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PubMed2006

Quantitative thin-section CT analysis of the enlargement and coalescence of low-attenuation clusters in patients with emphysema.

BACKGROUND: The analysis of the number and size of low-attenuation clusters has been adopted as quantitative computed tomography (CT) analysis of emphysema; however, a detailed examination has not been made on the relation between the number of various cluster sizes and the extent of emphysema. OBJECTIVE: The aim of this study was to evaluate the relationship between the size and number of clusters on CT scans in patients with emphysema. METHODS: This retrospective study included 31 emphysema patients. The number (LAN) and mean size (LAS) of clusters below -950 HU, and relative low-attenuation area below -950 HU (RA950) were calculated using an image-processing program. The size of clusters was divided into 3 categories, and the number in each size category was obtained as follows: small (sLAN 0.4-8 mm(2)), medium (mLAN 8.4-40 mm(2)), and large (lLAN >40 mm(2)). The relationships between the RA950 and sLAN, mLAN, or lLAN were evaluated. Patients were divided according to the extent of RA950 (>25% = severe emphysema, <25% = mild emphysema), and the relations between RA950 and LAN, and between RA950 and sLAN, mLAN, or lLAN were evaluated. RESULTS: The sLAN decreased as RA950 increased (r = -0.477), whereas mLAN and lLAN increased (r = 0.421, and r = 0.819). In severe emphysema, sLAN and mLAN decreased as RA950 increased (r = -0.722, and r = -0.698). In mild emphysema, mLAN and lLAN increased as RA950 increased (r = 0.732, and r = 0.972). CONCLUSIONS: The degree of the coalescence of the clusters depends on the size of clusters and the extent of emphysema. Quantitative CT analyses of clusters are helpful to elucidate the pathophysiology and progressive nature of emphysema.

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PubMed1989

Comparison of single breath carbon monoxide diffusing capacity and pressure-volume curves in detecting emphysema.

To evaluate the sensitivity of diffusing capacity (DLCO) and pressure-volume (P-V) curves in the detection of emphysema, these tests were compared with pathologic assessment of emphysema in patients undergoing lung resection for a localized tumor, and with the overall extent of emphysema as assessed by computed tomography (CT). The resected lung specimens were fixed in the inflated state and cut at 1-cm intervals in the horizontal plane. The pathologic extent of emphysema was quantitated by comparison with a standard reference panel of emphysema grading. The overall extent of emphysema on CT was assessed by a visual scoring system in a total of 55 patients, 19 undergoing lung resection and 36 not undergoing lung resection. Analysis of 37 patients by pathology scores revealed 18 with no or trivial emphysema (emphysema grades less than or equal to 5; mean grade, 2.2 +/- SD 2.6) and 19 with emphysema (grades greater than or equal to 10; mean grade, 33.2 +/- SD 24.2). Diffusing capacity, the ratio of DLCO to alveolar volume (DLCO/VA), maximal lung elastic recoil (PLmax), and lung elastic recoil at 90% of total lung capacity (PL90) were significantly different between the two groups, whereas K (the exponential constant describing the shape of the P-V curve) was not. The pathology grade of emphysema showed a significant correlation with (DLCO) (r = -0.53) and DLCO/VA (r = -0.55), which was greater than the correlation with PLmax (r = -0.42) and PL90 (r = -0.43).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2005

Hepatocyte and keratinocyte growth factors and their receptors in human lung emphysema.

BACKGROUND: Hepatocyte and keratinocyte growth factors are key growth factors in the process of alveolar repair. We hypothesized that excessive alveolar destruction observed in lung emphysema involves impaired expression of hepatocyte and keratinocyte growth factors or their respective receptors, c-met and keratinocyte growth factor receptor. The aim of our study was to compare the expression of hepatocyte and keratinocyte growth factors and their receptors in lung samples from 3 groups of patients: emphysema; smokers without emphysema and non-smokers without emphysema. METHODS: Hepatocyte and keratinocyte growth factor proteins were analysed by immunoassay and western blot; mRNA expression was measured by real time quantitative polymerase chain reaction. RESULTS: Hepatocyte and keratinocyte growth factors, c-met and keratinocyte growth factor receptor mRNA levels were similar in emphysema and non-emphysema patients. Hepatocyte growth factor mRNA correlated negatively with FEV1 and the FEV1/FVC ratio both in emphysema patients and in smokers with or without emphysema. Hepatocyte and keratinocyte growth factor protein concentrations were similar in all patients' groups. CONCLUSION: The expression of hepatocyte and keratinocyte growth factors and their receptors is preserved in patients with lung emphysema as compared to patients without emphysema. Hepatocyte growth factor mRNA correlates with the severity of airflow obstruction in smokers.

