 0.134 l (11.2%) above baseline after 2 h. Nine of 16 patients showed an increase in FEV(1)of at least 15% above baseline after zafirlukast. The maximum mean increase in FEV(1)after zafirlukast in these subjects, who were considered responders, observed after 2 h, was 0.221 (19.4%). The mean difference of post-salbutamol FEV(1)values after zafirlukast and placebo (-0.036 l) was not significant (P<0.05). In responders, the mean of differences in pre- and post-salbutamol FEV(1)values after zafirlukast was 0.077 l, whereas the mean of differences between post-salbutamol values after zafirlukast and those after placebo was -0.064 l. The mean AUC(0-4 h)for all patients was 0.121 l for placebo and 0.385 l for zafirlukast. The difference between the placebo and zafirlukast AUC(0-4 h)was significant (P<0.05). The individual FEV(1)AUC(0-4 h)after zafirlukast were higher than those after placebo in 12 out of 16 patients. These findings suggest that cysteinyl leukotrienes might be one of the causes of persistent bronchoconstriction in COPD, at least in several smokers, but do not confirm the hypothesis that the effects of zafirlukast and salbutamol are independent and additive., (Copyright 2000 Academic Press.)

Objective: To study the roles of apoptosis and proliferation and relative genes expression in chronic obstructive pulmonary disease (COPD) and pulmonary hypertension., Methods: Immunohistochemical technique was used for the detection of cell proliferation and expression of relative genes. In situ end labeling technique was used for the detection of nucleosomal DNA fragmentation of apoptotic cells, and Northern blot for the detection of expression of c-myc, bcl-2 and p53 genes in the lungs with COPD., Results: Both proliferative cells and apoptotic cells were found in the lungs with COPD or without COPD. In lung tissue with COPD. The proliferation index was increased significantly, whereas the apoptosis index was decreased significantly. Compared with controls, the ratio of proliferation to apoptosis in lungs with COPD was increased by 4 folds, and the expression of c-myc or bcl-2 mRNA was significantly increased by 2.5-3 folds in lungs tissue with COPD. The expression of c-myc and bcl-2 protein was also increased significantly in lungs with COPD, the two antigen were predominantly localized in small pulmonary vessels. The expression of p53 mRNA was significantly decreased by 3 folds in lung tissue with COPD., Conclusion: The abnormality of apoptosis versus proliferation activities induced by c-myc, bcl-2 and p53 genes may contribute to pulmonary vascular structural remodeling in COPD.

To investigate whether the inflammatory process in peripheral airways is different in smokers who develop symptoms of chronic bronchitis and chronic airflow limitation and in asymptomatic smokers who do not develop chronic airflow limitation, we examined surgical specimens obtained from 16 smokers undergoing lung resection for localized pulmonary lesions. Nine had symptoms of chronic bronchitis and chronic airflow limitation and seven were asymptomatic with normal lung function. In peripheral airways, immunohistochemical methods were performed to identify neutrophils, macrophages, CD4+ and CD8+ T-lymphocytes infiltrating the airway wall, and morphometric methods were used to measure the internal perimeter, the airway wall area, and the smooth muscle area. The number of CD8+ T-lymphocytes and the smooth muscle area were increased in smokers with symptoms of chronic bronchitis and chronic airflow limitation as compared with asymptomatic smokers with normal lung function, while the number of neutrophils, macrophages, and CD4+ T-lymphocytes were similar in the two groups of subjects examined. We concluded that smokers who develop symptoms of chronic bronchitis and chronic airflow limitation have an increased number of CD8+ T-lymphocytes and an increased smooth muscle area in the peripheral airways as compared with asymptomatic smokers with normal lung function, supporting the important role of CD8+ T-lymphocytes and airway remodeling in the pathogenesis of chronic obstructive pulmonary disease.

