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PubMed2001

Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema.

Pulmonary emphysema is believed to result from an imbalance between proteolytic enzymes and their inhibitors. Multiple studies have examined the presence of various proteases within the bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease (COPD). However, to date extensive examination of the lung parenchyma for the expression of destructive enzymes has not yet been determined. The following study examines the lung parenchyma of 23 patients with emphysema and 8 normal control samples for the expression of matrix matalloproteinase-1 (MMP-1), MMP-12, and MMP-9. We report here that interstitial collagenase (MMP-1) RNA, protein, and activity are present in the lung parenchyma of patients with emphysema and not in the lung of normal control subjects. In contrast, metalloelastase (MMP-12) expression is absent in these samples. Immunohistochemistry studies localized MMP-1 to the Type II pneumocyte in patients with emphysema and not normal control subjects or smokers without emphysema. This observation demonstrates that the lung is altered in emphysema such that the Type II pneumocyte secretes MMP-1 and suggests that MMP-1 may be an important enzyme involved in the destruction of the lung in the human disease. In addition, the induction of a proteolytic enzyme within the Type II pneumocyte suggests that the cells within the lung itself are capable of producing degradative enzymes in this disease process.

Adult↗
PubMed1988

Experimental pulmonary histoplasmosis and emphysema.

Chronic pulmonary histoplasmosis often occurs in the setting of emphysema. However, it is unknown whether emphysema directly predisposes to the development of the necrotizing lesions of chronic pulmonary histoplasmosis. We evaluated this possibility using a murine model of pulmonary histoplasmosis. Using intratracheal inoculation of elastase, we induced pulmonary emphysema in Balb/c mice. When mice with emphysema were challenged intranasally with H. capsulatum (HC) yeast cells, the course of their disease was not significantly different from that of normal mice. Mice were also exposed to HC antigens by sublethal intranasal challenge with viable or heat-killed HC, or immunized with histoplasmin. Prior sublethal challenge with viable HC did not cause prolonged illness or increased mortality in the setting of emphysema. In contrast, such mice were protected against a severe rechallenge. Additional studies showed that intranasal administration of heat-killed HC or subcutaneous immunization with histoplasmal antigens had neither protective nor deleterious effects on the course of histoplasmosis. Therefore, in this murine model, we could not substantiate an interaction of underlying emphysema with acute primary or rechallenge pulmonary histoplasmosis.

Animals↗
PubMed1981

Lung sounds in patients with emphysema.

We recorded an index of breath sound intensity (Ib) and the transmission of white noise (Tn) over four lung regions between apex and base in eight subjects with emphysema. The Ib and Tn were recorded over the whole range of lung volume from residual volume to total lung capacity. Each value was expressed as a fraction of the value recorded over the apical region with the help of an analog divider. The ratio of Ib to Tn was computed to correct for differences in Ib due to differences in transmission of sound. The ratio of Ib and Tn was computed to correct for differences in Ib due to differences in transmission of sound. The ratio of Ib to Tn was also expressed as a fraction of the value recorded over the apex. Both Ib and Tn had definite patterns in subjects with emphysema but varied considerably from breath to breath. The Ib and Tn were more reproducible in normal subjects. The magnitude and the sequence of Ib, Tn, and Ib/Tn were also different in subjects with emphysema and normal subjects. The ratio of Ib to Tn is an index of sound production in both normal subjects and subjects with emphysema. We conclude that both production and transmission of breath sounds vary from breath to breath in patients with emphysema. There are areas of both increased and decreased production and transmission of sound. If regional breath sound production (Ib/Tn) is related to regional ventilation in persons with emphysema as in normal subjects, these findings further suggest that regional ventilation varies from breath to breath and is also altered drastically from the normal pattern, leading to a severe ventilation and perfusion inequality so characteristic of emphysematous lungs.

Female↗
PubMed1982

A new anodal alpha 1-antitrypsin variant associated with emphysema: Pi Bsaskatoon.