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PubMed2002

Classification of emphysema in candidates for lung volume reduction surgery: a new objective and surgically oriented model for describing CT severity and heterogeneity.

OBJECTIVE: To elaborate a surgically oriented and objective model for classification of emphysema heterogeneity. PATIENTS AND INTERVENTIONS: CT examinations of 66 candidates for lung volume reduction surgery. DESIGN: Emphysema severity was calculated by computer as the emphysema index (EI), a commonly used computer-based quantification that accurately assesses the extent of emphysema of a CT image. The distribution of the EI in different parts of each lung was illustrated in a diagram with the position in the lung (from cranial to caudal) on the x-axis and the EI on the y-axis. The slope of the fitted line was calculated. As a measure of the variation of the EI within each lung, the EI difference was calculated. RESULTS: A diagram was constructed with the absolute value of slope, k, on the x-axis and EI difference on the y-axis. This resulted in a diagram differentiating markedly heterogeneous, intermediately heterogeneous, and homogeneous emphysema. Nineteen patients fulfilled the criteria of bilateral markedly heterogeneous emphysema, 3 patients filled the criteria of bilateral intermediately heterogeneous emphysema, and 18 patients filled the criteria of bilateral homogeneous emphysema. Twenty-six patients had different types of emphysema in the right and left lung. CONCLUSION: We present a method for classification of emphysema heterogeneity that is (1) objective, (2) surgically oriented, and (3) classifies both lungs separately.

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PubMed2005

Emphysema: an autoimmune vascular disease?

We propose that an endogenous maintenance program controls lung cell turnover, apoptosis, and tissue repair, and that emphysema is a manifestation of the breakdown of the lung structure maintenance program. Emphysema can be induced experimentally in rats by three methods: blockade of vascular endothelial growth factor receptors using SU5416, a small molecule-tyrosine kinase inhibitor; methylprednisolone, which activates matrix metalloproteinase-9 and decreases Akt phosphorylation; and antibodies directed against endothelial cells (autoimmune emphysema). SU5416-induced emphysema is associated with lung induction of cytochrome P450 and oxidant stress, and a superoxide dismutase mimetic or N-acetylcysteine prevents this form of emphysema. A broad-spectrum metalloproteinase inhibitor prevents methylprednisolone-induced emphysema and, finally, autoimmune emphysema is associated with increased lung tissue metalloproteinase-9 expression and alveolar septal cell apoptosis. Athymic rats, which lack CD4+ T cells, are protected against autoimmune emphysema, whereas adoptive transfer of CD4+ T cells causes autoimmune emphysema in naive adult rats. It appears that vascular endothelial growth factor and signaling via its receptors plays a central role in the lung structural maintenance program, and oxidative stress, proteolysis, and apoptosis may coincide in the moment of lung cell destruction. Interestingly, the methylprednisolone model illustrates that inflammation is not necessary for the development of emphysema.

Animals↗

PubMed2004

[Diplopia and blepharoptosis associated with orbital emphysema following thoracotomy with lung cancer; report of a case].