We have determined that fractal analysis of the alveolar perimeter (Df) changes with aging in human lung tissue in twenty-nine patients, age range of 25 hours to 76 years, who died of non-respiratory related causes. There was a very significant difference (p = 0.0004) in Df between the young (less than 16 years old, N = 9, mean Df of 1.047 [0.01]) and adult (greater than 16 years old, N = 20, mean Df of 1.093 [0.013]) groups. Furthermore, there was a significant difference in Df between the Adult group and the group of patients who died of chronic obstructive pulmonary disease (COPD, N = 10) (p = 0.012). Additionally, the Df values for the COPD and cystic fibrosis (CF, N = 5) groups were virtually identical; 1.061 and 1.070, respectively. Regression analysis showed a significant (p = 0.0041) exponential relationship with a correlation coefficient of 0.59 between aging and Df. We have demonstrated that the correlation between Df and aging in humans is an exponential function and that the end-stage pulmonary diseases of COPD and CF decrease Df.

The purpose of this study was to describe the 3He MRI findings of normal pulmonary ventilation in healthy volunteers and to evaluate abnormalities in patients with different lung diseases. Hyperpolarized 3He gas (300 ml, 3 x 10(5) Pa, polarized to 35-45% by optical pumping, provided in special glass cells) was inhaled by 8 healthy volunteers and 10 patients with different lung diseases. Imaging was performed with a three-dimensional fast low-angle shot (FLASH) sequence (TR = 11.8 msec; TE = 5 msec; transmitter amplitude, 5-8 V; corresponding flip angle, < 5 degrees) in a single breath-hold (22-42 seconds). Clinical and radiological examinations were available for correlation. The studies were performed successfully in eight of eight volunteers and in 8 of 10 patients. The lung parenchyma of volunteers with normal ventilatory function exhibited rather homogeneous intermediate to high signal, whereas patients with chronic obstructive lung disease or bronchiectasis presented with severe signal inhomogeneities with patchy or wedge-shaped defects. The mass effect of bronchogenic carcinoma, chronic empyema, lymphadenopathy, or pleural effusion caused large signal defects, representing the lesion and adjacent hypoventilation, the extent of which had not been presumed from chest x-ray or CT. 3He MRI is a promising new modality for the assessment of pulmonary ventilation and its abnormalities. Additional studies are needed to determine its potential clinical role.

Background: A study was performed to determine the elastic equilibrium volume (Vr) of the respiratory system in patients with chronic obstructive pulmonary disease (COPD)., Methods: Voluntary relaxed expiration from total lung capacity (TLC) was studied in three groups of subjects: seven patients with severe chronic airways obstruction (COPD), 10 normal subjects, and 15 subjects with restrictive disease., Results: In the normal subjects and the patients with restrictive disease voluntary relaxed expiration from TLC stopped close to end tidal volume (FRC) and the volume expired in this manoeuvre was less than that expired in a slow vital capacity manoeuvre (SVC). In the patients with COPD the voluntary relaxed expiration continued beyond the end tidal volume (FRC) and the volume expired was not different from the SVC. Oesophageal (pleural) pressures and surface diaphragmatic EMG recordings in the patients with COPD supported the premise that relaxation was achieved., Conclusions: In patients with COPD, end tidal volume (FRC) is higher than the elastic equilibrium volume, Vr, of the respiratory system. This is in contrast to patients with restrictive disease and normal subjects in whom end tidal volume (FRC) is close to Vr. This study shows that, in patients with severe chronic obstructive pulmonary disease, Vr is at least as small as residual volume (RV).

We used published data for the elastic properties of a 2-mm outer-diameter canine bronchus and assumed values for the thickness of the wall components and lung parenchymal shear modulus to estimate the load on airway smooth muscle and its effect on airway narrowing. The following relationships were calculated: (1) luminal and smooth muscle radii of curvature and transmural pressure; (2) the isovolume, transmural pressures developed by the smooth muscle to narrow the lumen at distending pressures of 20, 10, 5, and 2 cm H2O; (3) the equilibrium tension developed by, and thus the load on, the airway smooth muscle as a function of smooth muscle length during isovolume bronchoconstriction. From these calculations a smooth muscle length-tension diagram was drawn allowing the interactions between submucosal thickening, peribronchial thickening, load, and smooth muscle contractility to be analyzed. The analysis indicates that: (1) the load on smooth muscle decreases by more than an order of magnitude between a distending pressure of 20 and 2 cm H2O; (2) increasing smooth muscle contractility has more effect at large rather than at small distending pressures; (3) peribronchial inflammation decreases both load and the slope of the relationship between peribronchial and pleural pressures. Decreases in load may be an important mechanism producing excessive bronchoconstriction in asthma.