A new anodal alpha 1-antitrypsin (alpha 1 AT) variant was identified in a 48-yr-old woman with severe pulmonary emphysema. Isoelectric focusing produced extra bands lying between those of the Pi B and Pi C variants. The new variant was present in 2 of her 3 siblings, 5 of 11 offspring, and probably in her father, all in the heterozygous state. Mean serum alpha 1 AT concentrations and elastase inhibitory capacities were the same in variant and M offspring. The father had reported emphysema, the 2 variant siblings had documented emphysema, and 1 of 5 variant offspring had an area of focal emphysema. The Pi type M sibling and the remaining 10 offspring had no emphysema. Despite normal concentrations and activities, this new variant, which has been designated "Bsaskatoon," may be associated with the development of emphysema within this family.

Female↗
PubMed1982

The effect of oxygen on Cor pulmonale in experimental emphysema induced by elastase or elastase and beta-aminopropionitrile in hamsters.

Right ventricular hypertrophy in elastase-induced emphysema in the System hamster was assessed by either the weight of the right ventricle as a fraction of body-weight or by the ratio of the weight of the right to the left ventricle. Right ventricular hypertrophy accompanies elastase-induced emphysema and is more severe in hamsters injected with elastase while fed a diet containing 0.5% beta-aminopropionitrile (BAPN), a combination that causes more severe emphysema. Measurements of arterial blood oxygen pressures showed that emphysematous animals were hypoxemic. Treatment of emphysematous animals with 35% O2 either during the development of right ventricular hypertrophy or after it had developed produced measurable amelioration of the hypertrophy in those groups with the more severe emphysema (elastase plus BAPN diet) but did not completely prevent it. The oxygen had no effect on the severity of the emphysema measured morphometrically. These results indicate that the cor pulmonale in elastase-induced emphysema is probably multifactorial, but hypoxia appears to be one of the major factors.

Aminopropionitrile↗
PubMed1986

The diagnosis of emphysema. A computed tomographic-pathologic correlation.

To assess the accuracy of computed tomography (CT) in the diagnosis of emphysema, we performed CT on 32 patients prior to surgery for removal of suspected tumors. The CT scans were assessed visually for emphysema by 2 independent radiologists and 1 chest physician. Intraobserver and interobserver variation were assessed. Pathologic emphysema was graded on the resected lung specimens. These grades were correlated with the CT scores and with pulmonary function tests obtained prior to surgery. Significant correlation was found between the pathologic grade on resected lung specimens and the preoperative CT score of both the resected lobe (r greater than or equal to 0.57, p less than 0.001) and the whole lung (r greater than or equal to 0.63, p less than 0.001). Compared with pulmonary function tests, CT was a better predictor of emphysema and distinguished patients with moderate emphysema from patients with normal lungs. We conclude that CT is a useful adjunct in assessing the presence and severity of emphysema.

Adult↗
PubMed2005

Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice.

RATIONALE: Oxidants are believed to play a major role in the development of emphysema. OBJECTIVES: This study aimed to determine if the expression of human copper-zinc superoxide dismutase (CuZnSOD) within the lungs of mice protects against the development of emphysema. METHODS: Transgenic CuZnSOD and littermate mice were exposed to cigarette smoke (6 h/d, 5 d/wk, for 1 yr) and compared with nonexposed mice. A second group was treated with intratracheal elastase to induce emphysema. MEASUREMENTS: Lung inflammation was measured by cell counts and myeloperoxidase levels. Oxidative damage was assessed by immunofluorescence for 3-nitrotyrosine and 8-hydroxydeoxyguanosine and lipid peroxidation levels. The development of emphysema was determined by measuring the mean linear intercept (Lm). MAIN RESULTS: Smoke exposure caused a fourfold increase in neutrophilic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke-exposed CuZnSOD mice. Similarly, CuZnSOD expression prevented the 58% increase in lung lipid peroxidation products that occurred after smoke exposure. Most important, CuZnSOD prevented the onset of emphysema in both the smoke-induced model (Lm, 68 exposed control vs. 58 exposed transgenic; p < 0.04) and elastase-generated model (Lm, 80 exposed control vs. 63 exposed transgenic; p < 0.03). These results demonstrate for the first time that antioxidants can prevent smoke-induced inflammation and can counteract the proteolytic cascade that leads to emphysema formation in two separate animal models of the disease. CONCLUSIONS: These findings indicate that strategies aimed at enhancing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease.