BACKGROUND: Orbital emphysema is a common complication of trauma and fracture of orbital bones. However, subcutaneous emphysema also can rarely lead to orbital emphysema. We reported the clinical and radiological findings in a patient with diplopia and blepharoptosis following thoracotomy for lung cancer. CASE: A 76-year-old man had undergone left inferior lobectomy and ND 2 a in October 2002, based on the clinical diagnosis of stage IB lung squamous cell carcinoma. He presented with diplopia and blepharoptosis several days following thoracotomy. Chest X-ray demonstrated extensive subcutaneous emphysema, and physical examination also revealed diffuse subcutaneous emphysema including face and palpebrae. Head computed tomography (CT) revealed subcutaneous emphysema in the infratemporal fossa bilaterally. His diplopia and blepharoptosis gradually resolved, and he was discharged with no visual complaints on the fourteenth postoperative day. CONCLUSIONS: Subcutaneous emphysema can lead to diplopia and orbital emphysema in the absence of orbital trauma. Early surgical intervention for air leakage is highly recommended to avoid both the orbital emphysema and the visual complications in the event that subcutaneous emphysema should get to including face or palpebrae.

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PubMed2006

The presence of emphysema further impairs physiologic function in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Emphysema, especially in the upper lobes, is frequently observed in association with idiopathic pulmonary fibrosis (IPF). However, the combination of emphysema plus IPF has received little attention. OBJECTIVE: To investigate the additional functional impairment from emphysema in IPF patients. METHODS: Twenty-one patients (mean age 66 y, 20 men) (Group I) who had both IPF (mean 35% of total lung volume) and emphysema (mean 14% of total lung volume) were compared to a group of 21 subjects who had IPF but no emphysema (Group II). The groups were matched for (among other criteria) the total extent of disease. Pulmonary function tests, Medical Research Council dyspnea score, 6-min walk test, and radiographic extents of both IPF and emphysema were obtained for each patient. The Composite Physiologic Index was calculated. In the total population (n = 42), the independent contributions of IPF and emphysema to several physiologic variables were investigated by using stepwise multiple regression analysis. RESULTS: Despite the limited extent of emphysema, Groups I and II had similar physiologic impairment. Only residual volume and total lung capacity were significantly higher in Group I. According to stepwise multiple regression analysis, the extent of IPF and either the presence or the extent of emphysema in the total population were independent and significant predictors of dyspnea score, 6-min walk test, P(aO2), forced expiratory volume in the first second (FEV(1)), forced vital capacity (FVC), FEV1/FVC, the diffusing capacity of the lung for carbon monoxide, carbon monoxide diffusing capacity adjusted for alveolar volume (gas-transfer coefficient), and residual volume. The Composite Physiologic Index was closely related to the extent of IPF (r = 0.65, p < 0.0001) and to the dyspnea score (rho = 0.59, p < 0.0001). CONCLUSIONS: In former smokers with IPF, the presence and the extent of emphysema have a profound influence on physiologic function in terms of both further impairment and confounding effects.

Adult↗

PubMed1991

[Clinical and physiological features of chronic pulmonary emphysema with paroxysmal dyspnea attacks masquerading as bronchial asthma--improvement of respiratory function after combination therapy of intravenous aminophylline and subcutaneous epinephrine following daily oral administration of prednisolone].

Cases of chronic pulmonary emphysema accompanied with paroxysmal dyspnea attacks are often misdiagnosed as bronchial asthma. These patients repeatedly fall into a state of life-threatening respiratory failure. We must make an accurate diagnosis of emphysema to provide care of them. To clarify the possibility of doing this, we investigated the clinical and physiological features (primarily respiratory function) of emphysema. We observed twenty-five patients with chronic pulmonary emphysema and with chronic bronchial asthma, previously confirmed by selective alveolo-bronchogram (SAB); this technique reliably diagnoses emphysema, but often induces dyspnea attacks due to the stimulation resulting from intratracheal and intrabronchial procedures. In eight patients, chronic pulmonary emphysema was accompanied by an attack of paroxysmal wheezing and dyspnea; chronic pulmonary emphysema with wheezing (WPE). In eight other patients, chronic pulmonary emphysema was present without such attacks; usual pulmonary emphysema (UPE). In the final nine patients, chronic bronchial asthma (CBA) was present, while emphysema was ruled out by means of SAB. In all patients, we measured respiratory function before and after the combination therapy of intravenous aminophylline and subcutaneous epinephrine, which followed daily oral administration of prednisolone (PAE-treatment). In the WPE group, significant increases in measurement of various respiratory functions, including VC, RV, RV/TLC%, FVC, FEV1.0, PFR and V75 (p less than .05 excluded in FEV1.0 and PFR were p less than .01), were found after the PAE-treatment, compared with the values revealed before the treatment. In the UPE group, there were few changes PAE-treatment, compared with the values revealed before the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1991

The radiographic diagnosis of emphysema.