Purpose: Following percutaneous lung biopsy (PLB), we used fibrin glue as a sealant in 26 patients for the purpose of decreasing the incidence of pneumothorax., Methods: All 26 patients (group A) had chronic obstructive pulmonary disease (COPD). The results for group A were compared with a control group of 32 patients (group B), also with COPD and in whom fibrin glue was not used. All biopsies were conducted under computed tomography (CT) using a coaxial needle system consisting of 19-gauge and 22-gauge needles., Results: Pneumothorax developed in five patients (19.2%) in group A and in one instance, drainage was required (3.8%). In group B, pneumothorax developed in 13 patients (40.6%) and in six instances (18.8%) drainage was required. Comparing the use of chest-tube drainage in the two groups, a statistical significance was observed, p < 0.0025). No adverse reactions related to the fibrin glue were observed., Conclusion: Our results indicate that fibrin glue is a safe sealing material for lung PLB and serves to decrease the incidence and, in particular, the severity of pneumothorax, especially in high-risk patients.

Monodisperse aerosol particles can be used to assess noninvasively intrapulmonary airspace dimensions. Since emphysematic changes in the peripheral lung are difficult to detect with most of the common lung function tests, aerosol-derived airway morphometry was used to assess the peripheral airspace dimensions (EAD800) in 25 patients with COPD and in 36 healthy volunteers. Spirometric and body plethysmographic measurements were performed in all patients. In ten patients, high-resolution CT-derived mean lung density (MLD) was additionally assessed. In healthy subjects, EAD800 was 0.39 +/- 0.05 mm. In patients, EAD800 was significantly increased (0.82 +/- 0.33 mm). In a subset of nine patients with severe alpha 1-antitrypsin deficiency and clinically severe emphysema, EAD800 was even larger (1.14 +/- 0.32 mm). In patients, EAD800 correlated with MLD (r = 0.82), diffusion capacity (DCO) (r = 0.78), and FEV1 (r = -0.75). Since MLD is considered a valid indicator for lung emphysema, the close correlation between EAD800 and MLD suggests that EAD800 reflects enlarged peripheral airspace dimensions in patients with emphysema.

Airway wall remodeling in asthma and chronic obstructive pulmonary disease (COPD) can have a profound effect on the function of the airways. We tested the hypothesis that airflow obstruction and estimates of peripheral airway inflammation correlate with airway wall thickness and the amount of bronchial smooth muscle in cartilaginous airways. In addition, we estimated the theoretical relation between airway dimensions and airway resistance with a computational model. Lung tissue was obtained from 72 patients with different degrees of COPD who were operated on for a solitary peripheral lung lesion. In 341 transversely cut cartilaginous airway sections we measured airway size and airway wall dimensions. Inflammatory changes from the same lungs were scored in noncartilaginous airways. Preoperatively measured maximum expiratory flows and the response to a bronchodilator were correlated with airway wall dimensions. Maximum expiratory flow, the reversibility of airflow obstruction, and peripheral airway inflammation were significantly related to the airway wall area but not to the smooth muscle area. We conclude that airflow obstruction and its reversibility in COPD is in part caused by thickening of the cartilaginous airway wall and is related to inflammatory changes.

