Gene expression profiling of human lung tissue from smokers with severe emphysema

The mechanism by which inhaled smoke causes the anatomic lesions and physiologic impairment of chronic obstructive pulmonary disease remains unknown. We used high-density microarrays to measure gene expression in severely emphysematous lung tissue removed from smokers at lung volume reduction surgery (LVRS) and normal or mildly emphysematous lung tissue from smokers undergoing resection of pulmonary nodules. Class prediction algorithms identified 102 genes that accurately distinguished severe emphysema from non-/mildly emphysematous lung tissue. We also defined a number of genes whose expression levels correlated strongly with lung diffusion capacity for carbon monoxide and/or forced expiratory volume at 1 s. Genes related to oxidative stress, extracellular matrix synthesis, and inflammation were increased in severe emphysema, whereas expression of endothelium-related genes was decreased. To identify candidate genes that might be causally involved in the pathogenesis of emphysema, we linked gene expression profiles to chromosomal regions previously associated with chronic obstructive pulmonary disease in genome-wide linkage analyses. Unsupervised hierarchical clustering of the LVRS samples revealed distinct molecular subclasses of severe emphysema, with body mass index as the only clinical variable that differed between the groups. Class prediction models established a set of genes that predicted functional outcome at 6 mo after LVRS. Our findings suggest that the gene expression profiles from human emphysematous lung tissue may provide insight into pathogenesis, uncover novel molecular subclasses of disease, predict response to LVRS, and identify targets for therapeutic intervention.     

Lung transplantation in patients with pulmonary emphysema

Lung transplantation is a viable option for patients with chronic obstructive pulmonary disease (COPD), and emphysema is the most common indication to undergo lung transplantation. A total of seven lung and one heart-lung transplantations were performed between July 1996 and June 2004 at the Yongdong Severance Hospital, and herein, three emphysema patients who underwent single lung transplantations are reviewed. There were 2 males and 1 female, with a mean age of 50 years (35, 57 and 58 years). They all underwent an operation, without cardiopulmonary bypass, and there was no operative mortality. The mean survival was 12 months (4 months, 15 months and 17 months) and all succumbed to death due to activation of pulmonary tuberculosis, post-transplantation lymphoproliferative disease and cytomegalovirus (CMV) gastritis associated with asphyxia. Infection was the most common postoperative complication, resulting in longer hospital stays, higher medical expenses and shorter survival rates, necessitating aggressive prophylactic management. The accumulation of experience, modifications to operative procedures and perioperative care may lead to improved early and long-term survival in patients with emphysema undergoing single or bilateral lung transplantations.     

Differential diagnosis of persistent interstitial emphysema and other cystic lesions of the lung

Neonatal interstitial emphysema (IE) may develop as a complication of the respiratory distress syndrome. IE is classified as acute and persistent and as diffuse and local forms. The differential diagnosis of persistent IE and congenital cystic malformations from clinical and imaging data may present problems. The histological pattern of persistent IE has specific features that permit the morphological diagnosis of this condition.     

Chromosomal abnormalities in bronchial epithelium from smokers, nonsmokers, and lung cancer patients

The identification of individuals who are at greatest risk of developing lung cancer would greatly improve diagnosis and possibly lead to early treatment. To study the use of karyotypes for this purpose, we used short-term human bronchial epithelial (hBE) cell cultures from nonsmokers, smokers, and lung cancer patients. Twenty-five metaphases were scored for hBE cell cultures obtained from 32 patients: 8 were nonsmokers, and 24 had a history of smoking (of whom 11 had had lung cancer surgery). The number of abnormal metaphases ranged from 0 to 4 per cell culture. No overall differences in the number of abnormal metaphases were observed between nonsmokers and smokers or between lung cancer patients and non-lung cancer patients. The most commonly observed abnormalities were structural changes in chromosome 1 (six cultures), loss of chromosome 17 (six cultures), and trisomy of chromosome 20 (three cultures). These specific alterations were found almost exclusively in patients with a history of tobacco smoking. The results did not indicate that general chromosomal abnormalities are a useful marker for tobacco smoke exposure or cancer risk.     