Animals↗
PubMed1997

Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer.

1. Genetic variation at the glutathione S-transferase M1 locus (GSTM1) has been associated with a number of apparently unrelated cancers, including lung cancer. Emphysema is a common lung disease often found concomitant with lung cancer. Both emphysema and lung cancer may result from chemical and oxidative damage caused by reactive species present in cigarette smoke or released from neutrophils recruited following cigarette smoke induced injury. GSTM1 may protect against such damage through detoxification of cigarette smoke components. Polymorphism of this gene may thus influence susceptibility not just to lung cancer, but to other forms of lung disease. 2. Resection specimens from a group of 168 lung cancer patients were assessed for the presence of macroscopic centriacinar and panacinar emphysema. DNA was extracted from archival material and genotyped for the GSTM1 polymorphism using the polymerase chain reaction. A control group of 384 anonymous blood donations was used to determine the frequency of the GSTM1 gene deletion in a random control population. Reverse transcription on lung tissue was performed to investigate mRNA expression of GSTM1 and GSTM4. 3. In 57 lung cancer cases with no emphysema there was no association with homozygous deletion of the GSTM1 gene (51% null in cancer and 53% null in control groups). However in 111 patients with emphysema and lung cancer there was an increase in the frequency of deletion (65%, P = 0.032) giving an odds ratio of 1.36(0.32-2.40). In 43 cases there was evidence of both centriacinar and panacinar emphysema. The frequency of GSTM1 deletion was 70% (Odds ratio 2.11, 0.97-3.25). Both GSTM1 and GSTM4 mRNAs were expressed in lung tissue. 4 These findings suggest that GSTM1 has a general but rather small protective effect against toxicological injury in the lung which is not specific to cancer. This is of relevance in considering the health effects of exposure to a wide range of reactive chemicals in the environment.

Base Sequence↗
PubMed2001

Quantitative computed tomography assessment of lung structure and function in pulmonary emphysema.

Accurate diagnosis and quantification of pulmonary emphysema during life is important to understand the natural history of the disease, to assess the extent of the disease, and to evaluate and follow-up therapeutic interventions. Since pulmonary emphysema is defined through pathological criteria, new methods of diagnosis and quantification should be validated by comparisons against histological references. Recent studies have addressed the capability of computed tomography (CT) to quantify pulmonary emphysema accurately. The studies reviewed in this article have been based on CT scans obtained after deep inspiration or expiration, on subjective visual grading and on objective measurements of attenuation values. Especially dedicated software was used for this purpose, which provided numerical data, on both two- and three-dimensional approaches, and compared CT data with pulmonary function tests. More recently, fractal and textural analyses were applied to computed tomography scans to assess the presence, the extent, and the types of emphysema. Quantitative computed tomography has already been used in patient selection for surgical treatment of pulmonary emphysema and in pharmacotherapeutical trials. However, despite numerous and extensive studies, this technique has not yet been standardized and important questions about how best to use computed tomography for the quantification of pulmonary emphysema are still unsolved.

Humans↗
PubMed2002

Role of secretory leukocyte protease inhibitor in the development of subclinical emphysema.