A retrospective analysis of lung signal intensity normalized for fat and lung cross-sectional area normalized for body surface area was obtained from cardiac gated spin-echo (echo time 40 ms) images before and after single-lung transplantation in 12 patients with pulmonary airway disease (seven emphysema, two bronchiectasis and three obliterative bronchiolitis) and 14 with interstitial lung disease (three pulmonary fibrosis, four fibrosing alveolitis and seven lymphangioleiomyomatosis). Nine healthy volunteers were studied for comparison. The native lung in pulmonary airway disease without inflammatory processes has normalised signal intensity (79 +/- 12%) similar to that of the control (100 +/- 6%) while interstitial lung disease had a higher normalised signal intensity (172 +/- 33%; P = < 0.05). The transplanted lung had a similar normalised signal intensity (103 +/- 12%) to that of the control except when there was a rejection reaction (one patient) or infection (two patients). Compared with the control, the native lung was smaller in pulmonary fibrosis (50 +/- 8%) and fibrosing alveolitis (78 +/- 8%), while larger in lymphangioleiomyomatosis (136 +/- 6%) and pulmonary airway disease (165 +/- 8%). The cross-sectional area of the transplanted lung was comparable to that of the control (100 +/- 13%). Distinctive features of lung normalised signal intensity and cross-sectional area were demonstrated in patients with pulmonary airway disease and interstitial lung disease before lung transplantation. These measurements could be useful noninvasive indices for assessment of the transplanted lung and for frequent follow-up of patients without exposure to ionizing radiation. Future developments are required to enhance lung signal sufficiently to detect less severe diseases.

Autopsy lungs from 10 patients with various types of chronic obstructive pulmonary disease were submitted to morphometry and computer-aided three-dimensional reconstruction of airways to study, by the former technique, the severity and the site of obstruction in the bronchioles and to visualize, by the latter, how far the whole airway bed was involved. The site of obstruction in the bronchioles was shown to be different between diffuse panbronchiolitis and bronchobronchiolitis obliterans. There was also a case where the entire bronchiolar tree was mildly but uniformly stenosed with mucous hypersecretion, chronic inflammation, and fibrosis, a pattern considered to correspond to small airways disease. Thus, the combination of the above techniques proved to be useful in studying the state of the airway bed in chronic obstructive pulmonary disease, a task not accessible by the usual microscopic examination of a single lung section.

In chronic obstructive pulmonary disease, obscurities remain in the degree of obstruction and its distribution in the airway tree. To overcome these obscurities, a technique was introduced to estimate the original diameter of an airway in lung sections; this technique involved measurement of the accompanying artery. Ordinary lungs had been obtained at autopsy from 17 deceased patients of various ages; from these lungs, 695 pairs of airways and pulmonary arteries were subjected to computer-assisted measurement of their diameters: the whole range of airways from the segmental bronchi to the respiratory bronchioles was sampled. We proved that a log-log regression existed between the diameter of an airway and that of the pulmonary artery; this regression was sufficiently close to allow one to estimate the diameter of an airway from the diameter of the pulmonary artery, even in chronic obstructive pulmonary disease, in which airways are usually strongly stenosed or dilated. In an additional study of three lungs with various types of chronic obstructive pulmonary disease, the diameters of the pulmonary arteries were shown to remain essentially unaffected.

Recent investigations suggest that airway wall remodelling and chronic airflow obstruction are almost always associated with increased pulmonary neuroendocrine (NE) cells and increased levels of bombesin-like peptides (BLPs), particularly among cigarette smokers. In contrast, most normal subjects and even smokers who do not develop airflow obstruction do not exhibit such airway wall remodelling, increased NE cells, or increased BLP levels. The hypothesis forwarded, therefore, is that NE cells and BLPs may play a role in the pathogenesis of airway wall remodelling and chronic airflow obstruction.