There are many findings of emphysema by conventional radiography, but the most reliable and reproducible is that of overinflation, which is best judged by the height and contour of the hemidiaphragm. Even in expert hands, the diagnosis of emphysema by conventional radiography is 65% to 80% accurate, depending to a large degree on the clinical population studied. Although most patients with severe emphysema are diagnosed correctly, only half of those patients with mild-to-moderate levels of parenchymal destruction are detected. Emphysema is identified by CT as focal, unmarginated, hypodense areas unassociated with fibrosis. Emphysema also may be detected by computer programs selecting pixels with abnormally low attenuation values. By either method, CT is superior to chest radiography in detection of mild and moderate degrees of emphysema and has detection rates of more than 90% and correlation with extent and severity of disease in more than 80% of patients. CT may be more sensitive to the presence of mild emphysema than pulmonary function tests, which are global indications of lung function. HRCT appears to offer a small, but real, advantage over 10-mm collimation in identification of small areas of emphysema, but areas of emphysema smaller than 0.5 cm in diameter are commonly missed, even with HRCT. Wider use of CT for investigation of relatively asymptomatic smokers may allow early diagnosis of emphysema and provide more information of the natural history of this disease, information that is sorely lacking at this time. Assessment of potential therapy such as smoking cessation or antioxidants will only be possible with widespread use of a method that is of relatively low risk, easy to duplicate, and accurate.

Humans↗

PubMed2025

Proteomic discovery analysis of quantitatively assessed emphysema in the general population. The MESA Lung Study.

BACKGROUND: Pulmonary emphysema occurs frequently in older adults, often without airflow limitation. Its presence predicts symptoms, respiratory hospitalizations and deaths, and all-cause mortality. Proteomics may provide further insights into emphysema pathogenesis and inform therapeutic targets. OBJECTIVE: We performed a proteomic discovery analysis of percent emphysema on computed tomography (CT) in a population-based, multiethnic sample from the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Replication was performed in two chronic obstructive pulmonary disease (COPD)-based studies, the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) and the Genetic Epidemiology of COPD (COPDGene) Study. METHODS: MESA recruited participants from the general population in 2000-02. The MESA Lung Study performed full-lung CT scans in 2010-12. Percent emphysema was defined as the percentage of lung voxels < -950 Hounsfield units. Over 7,200 plasma aptamers were measured via SomaScan. Cross-sectional linear and least absolute shrinkage and selection operator (LASSO) regression models were adjusted for demographics, anthropometrics, smoking, renal function, and scanner parameters. Statistical significance was defined as a false discovery rate p-value < 0.05. Gene Ontology (GO)/Reactome enrichment analyses were performed. LASSO-selected proteins' predictive performance was evaluated. RESULTS: Among 2,504 participants in the MESA Lung Study, mean age was 69.4 years, 1,291 had ever smoked, and median percent emphysema-like lung was 1.4%. In total, 1,234 aptamers were significantly associated with percent emphysema in the MESA Lung Study, and 35 replicated in the SPIROMICS and COPDGene Studies. Novel associations included protein family with sequence similarity (FAM) 177A1, syntenin-2, ubiquitin carboxyl-terminal hydrolase 25, and uncharacterized protein C20orf173. Previously identified emphysema-associated proteins included soluble advanced glycosylation end product-specific receptor (sRAGE), protein S100-A12, high mobility group protein B1, and roundabout homolog 2. Enrichment analyses identified 40 GO biological processes, including chemokine production and regulation and cell-cell adhesion and regulation, and two Reactome pathways, including RAGE signaling. In tenfold cross-validation, novel proteins were largely retained by LASSO (R2 = 5.4%), improved overall model performance (R2 = 24.8%), and uniquely explained greater variance in percent emphysema. CONCLUSIONS: This analysis in a general population sample identified novel and previously characterized proteins whose functional roles were validated by GO/Reactome enriched pathways, offering new insights into emphysema pathophysiology and therapeutics.