Characterization of the interstitial lung and peripheral blood T cell receptor repertoire in cigarette smokers

T lymphocytes modulate the pulmonary inflammatory response. The aim of this study was to evaluate the clonality within the interstitial lung and peripheral blood T cell receptor (TCR) repertoire in smokers. Interstitial T lymphocytes were isolated from surplus tissue of 16 patients (63 +/- 9 [+/- SD] yr old, 11 male) undergoing surgery due to lung cancer (n = 15) or emphysema. TCR clonality was assessed by PCR amplification followed by spectratyping. Nearly all TCR of interstitial lung lymphocytes showed oligoclonal bands (CD4(+) subset 13/16 patients, 81%; CD8(+) 100%) indicating a specific differentiation. Peripheral blood T lymphocytes (PBL) TCR (especially CD4(+)) had less oligoclonal bands (CD4(+) 31%, CD8(+) 88%). Likewise, more oligoclonal bands were seen in lung TCR (total of 168 bands; 37 CD4(+); 131 CD8(+)), compared with 59 bands in PBL TCR (13 CD4(+); 46 CD8(+)). Intraindividual comparison revealed a more prominent difference in TCR oligoclonality between lung and blood in CD8(+) T cells (median of difference lung minus blood 5; interquartile range 1-10; P = 0.002) compared with CD4(+) T cells (median 2, 0-3, P = 0.039). Thus, TCR oligoclonality is preferentially found in the CD8(+) T cell subset, most distinctive in the lung. These findings indicate a specific interstitial T cell differentiation in response to local stimuli.     

Lung reflexes in anaesthetized rabbits with elastase-induced emphysema

The effects of elastase-induced emphysema on vagal pulmonary reflexes were studied in seven rabbits, given 600 IU of porcine pancreatic elastase intratracheally (E group), and eight untreated rabbits (U group) under pentobarbital anaesthesia. The presence of emphysema was confirmed by histological and pathological criteria and by documented changes in lung mechanics seven months after treatment. The strength of the Hering-Breuer inflation reflex (HBIR), indicative of pulmonary stretch receptor excitability, was unchanged in the U group, but was significantly increased in the E group at inflation volumes greater than the tidal volume (VT) range, as she slope of the curve relating HBIR to inflation volume was significantly steeper (0.40 vs 0.22 ml-1; p less than 0.05). The early ventilatory response (first 3 breaths) to right atrial injections of phenyldiguanide (20 and 30 micrograms X kg-1 i.v.) was used as an indication of the excitability of lung receptors with non-myelinated vagal afferents. This response, characterized by a significant decrease in expiratory duration (TE) without effect on VT or inspiratory time (TI), was not significantly different between the E and U groups. The overall pattern of breathing in the E group showed a significant decrease in VT associated with an increase in TI.     

A computerized analysis system in chest radiography: Evaluation of interstitial lung abnormalities

We evaluated the usefulness of a computerized analysis system in the detection of interstitial lung abnormalities in digitized chest radiography. This system uses the processes of four-directional Laplacian-Gaussian filtering, linear opacity judgment, and linear opacity subtraction. For qualitative analysis, we employed a combined radiographic index, which was calculated from two normalized radiographic indices obtained by linear opacity judgment and subtraction of linear opacities. We selected 50 regions of interest (ROIs) in patients with mild interstitial lung abnormalities, 50 ROIs in patients with severe interstitial lung abnormalities, and 50 ROIs in individuals with normal lung parenchyma. High-resolution computed radiography (HRCT) findings were used as the standard of reference for this study. These ROIS were processed by our computerized analysis system, and radiographic indices were obtained from each ROI. The area under the receiver operating characteristic curve (Az) was used as the measure of performance. The combined radiographic index provided better results in the mild interstitial lung abnormality group (Az=0.94±0.02), but it also yielded good results in the severe interstitial lung abnormality group (Az=0.98±0.01). These results indicate that this system of combining radiographic indices has improved the detection performance over that with our previous system.     

Detection of interstitial lung abnormalities on picture archive and communication system video monitors