Background: Cigarette smoking produces an inflammatory response in the airways of everyone but only 15-20% of smokers develop airways obstruction. The present study concerns the relative importance of peripheral airways inflammation and the emphysematous destruction of the parenchymal support of the airways in the pathogenesis of this obstruction., Methods: A total of 407 patients with a diagnosis of lung tumour performed pulmonary function tests a day or two before a lung or lobar resection. The specimens were fixed in inflation and analysed at the gross and microscopic level to determine the extent and severity of the emphysematous process, the number of alveoli supporting the outer walls of the airways, and the average distance between alveolar walls. The severity of the inflammatory process in the respiratory and nonrespiratory bronchioles was also assessed using a previously established grading system., Results: The lung function test showed that a decline in FEV1 was associated with an increase in residual volume and a decrease in the diffusing capacity for carbon monoxide and a reduction in the lung maximum elastic recoil pressure. The prevalence of grossly visible emphysema increased as FEV1 declined, but the extent and severity of these lesions and the number of alveoli supporting the outer walls of the peripheral airways was similar at all levels of FEV1. The system used to grade inflammatory response in the peripheral airways failed to identify a specific defect responsible for the physiological abnormalities., Conclusion: The reduction in FEV1 associated with chronic cigarette smoking can be partially explained by loss of lung elastic recoil pressure which reduces the force driving air out of the lung. This loss of elastic recoil pressure is attributed to microscopic enlargement of the air spaces rather than to grossly visible emphysema. The exact nature of the lesions responsible for the peripheral airways obstruction remains to be identified.

A numerical single path model of respiratory gas exchange with distributed alveolar gas sources was used to estimate the anatomical changes in small peripheral airways such as occur in chronic obstructive pulmonary diseases (COPD). A previous sensitivity analysis of the single path model showed that decreasing total acinar airway cross-sectional area by an area reduction factor, R, results in computed gas expirograms with Phase III steepening similar to that observed in COPD patients. From experimental steady state CO2 washout data recorded from six healthy subjects and six COPD patients, optimized area reduction factors for the single path model were found that characterize peripheral airway anatomy for each subject. Area reduction factors were then combined with measured functional residual capacity data to calculate the normalized peripheral airspace diameters in a given subject, relative to the airspace diameters in the generations of an idealized standard lung. Mean area reduction factors for the patient subgroup were 63% of those for the healthy subgroup, which is related to the gas transport limitation observed in disease. Mean airspace sizes for the patient subgroup were 235% of the healthy subgroup, which characterizes the increase in size and reduction in number of peripheral airspaces due to tissue erosion in emphysema. From these results, the air-phase diffusive conductance in COPD patients was calculated to be 32% of the mean value in the healthy subjects. These findings correlated well with standard pulmonary function test data for the patients and yield the recovery of acinar airway information from gas washout by combining the single path model with experimental measurements.

Critical to an understanding of the pulmonary disease in cystic fibrosis (CF) and the development of effective gene therapies is a definition of the distribution and regulation of CF gene expression in adult human lung. Previous studies have detected the product of the CF gene, the CF transmembrane conductance regulator (CFTR), in submucosal glands of human bronchi. In this report, we have characterized the distribution of CFTR RNA and protein in the distal airway and alveoli of human lungs. Samples from eight human lungs were analyzed for CFTR expression by in situ hybridization and immunocytochemistry. CFTR was detected in a subpopulation of epithelial cells at every level of the distal lung, including proximal, terminal, and respiratory bronchioles, and the alveoli. However, there was substantial variation in the level of CFTR expression between samples. In bronchioles, CFTR protein localized to the apical plasma membrane and was found primarily in a subpopulation of nonciliated cells. CFTR was expressed in the same distribution as the Clara cell marker CC10 in proximal bronchioles, however, expression was discordant in the more distal bronchioles and alveoli where CC10 was not detected. These studies suggest that epithelial cells of the distal lung may play a primary role in the pathogenesis of CF as well as expand the spectrum of target cells that should be considered in the development of gene therapies.