Secretory leukocyte protease inhibitor (SLPI) is a potent inhibitor of human leukocyte elastase. In some chronic airway diseases, the level of SLPI is decreased in sputum, leading to the continuation of neutrophil inflammation. In this study, the role of SLPI in subclinical pulmonary emphysema was examined. Sequential bronchoalveolar lavage was performed in an attempt to separately evaluate the levels of SLPI in the large airways and in the peripheral airways for two groups of smokers. One group had subclinical emphysema by computed-tomography scans and one group did not. SLPI localized in alveolar macrophages (AM) was also assessed. The level of SLPI was significantly elevated in the peripheral airways from the subjects with emphysema compared to those without emphysema (1589.2+/-353.9 versus 729.1+/-31.0 ng x mL(-1)), although it was similar in the large airways (3442.3+/-499.6 versus 2535.7+/-578.8 ng x mL(-1)). There was a trend for higher amount of SLPI to be released from AM in subjects with subclinical emphysema, although this did not reach statistical significance. In conclusion, there is compensatory upregulation of secretory leukocyte protease inhibitor in peripheral airways in subclinical pulmonary emphysema, which is in sharp contrast to the decreased level of secretory leukocyte protease inhibitor reported in some chronic airway diseases.

Adult↗
PubMed2005

Bronchoalveolar lavage in COPD: fluid recovery correlates with the degree of emphysema.

Bronchoscopy with bronchoalveolar lavage (BAL) is an important research tool for assessing airway inflammation in a variety of inflammatory lung diseases. In chronic obstructive pulmonary disease (COPD), BAL recovery is often low, making analysis of the recovered fluid difficult to interpret. The present authors hypothesised that the degree of emphysema may predict BAL recovery. A total of 20 COPD patients (mean age 57 yrs, range 49-69) with a median (interquartile range) forced expiratory volume in one second (FEV1) of 51 (33-69)% predicted underwent BAL. Matched "healthy" smokers and nonsmokers served as controls. Emphysema index in COPD patients was calculated on computed tomography scan as the percentage of the right lung with pixels <-950 Hounsfield units. The carbon monoxide diffusing capacity of the lung (DL,CO) was determined by the single-breath method. COPD patients had lower BAL recovery than controls. COPD patients with an emphysema index <1 had higher BAL recovery than patients with an emphysema index >1. BAL recovery correlated negatively to emphysema index and positively to DL,CO. However, no correlation was found between recovery and FEV1. In conclusion, the extent of emphysema evaluated by computed tomography-scan index and carbon monoxide diffusing capacity of the lung may predict a low bronchoalveolar lavage recovery in chronic obstructive pulmonary disease patients. These parameters may, therefore, be useful when chronic obstructive pulmonary disease patients are selected for bronchoscopy with bronchoalveloar lavage. The present study underlines the importance of careful phenotyping of chronic obstructive pulmonary disease patients.

Aged↗
PubMed1995

Does phase 2 of the expiratory PCO2 versus volume curve have diagnostic value in emphysema patients?

It has been postulated that serial inhomogeneity of ventilation in the peripheral airways in emphysema is represented by the shape of expiratory carbon dioxide tension versus volume curve. We examined the diagnostic value of this test in patients with various degrees of emphysema. The volumes between 25-50% (V25-50) and 25-75% (V25-75) of the expiratory carbon dioxide tension versus volume curve were determined in 29 emphysematous patients (20 severely obstructed and 9 moderately obstructed), 12 asthma patients in exacerbation of symptoms, and 28 healthy controls. Discriminant analysis was used to examine whether these diagnostic groups could be separated. With regard to phase 2 of the expiratory CO2 versus volume curve (mixture of anatomic deadspace and alveolar air), a plot of intercept versus slope of the relationships of (V25-50) and (V25-75) versus inspiratory volume (VI) from functional residual capacity (FRC), obtained during natural breathing frequency, proved to be most discriminating in the separation between healthy controls and severely obstructed emphysema patients. Separating healthy controls and severely obstructed emphysema patients on the basis of the discriminant line for V25-50, 9 of the 12 asthma patients in exacerbation were classified as normal, and only 5 of the 9 moderately obstructed emphysema patients as emphysematous. For V25-75 involvement of phase 3 of the curve (alveolar plateau) in asthma patients in exacerbation caused a marked overlap with the severely obstructed emphysema patients. In the healthy controls, a fixed breathing frequency of 20 breaths.min-1 led to an increase of both volumes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Cigarette smoke-induced pulmonary emphysema in scid-mice. Is the acquired immune system required?