The purpose of this study was to compare the detection of interstitial lung abnormalities on video display workstation monitors between radiologists experienced with video image interpretation and radiologists who lack this experience. Twenty-four patients with interstitial lung abnormalities documented by high-resolution computed tomography (HRCT) and lung biopsy, and 26 control patients with no history of pulmonary disease or a normal HRCT and normal chest radiographs were studied. Images were acquired using storage phosphor digital radiography and displayed on 1,640×2,048 pixel resolution video monitors. Five board-certified radiologists evaluated the images in a blinded and randomized manner by using a six-point presence of abnormality grading scale. Three radiologists were from 1 to 4 years out of residency and considered to be experienced workstation monitor readers with between 1 to 3 years of video monitor image interpretation. For the inexperienced readers, one radiologist had no prior experience with reading images from a video monitor and was direct out of residency, and the other radiologist had less than 4 months of intermittent exposure and was 1 year out of residency. Sensitivity and specificity were determined for individual readers. Positive predictive values, negative predictive values, accuracy, and receiver-operating curves were alsoggenerated. A comparison was made between experienced and inexperienced readers. For readers experienced with video monitor image interpretation, the sensitivity ranged from 87.5% to 92%, specificity from 69% to 92%, positive predictive value (PPV) from 73% to 87.5%, negative predictive value (NPV) from 87% to 90%, and accuracy from 80% to 88%. For inexperienced readers, these values were sensitivity 58%, specificity 50% to 65% PPV 52% to 61%, NPV 56.5% to 63%, and accuracy 54% to 62%. Comparing image interpretation between experienced and inexperienced readers, there were statistically significant differences for sensitivity (P<.01), specificity (P<.01), PPV (P<.05), NPV (P<.05), accuracy (P<.05), and area under the receiver operator curve (Az) (P<.01). Within the respective experienced and inexperienced groups, no statistical significant differences were present. Our results show that digitally acquired chest radiographs displayed on high-resolution workstation monitors are adequate for the detection of interstitial lung abnormalities when the images are interpreted by radiologists experienced with video image interpretation. Radiologists inexperienced with video monitor image interpretation, however, cannot reliably interpret images for the detection of interstitial lung abnormalities.     

手工缝合肺残面施行肺减容手术治疗重度肺气肿

目的 探讨手工缝合肺残面方法肺减客手术治疗重度慢性阻塞性肺气肿的疗效。方法 本组肺减容手术20例，其中双侧肺减容6例，单侧肺减容14倒。切口的选择依据手术切除靶区的位置，其中平卧位正中切口、双侧LVRS1例，侧卧住后外侧开胸LVRS14侧，前外侧开胸LVRS11侧。术前及术后6月查肺功能（FEV1，TLC，RV）、动脉血气分析、6分钟步行距离进行对比。结果 本组无手术死亡，患者术后肺功能指标比术前有明显改善（P〈0．05），动脉血氧分压术后比术前明显提高（P〈0．05），二氧化碳分压术后比术前明显降低（P〈0．05）；呼吸困难指数再分级，15例术前3级中6例转为1级，9例转为2级；5例4级中1例转为3级，3例转为2级，1例转为1级。结论 重度肺气肿病人行肺减容手术，能改善患者肺功能，提高生活质量。     

Rabbit lung plasma and erythrocyte volumes. Lung hematocrit in relation to total body hematocrit

The total body hematocrit has been reported to be 85–90% of packed cell volume (PCV) in several species. We have found similar values in rabbits. An “extra” plasma volume must exist somewhere in the vascular bed to explain this observation. We have looked for such an extra plasma volume in the pulmonary vasculature. The dynamic hematocrit was estimated in isolated, perfused rabbit lungs from distribution volumes for plasma and erythrocyte tracers. Estimation was also obtained from indicator-dilution curves using bolus-injections of such tracers avoiding their recirculation. It was thus possible to calculate mean transit times for the tracers from their dilution curves directly or applying monoexponential extrapolation from the first part of the downslope of the curves. The dynamic hematocrit of the lung vessels was about 94% of perfusate PCV and there was no difference between the results obtained by the different methods. We concluded that in the rabbit only a very small part of the extra plasma volume is located in the lung vessels. The lung plasma volume is not underestimated by the indicator-dilution technique.     

Rabbit lung plasma and erythrocyte volumes. Lung hematocrit in relation to total body hematocrit.

The total body hematocrit has been reported to be 85--90% of packed cell volume (PCV) in several species. We have found similar values in rabbits. An "extra" plasma volume must exist somewhere in the vascular bed to explain this observation. We have looked for such an extra plasma volume in the pulmonary vasculature. The dynamic hematocrit was estimated in isolated, perfused rabbit lungs from distribution volumes for plasma and erythrocyte tracers. Estimation was also obtained from indicator-dilution curves using bolus-injections of such tracers avoiding their recirculation. It was thus possible to calculate mean transit times for the tracers from their dilution curves directly or applying monoexponential extrapolation from the first part of the downslope of the curves. The dynamic hematocrit of the lung vessels was about 94% of perfusate PCV and there was no difference between the results obtained by the different methods. We concluded that in the rabbit only a very small part of the extra plasma volume is located in the lung vessels. The lung plasma volume is not underestimated by the indicator-dilution technique.     