BACKGROUND--Smoking related fixed airway obstruction may be due to airway scarring and narrowing or decreased support due to loss of adjacent alveolar walls. In this study of resected specimens, preoperative pulmonary function was compared with results of a morphometric study of lung structure. METHODS--Morphometric measurements were made on 42 inflation fixed lung specimens as follows: airspace wall surface area per unit volume (AWUV) was measured on at least 25 l mm2 histological fields from each specimen, expressed as a mean, and the mean of the lowest five measurements for each case (LF5). Minimum diameter, maximum diameter, diameter ratio (ellipticality), lumen area, and lumen circumference were measured on at least 16 non-respiratory bronchioles from each lung. Peribronchiolar alveolar support was measured as mean interalveolar attachment distance (IAAD). Measurements of pulmonary function included forced expiratory volume in one second (FEV1) (absolute and % predicted values; n = 42), slope of phase III (single breath nitrogen test; n = 28), closing volume (expressed as a percentage of vital capacity (CV/VC%); n = 28). RESULTS--Bronchiolar size was not independently related to the tests of lung function used. Percentage predicted FEV1 was related to mean IAAD, ellipticality, and mean AWUV. CV/VC% showed significant relation with ellipticality, mean AWUV, and LF5 AWUV. Slope of phase III increased with increasing IAAD. Significant correlations were found between ellipticality and AWUV (mean and LF5), and between ellipticality and IAAD. Both IAAD and ellipticality were significantly increased in patients with abnormally low FEV1. CONCLUSION--Destruction of airspace walls, particularly those attached to the peripheral bronchioles, is more influential in determining airflow limitation than bronchiolar size.

Previous studies have shown that bronchoalveolar lavage fluid from horses with allergic respiratory disease and showing clinical symptoms contains increased numbers of neutrophils. In some cases, the eosinophil count is also increased. In this study the time course of changes in lung function and the accumulation of radiolabelled leucocytes and platelets in the lungs of allergic and normal horses has been examined during a 7 hr allergen exposure. Antigen challenge had no effect on pleural pressure or the distribution of radiolabelled neutrophils, eosinophils or platelets in normal horses. In contrast, in 6/8 allergic horses, there was an increase in pleural pressure and neutrophil accumulation in the lungs, both of which were evident after 4-5 hr. However, during the 7 hr challenge period radiolabelled eosinophils were detected in the lungs of only 1/6 horses exhibiting an increase in pleural pressure and in 1/7 horses that failed to show a change in airway function despite a clinical history of allergic respiratory disease. Antigen challenge did not alter the distribution of radiolabelled platelets in the five allergic horses tested. These results demonstrate that increased pleural pressure is not accompanied by eosinophil or platelet accumulation in the lungs of horses with allergic respiratory disease following exposure to antigen. However, changes in airway function can be associated with neutrophil accumulation but can also take place in the absence of this cell recruitment. This raises the possibility that the presence of neutrophils in the lung is not a prerequisite for changes in lung function.

We report two patients with systemic necrotizing vasculitis (microscopic polyarteritis) and associated recurrent pulmonary capillaritis, in whom progressive irreversible airway dysfunction began approximately 10 yr after disease onset. Their course was characterized by repeated episodes of diffuse alveolar hemorrhage, glomerulonephritis, palpable purpura, and splinter hemorrhages. The lung revealed intraalveolar hemorrhage, neutrophilic infiltration and cellular fragmentation, fibrinoid necrosis of the alveolar interstitium, and parenchymal hemosiderin deposits. No medium-sized vessel involvement, granulomatous inflammation, or bronchiolar obliteration were seen. Renal biopsies revealed focal segmental necrotizing glomerulonephritis, and a cutaneous biopsy in one case showed a leukocytoclastic vasculitis. Immunofluorescent studies of lung and kidney showed minimal or no immunoreactivity. The clinical course and serologic tests did not support another systemic vasculitis, connective tissue disease, or antiglomerular basement membrane antibody disease. The acute episodes responded to antiinflammatory and immunosuppressive therapy. Symptoms, serial pulmonary function tests, and chest imaging documented the development of a progressive irreversible obstructive airway disease. No other predisposing factors were identified. These cases demonstrate the unexpected appearance of an irreversible obstructive airway disease with lung parenchymal hyperinflation after systemic necrotizing vasculitis associated with recurrent pulmonary capillaritis and diffuse alveolar hemorrhage.