BACKGROUND: Chronic obstructive pulmonary disease is associated with a chronic inflammatory response of the host to chronic exposure to inhaled toxic gases and particles. Although inflammatory cells of both the innate and adaptive immune system infiltrate the lungs in pulmonary emphysema and form lymphoid follicles around the small airways, the exact role of the acquired immune system in the pathogenesis of emphysema is not known. METHODS: In this study, wild type Balb/c mice and immunodeficient scid mice--which lack functional B- and T-cells--were exposed to mainstream cigarette smoke (CS) for 5 weeks or 6 months. RESULTS: Subacute CS-exposure for 5 weeks significantly increased innate inflammatory cells (neutrophils, macrophages and dendritic cells) in the bronchoalveolar lavage (BAL) fluid of wild type mice and scid mice, which correlated with the CS-induced upregulation of the chemokines Monocyte Chemotactic Protein-1, Macrophage Inflammatory Protein-3alpha and KC (= mouse Interleukin-8). Chronic CS-exposure for 6 months significantly increased the number of neutrophils, macrophages, dendritic cells, CD4+ and CD8+ T-lymphocytes in BAL fluid and lungs of wild type mice compared to air-exposed littermates, and augmented the size and number of peribronchial lymphoid follicles. In contrast, neither B-lymphocytes, nor T-lymphocytes, nor lymphoid follicles could be discerned in the lungs of air- or CS-exposed scid mice. Importantly, chronic CS-exposure induced pulmonary emphysema in both wild type animals and scid mice, as evidenced by a significant increase in the mean linear intercept and the destructive index of CS-exposed versus air-exposed animals. The CS-induced emphysema was associated with increased mRNA expression of matrix metalloproteinase-12 in the lungs and increased protein levels of Tumor Necrosis Factor-alpha in the BAL fluid of CS-exposed Balb/c and scid mice compared to air-exposed littermates. CONCLUSION: This study suggests that the adaptive immune system is not required per se to develop pulmonary emphysema in response to chronic CS-exposure, since emphysema can be induced in scid mice, which lack lymphoid follicles as well as functional B- and T-cells.

Animals↗
PubMed1997

Histopathologic diagnosis made in lung tissue resected from patients with severe emphysema undergoing lung volume reduction surgery.

STUDY OBJECTIVES: This study reports histopathologic findings in a group of emphysema patients who underwent thoracoscopic lung volume reduction surgery (75) or sternotomy (five) with the purpose to induce functional improvement and relief of dyspnea. Immediate outcome and complications were correlated to histologic patterns. DESIGN: Histopathologic material obtained in lung volume reduction surgery in 80 consecutive patients was analyzed. Thirty patients who had other histopathologic diagnoses in addition to emphysema were grouped and compared with 50 patients found to have emphysema exclusively. Postoperative outcome and preoperative lung function variables were compared. MEASUREMENTS AND RESULTS: All patients had severe obstructive lung disease and significant air trapping preoperatively documented by pulmonary function testing. All had severe exertional dyspnea. All had chest radiographs, CT, and nuclear medicine lung scans consistent only with emphysema. All portions of resected lung tissue were weighed, lung volume was estimated, and routine histopathologic studies were made. Thirty patients (37.5%) had unsuspected findings such as interstitial fibrosis, noncaseating granulomatosis, chronic inflammation, and unsuspected neoplasia (three carcinomas, one carcinoid). Retrospective review of imaging studies in these patients failed to show infiltrative processes. The average lung weight resected in this group was significantly heavier (65+/-18 g) compared with the other group (56+/-13 g), although both had the same estimated lung volume. Average number of days requiring chest tubes and length of hospitalization was also significantly higher (12.8+/-19 vs 6.4+/-5 days with chest tubes and 17.4+/-22 vs 8.5+/-6 days of hospitalization, respectively). None of the preoperative pulmonary function tests variables were different between the two groups. Serious postoperative complications were more frequent in these patients compared with those who showed only emphysema. CONCLUSIONS: A significant portion of patients diagnosed as having severe emphysema will have other unsuspected histologic findings. When subjected to lung volume reduction surgery, this subgroup will have more serious complications and longer periods of air leaks, requiring longer hospitalization time. Retrospective review of imaging studies and preoperative pulmonary function tests used to select patients for lung volume reduction failed to identify this subgroup.