Humans↗

PubMed1998

Comparison of different computed tomography scanning methods for quantifying emphysema.

Computed tomography (CT) is used to detect emphysematous changes in the lungs of living patients. It is therefore important to develop a standard method for the radiographic quantification of emphysematous lesions using CT. The authors determine the best CT scanning methods for assessing the degree of pulmonary emphysema. Computed tomography scanning was performed in 85 consecutive patients with stable chronic obstructive pulmonary disease. Scans were obtained using 2-mm or 5-mm collimation, at full inspiration or full expiration, and with standard or high spatial-resolution reconstruction images (eight images each). Emphysema was then assessed by visual scoring using a five-point scale for each lung. Emphysema was scored as significantly less severe using standard reconstruction images. There were no significant differences in CT-scored emphysema on scans obtained with 2-mm and 5-mm collimation. Emphysema was scored as significantly less severe on expiratory scans. The postbronchodilator forced expiratory volume in one second value correlated better with emphysema scored on expiratory scans. Computed tomography-scored emphysema obtained by all methods correlated well with the diffusion capacity and total lung capacity, regardless of the method used. Using a visual scoring system with a five-point scale, narrow collimation is probably not necessary for the quantification of emphysema, although a high spatial-resolution reconstruction appears to be of value. Scans obtained in exhalation appear to underemphasize the severity of emphysema.

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PubMed2005

Peripheral solitary pulmonary nodule: CT findings in patients with pulmonary emphysema.

PURPOSE: To analyze retrospectively the computed tomographic (CT) features of peripheral noncalcified solitary pulmonary nodules in patients with and those without emphysema. MATERIALS AND METHODS: The authors' institutional review board required neither its approval nor patient informed consent for this retrospective study. The authors retrospectively reviewed 2-mm-thick CT images of 41 nodules (21 malignant, 20 benign) in 41 patients with emphysema (age range, 58-88 years; mean, 71.9 years) and 40 nodules (20 malignant, 20 benign) in 40 patients without emphysema (age range, 50-85 years; mean, 69.2 years). Two radiologists who were unaware of the diagnosis independently evaluated the shape and margin of the nodule, recorded the presence of ground-glass opacities and air bronchograms, and classified nodules into two diagnostic categories: malignant and benign. Final decisions were reached by consensus. For quantitative assessment of the nodules, the fractal dimensions of the nodule interfaces and circularity of the nodule shape were calculated with an image-processing program, and the percentage of the nodule surrounded by emphysema was obtained. Statistical comparisons were made with a chi(2) or Fisher exact test and the Mann-Whitney U test. RESULTS: In patients with emphysema, there were no significant differences in fractal dimension, circularity, or frequency of lobulation or spiculation between malignant and benign nodules. Of the 41 nodules in patients with emphysema, 26 (63%) were correctly diagnosed. Thirteen benign nodules (65%) were diagnosed as malignant in patients with emphysema. Of the 40 nodules in nonemphysematous lungs, 37 (93%) were correctly diagnosed. The mean percentage of emphysema around the nodule was greater for misdiagnosed nodules than for correctly diagnosed nodules (P = .003). CONCLUSION: Malignant and benign nodules associated with emphysema exhibited considerably more overlap in CT features than did nodules in nonemphysematous lungs.

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PubMed1992

Regional distribution of emphysema: correlation of high-resolution CT with pulmonary function tests in unselected smokers.

High-resolution computed tomography (CT) was correlated with pulmonary function tests in the evaluation of regional emphysema in 59 smokers. The lung was divided into upper (above the carina tracheae) and lower (below the carina tracheae) zones, and the degree of emphysema was graded with a subjective and an objective measurement. Functional emphysema was defined as a diffusion capacity less than 75% of predicted and forced expiratory volume in 1 second less than 80% of predicted. Three of 15 (20%) subjects with functional emphysema had no subjective evidence of emphysema at high-resolution CT, and 10 of 25 (40%) with emphysema at high-resolution CT had no functional abnormalities consistent with emphysema. Even though the upper lung zones were more severely affected by emphysema, the degree of emphysema in the lower zones had a stronger correlation with pulmonary function abnormalities. The upper lung zones are a relatively silent region where extensive destruction may occur before functional abnormalities become known.