A comparison was made of the cellular and molecular components of bronchoalveolar lavage fluid (BALF) harvested from the left and right diaphragmatic lobes, the accessory lobe of the right lung and the apical lobe of the left lung, of seven control horses and six horses with symptomatic chronic obstructive pulmonary disease (COPD). Neither control nor symptomatic COPD affected horses showed significant regional differences in BALF recovery volumes, total and differential BALF cell counts, albumen adjusted total and absolute BALF cell counts, total and absolute pulmonary epithelial lining fluid (PELF) cell counts, and BALF albumen and urea concentrations. This suggests that the composition of PELF is uniform throughout the lungs of normal horses and horses with symptomatic COPD and that a single BALF sample is representative of the entire lung in these horses.

The aim of this study was to determine the effect of surfactant treatment on the number and distribution of inflammatory cells in bronchoalveolar lavage fluid (BALF) from mechanically ventilated preterm infants over the first week of life in relation to the subsequent development of chronic lung disease (CLD). The study included 25 babies who received surfactant on clinical grounds and 29 babies of similar severity who did not. BALF was collected on days 1, 3, 5, and 7 after birth. Cell counts were performed and differentials were calculated on 300 cells. CLD was equally common in both treatment groups. Of the 54 infants, 29 (53%) who developed CLD had a higher incidence of patent ductus arteriosus and air leak and needed a higher concentration of inspired oxygen on the fifth and seventh days of life. Babies who developed CLD had more polymorphonuclear leucocytes and fewer macrophages on days 5 and 7 than those who recovered. Surfactant treatment was associated with a higher total white cell count on day 3. Between days 3 and 7, macrophage numbers were higher in surfactant treated babies, whatever the pulmonary outcome. This data suggests that CLD was associated with persistence of high numbers of polymorphonuclear leucocytes in BALF at the end of the first week. Surfactant treatment caused a persistent increase in macrophage numbers. The association between persistent neutrophilia and CLD was unaffected by surfactant treatment.

A commercial radioimmunoassay kit was used to quantify histamine concentrations of plasma, bronchoalveolar lavage fluid (BALF) and pulmonary epithelial lining fluid (PELF) of normal horses and horses with chronic obstructive pulmonary disease (COPD), before and after 'natural (hay and straw) challenge' (NC). There were no significant changes in the concentrations of histamine in plasma or BALF at 0.5 or 5 h after NC, but the PELF histamine concentration of COPD affected horses was significantly increased at 5 h, but not at 0.5 h, following NC. As the histamine concentrations of whole BALF lysates were significantly correlated with the numbers of metachromatically staining cells, presumed to be mast cells and/or basophils, these findings support involvement of a late phase, IgE mediated, hypersensitivity reaction in the pathogenesis of equine COPD.

Lung tissue from 20 patients undergoing resection for a peripheral carcinoma was studied using monoclonal antibodies to identify inflammatory cell types in the peripheral airways and to determine the location of the bronchial-associated lymphoid tissue (BALT). The patients were grouped according to their percent predicted FEV1 (%FEV1) into obstructed (%FEV1 less than 80%) and control (%FEV1 greater than 80%). The resected lungs were filled with dilute cryoembedding media (Tissue-Tek R), frozen over liquid nitrogen, sliced into 2-cm sagittal slices using a band saw, and sampled using a cork bore. Ten serial histologic sections cut from these samples were stained with monoclonal antibodies for specific inflammatory cell types, which were counted and expressed per square millimeter of airway wall area. The results showed that the patients with airway obstruction had more B-lymphocytes in the airway adventitia than did the control subjects (p less than 0.001) and that the number of submucosal polymorphonuclear leukocytes is related to the amount smoked (p less than 0.02). They also show the BALT has a different distribution in human than in rodent lungs in that the lymphoid collections are found in the outer walls of the airway rather than in the submucosa.