Adult↗
PubMed2001

Anatomic landmarks to estimate the length of the diaphragm from chest radiographs: effects of emphysema and lung volume reduction surgery.

STUDY OBJECTIVES: To define anatomic landmarks that can be used to predict insertions of the diaphragm on chest radiographs and to estimate diaphragm length. DESIGN: Prospective clinical trial with a parallel group design. SETTING: Laboratory investigations in normal volunteers recruited by advertisement and in emphysema outpatients being evaluated for elective bilateral lung volume reduction surgery (LVRS). PATIENTS: Twenty-six normal subjects classified into young and older age groups, with a third group of 13 emphysema patients matched for age and sex with the older group. MEASUREMENTS: Identification and between-group comparisons were made of anatomic landmarks on anteroposterior and lateral chest radiographs obtained at total lung capacity. Predicted landmarks were generated from normal subjects. Within-subject and between-group comparisons were made of diaphragm length index (DLI) based on observed anatomic landmarks (DLIobs) and diaphragm length index based on predicted anatomic landmarks (DLIpred) at functional residual capacity. RESULTS: Anatomic landmarks were not different between the three groups or between male and female subjects, and were not different before and after LVRS in emphysema patients. No difference was found between DLIobs and DLIpred in normal subjects and emphysema patients, but both were smaller in emphysema patients than in normal subjects and increased after LVRS in emphysema patients. CONCLUSION: This study validates the use of anatomic landmarks to estimate DLI. Using these landmarks simplifies the determination of diaphragmatic lengths and could be a useful tool for the evaluation of the functional capacity of the diaphragm, and possibly as a prognostic indicator of patients who are candidates for LVRS.

Adult↗
PubMed2002

Effects of a novel implantable elastomer device for lung volume reduction surgery in a rabbit model of elastase-induced emphysema.

OBJECTIVES: There is intense interest in lung volume reduction surgery (LVRS) for treatment of severe symptomatic emphysema. LVRS results in objective and subjective improvement in lung function in selected patients. However, LVRS is complicated by substantial morbidity, including prolonged pulmonary air leak associated with resection of emphysematous lung tissue. In this study, we investigated the use of a novel implanted silicone elastomer device that reduces lung volume without surgical resection, in a previously reported emphysematous animal model. The purpose of this investigation was to determine the applicability, physiologic effects, complications, and air-leak results of this lung volume reducer (LVR) approach. DESIGN: Controlled, randomized, prospective animal study. Emphysema was induced in 20 New Zealand white rabbits with three nebulizations of 10,000 U of porcine elastase. After 6 weeks, the animals were randomized to control sham surgery (n = 10) vs implanted silicone elastomer LVR (n = 10) treatment groups. Lung function, including helium-dilution lung volumes, static respiratory system compliance curves, and diffusion capacity of the lung for carbon monoxide (DLCO), was measured at baseline, following emphysema induction (week 6), and when the animals were killed (1 week after LVR or sham surgery). Histologic evaluation was performed in all lung specimens after fixation. RESULTS: Moderate emphysema developed after elastase nebulization, assessed by lung function and postmortem histology. Functional residual capacity (FRC) and an upward shift of lung compliance curves was observed with development of emphysema at 6 weeks (p < 0.05). Following LVR, FRC decreased (p = 0.005) and compliance curves shifted back downward (p = 0.002), without reduction in DLCO. There was no change in control sham animals. DLCO did not change in either group. CONCLUSIONS: In this short-term, randomized, controlled animal model study, the implantable LVR approach produced safe and effective lung volume reduction without tissue resection in the treated animals. The implant procedure produced minimal morbidity, no mortality, and no observed air-leak complications in the treated animals. Limitations include the short-term follow-up and moderate degree of emphysema in this animal model. Further research is required to assess long-term effects and complications of this method for lung volume reduction.