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PubMed2006

Computed tomography-diagnosed emphysema, not airway obstruction, is associated with the prognostic outcome of early-stage lung cancer.

PURPOSE: Because both emphysema and lung cancer can arise from biological damage caused by cigarette smoking, we investigated if the development of emphysema is associated with the clinical features of smoker's lung cancer. EXPERIMENTAL DESIGN: The subjects were a consecutive series of 100 smokers who underwent lobectomy with hilar and mediastinal dissection for clinical stage I non-small cell lung cancer. We studied the relationship between the presence or absence of emphysema at the onset of the lung cancer and clinicopathologic features. Emphysema was diagnosed by measuring the low-attenuation area using computed tomography densitometry. RESULTS: There were no differences in clinicopathologic variables, including the degree of smoking exposure between the patients with (n=58) and those without (n=42) emphysema, although male gender and airflow limitation were predominant in the patients with emphysema. The presence of emphysema, but neither male gender nor airflow limitation, adversely affected both overall and disease-specific survival. According to Cox regression analysis, emphysema was an independent prognosticator among age, gender, degree of smoking exposure, tumor size, nodal status, histologic subtype, histologic grade, and microvessel invasion. These results were stabilized by a bootstrap sampling model. CONCLUSIONS: Computed tomography-diagnosed emphysema, but not airway obstruction, is associated with poor prognosis in smokers with early-stage lung cancer. Thus, routine computed tomography densitometry in smokers with lung cancer should be mandatory.

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PubMed1982

Exponential analysis of the lung pressure-volume curve as a predictor of pulmonary emphysema.

To compare the predictive value of different pulmonary function tests in the diagnosis of morphologic emphysema, we performed measurements of subdivisions of lung volume, gas exchange, maximal expiratory flow rates, and static deflation pressure-volume curves on 55 subjects prior to surgery for removal of an isolated peripheral pulmonary lesion. Emphysema was graded on the resected lung specimen and the pressure-volume data were fitted to an exponential equation (V = A - Be-KP). By chi-square analysis, K was the best predictor of emphysema in individual subjects and it was the only test that distinguished subjects with moderate emphysema from subjects with mild or without emphysema, but K did not distinguish those with mild emphysema from those without emphysema. As a group those with mild emphysema were distinguishable from predicted normal with K and elastic recoil pressures at 90 and 60% of predicted total lung capacity. We conclude that minimal emphysema may be detected by exponential analysis of the lung pressure-volume curve.

Adult↗

PubMed2004

Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment.

FEV(1) is fundamental to the diagnosis and staging of chronic obstructive pulmonary disease. In emphysema, airflow obstruction usually coexists with impairment of gas exchange, but discordance is not infrequent. We hypothesized that variations in the distribution of emphysema would be associated with functional differences and therefore account for discordant physiology. We used quantitative computed tomography to assess emphysema severity and distribution in 119 subjects with alpha1-antitrypsin deficiency (PiZ phenotype) and grouped them according to distribution pattern. In the 102 subjects with emphysema, 65 had a predominantly basal pattern ("basal"), but 37 (36%) had greater involvement of the upper regions ("apical"). Subjects from each group were matched for total volume of emphysema and age, and matched pairs analysis was used to relate emphysema distribution to clinical phenotype. Basal distribution was associated with greater impairment of FEV(1) (mean difference, 9.9% predicted; 95% confidence interval, 3.8 to 16.0; p = 0.002) but less impairment of gas exchange (Pa(O(2)) mean difference, 0.5 kPa, 0.03 to 0.1; p = 0.016) and alveolar-arterial oxygen gradient (mean difference, 0.7 kPa; 0.2 to 1.2; p = 0.007) than the apical distribution. Emphysema distribution correlated with physiologic discordance (r = -0.409, p < 0.001). The use of single physiologic parameters as a surrogate measure of emphysema severity may introduce systematic bias in the staging of subjects with emphysema.