Lung collagen synthesis and deposition in tight-skin mice with genetic emphysema.

The tight-skin (Tsk) mouse is a genetic model of pulmonary emphysema linked to a deficiency of serum antielastase. In this mouse occurrence of connective tissue abnormalities in various organs (systemic scleroderma) has been reported. The aim of the present work was to study lung collagen synthesis and deposition in Tsk mice. No differences in the collagen synthesis rate and morphology at the ultrastructural level were found in Tsk mice at birth. At 2 months of age, a marked increase in collagen was observed within the alveolar septa. At this time, an increased lung collagen synthesis, assessed by determining prolyl hydroxylase activity and incorporation of radiolabeled proline, was found in Tsk mice with respect to control mice. However, due to the ongoing parenchymal destruction, the values of total lung collagen at 6 and 12 months of age were only moderately but significantly increased with respect to those observed at 2 months. As a consequence, a progressive accumulation of lung collagen fibers was observed in the residual septa. The increase in collagen deposition was accompanied by a relative increase in type I collagen. Although the data in the literature would suggest a genetic cause for the lung collagen change in Tsk mice, the data presented here indicate that the change in lung collagen metabolism may be a part of a remodeling process taking place after lung destruction.     

Synthesis of lung collagen in hamsters with elastase-induced emphysema

Lung collagen was studied in hamsters which had been intratracheally instilled with elastase. Total and insoluble collagens in lungs among the elastase-instilled were higher than those of the age-matched controls and continued to be elevated even 4 months after the elastase-instillation. A transient increase in salt-soluble collagen during the period 6 to 20 days after the elastase-instillation was also found among the experimentals. Studies of incorporation of l-[¹⁴C]proline into lung collagen showed higher specific radioactivities in both hydroxyproline and collagen fractions as well as a many-fold increase in total radioactivities in collagen fractions of lungs among the elastase-instilled hamsters. The results indicated that collagen metabolism in hamster lungs was activated after the elastase-injury which led to an increase of collagen in lung.     

Hypoxemia in attack free asthmatic children: relationship with lung volumes and lung mechanics

In 113 asthmatic children (mean age +/- SD = 11.0 +/- 2.8 years), the presence of hypoxemia was evaluated during an attack free period. Blood gases were measured in arterialized blood samples. 71% of the patients were hypoxemic. Hypoxemia was defined as partial pressure of O2 (PaO2) below 90% of the mean value for normal children. In a first step, the relationship between hypoxemia and frequency of asthma attacks was examined: frequency of attacks appeared to be a poor predictor of hypoxemia in an attack free period. In a second step, the relationship between hypoxemia and 9 pulmonary function test variables was examined. The static lung volumes considered were: functional residual capacity (FRC: helium dilution technique); thoracic gas volume (TGV: body plethysmography technique) and trapped gases (TG: difference between TGV and FRC). TG was expressed as a percentage of 1) measured FRC (TG/FRCmeas), 2) measured TGV (TG/TGVmeas), 3) predicted FRC (TG/FRCpred). Lung mechanics variables were determined by the oesophageal catheter technique: lung resistance (RL) and dynamic lung compliance (CLdyn). RL and CLdyn were expressed 1) in absolute terms, 2) as a percentage of the index of distension (ID: TGV/FRCpred). All variables are expressed as a percentage of predicted values except for TG/FRCmeas and TG/TGVmeas. Considering lung volumes, hypoxemia was found when TG was present. When lung mechanics were altered, hypoxemia was also present. The relationship between PaO2 and PFT variables was best expressed by the following equation: PaO2 (%) = 85.393 + 0.121 CLdyn/ID--0.151 TG/FRCpred--0.026 RL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung volumes and diffusion capacity in sickle cell trait

Patients with sickle cell anemia have a restrictive ventilatory pattern, with reduction in diffusion capacity of the lung (DLco) and lung volumes. Diffusion capacity and lung volumes are reported as either normal or reduced in subjects with sickle cell trait. Thirteen subjects with sickle cell trait, age range 25 to 79 years, were compared with 13 normal subjects matched for age, sex, height, and smoking patterns. There was no significant difference in mean values of DLco or lung volume for the two groups. Neither was there a consistent difference for age-matched individuals. Normal lung function in sickle cell trait as opposed to sickle cell disease is probably related to the fact that the former have fewer, if any, pulmonary infectious and infarctive episodes.