Animals↗
PubMed2003

All-trans retinoic acid modulates the balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with emphysema.

STUDY OBJECTIVE: The balance between proteases and antiproteases plays an essential role in the pathogenesis of emphysema. This study was designed to evaluate the impact of all-trans retinoic acid (ATRA) on the balance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with emphysema. DESIGN AND SETTING: As part of a clinical study, ATRA was administered to 20 patients with emphysema for 12 weeks and evaluated for its effects on plasma levels of MMP-9 and TIMP-1. Plasma MMP-9 levels were also measured in a separate cohort of patients with emphysema and matched control subjects to evaluate the relationship of circulating enzyme levels to lung disease. To further investigate the effects of ATRA on protease activity within the lung microenvironment, alveolar macrophages (AM) recovered from the lungs of active smokers with COPD were cultured with ATRA in vitro. MEASUREMENTS AND RESULTS: Administration of ATRA to patients with emphysema produced a 45 +/- 14% reduction (mean +/- SEM) in plasma MMP-9 by enzyme-linked immunosorbent assay and a similar reduction in MMP-9 enzyme activity, while having little effect on TIMP-1 levels. Baseline MMP-9 levels were higher in patients with emphysema compared to nonsmoking control subjects, suggesting a relationship between plasma levels and the presence of lung disease. In vitro, concentrations of ATRA similar to those achieved in the plasma of study subjects significantly reduced both the production and enzyme activity of MMP-9 by AM. In the same experiments, TIMP-1 levels increased significantly, resulting in a marked reduction in the MMP-9/TIMP-1 molar ratio. CONCLUSION: We conclude that ATRA can modulate protease/antiprotease balance in a manner that may impact on disease pathogenesis.

Aged↗
PubMed2004

Assessment of emphysema in COPD: a functional and radiologic study.

OBJECTIVES: A combination of functional measurements reflecting a decrease in maximum flow, a degree of lung hyperinflation, the relationship between maximum inspiratory and expiratory flows, bronchodilator response, and diffusing capacity of the lung for carbon monoxide (DLCO) was used to quantify the extent of emphysema, as assessed by high-resolution CT (HRCT) scanning. DESIGN: Forced inspiratory and expiratory spirometry, lung volumes, reversibility test, and single-breath diffusing capacity were assessed before and after inhaling albuterol, 200 microg. Relationships between lung function variables and emphysema extent, as determined by HRCT scanning, were tested by univariate and multivariate analyses. SUBJECTS: Thirty-nine COPD outpatients with moderate-to-severe obstruction. MEASUREMENTS AND RESULTS: Emphysema extent, as assessed by HRCT scanning, ranged from 18 to 70%. All of the lung function parameters that were studied, except for the change in FEV1 percent predicted after salbutamol inhalation, correlated significantly with the extent of emphysema (r2 range, 0.19 to 0.44). Functional residual capacity, forced expiratory flow at 50% of FVC/forced inspiratory flow at 50% of FVC, DLCO/alveolar volume ratio, and bronchodilator-induced change in FEV1/FVC ratio were the only variables retained by stepwise multiple regression analysis. The multiple regression model explained 71% of the variability of emphysema extent measured by HRCT scanning. CONCLUSIONS: The combination of lung function measurements reflecting lung hyperinflation, bronchial collapsibility, lung diffusing capacity, and bronchodilator response provides a good estimate of the extent of emphysema, as evaluated by HRCT scanning. These data suggest that pulmonary function tests are useful in assessing and monitoring parenchymal damage in COPD patients.

Aged↗