Adult↗

PubMed2006

Lung fibroblasts from patients with emphysema show markers of senescence in vitro.

BACKGROUND: The loss of alveolar walls is a hallmark of emphysema. As fibroblasts play an important role in the maintenance of alveolar structure, a change in fibroblast phenotype could be involved in the pathogenesis of this disease. In a previous study we found a reduced in vitro proliferation rate and number of population doublings of parenchymal lung fibroblasts from patients with emphysema and we hypothesized that these findings could be related to a premature cellular aging of these cells. In this study, we therefore compared cellular senescence markers and expression of respective genes between lung fibroblasts from patients with emphysema and control patients without COPD. METHODS: Primary lung fibroblasts were obtained from 13 patients with moderate to severe lung emphysema (E) and 15 controls (C) undergoing surgery for lung tumor resection or volume reduction (n = 2). Fibroblasts (8E/9C) were stained for senescence-associated beta-galactosidase (SA-beta-Gal). In independent cultures, DNA from lung fibroblasts (7E/8C) was assessed for mean telomere length. Two exploratory 12 k cDNA microarrays were used to assess gene expression in pooled fibroblasts (3E/3C). Subsequently, expression of selected genes was evaluated by quantitative PCR (qPCR) in fibroblasts of individual patients (10E/9C) and protein concentration was analyzed in the cell culture supernatant. RESULTS: The median (quartiles) percentage of fibroblasts positive for SA-beta-Gal was 4.4 (3.2;4.7) % in controls and 16.0 (10.0;24.8) % in emphysema (p = 0.001), while telomere length was not different. Among the candidates for differentially expressed genes in the array (factor > or = 3), 15 were upregulated and 121 downregulated in emphysema. qPCR confirmed the upregulation of insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-rP1 (p = 0.029, p = 0.0002), while expression of IGFBP-5, -rP2 (CTGF), -rP4 (Cyr61), FOSL1, LOXL2, OAZ1 and CDK4 was not different between groups. In line with the gene expression we found increased cell culture supernatant concentrations of IGFBP-3 (p = 0.006) in emphysema. CONCLUSION: These data support the hypothesis that premature aging of lung fibroblasts occurs in emphysema, via a telomere-independent mechanism. The upregulation of the senescence-associated IGFBP-3 and -rP1 in emphysema suggests that inhibition of the action of insulin and insulin-like growth factors could be involved in the reduced in vitro-proliferation rate.

Biomarkers↗

PubMed2005

Pulmonary function tests fail to predict exercise intolerance in sheep with emphysema.

PURPOSE: The purpose of this study was to examine ventilatory parameters, gas exchange, and exercise tolerance in sheep undergoing cardiopulmonary exercise testing and pulmonary function testing at baseline and after induction of emphysema using nebulized papain, to improve our understanding of the contributions of parenchymal emphysema with minimal airway disease to exertional dysfunction in mild-to-moderate emphysema. METHODS: Static lung physiology (total lung capacity, residual volume, static elastance, and diffusing capacity of carbon monoxide) and lung (ZL) input impedance were measured, and cardiopulmonary exercise testing (CPET) was performed in 12 sheep before and after induction of emphysema. Papain treatment was delivered over a 12-wk period, as a single dose per week, to induce mild-to-moderate emphysema without airway disease. Static and dynamic lung physiology, as well as CPET, were then repeated. RESULTS: At the emphysema time point (EMPH), all animals were asymptomatic for emphysema at rest. There was a 60% increase in residual volume and a 57% decrease in static elastance, accompanied by a 36% reduction in diffusing capacity. Airway resistance was consistently, mildly increased, resulting in an increased expiratory time constant for all sheep at EMPH. There were no significant differences at EMPH versus baseline for any measured physiological variables during CPET (VO2peak, VCO2peak, RER, anaerobic threshold, O2 pulse, tidal volume, peak flow, peak VE/VO2, or peak VE). CONCLUSION: There is notable conservation of exercise capacity in sheep with mild-to-moderate parenchymal emphysema; this is not predicted by pulmonary function tests. In the absence of significant airway narrowing, mild-to-moderate emphysema is unlikely to result in airflow limitation.

Animals↗