RESUMO
Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.
Assuntos
Catepsina L/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Enfisema Pulmonar/genética , RNA Mensageiro/análise , Idoso , Catepsina L/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Volume Expiratório Forçado , Perfilação da Expressão Gênica , Humanos , Pulmão/enzimologia , Macrófagos Alveolares/enzimologia , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença , Capacidade VitalRESUMO
BACKGROUND: An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. METHODS: We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs' surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. RESULTS: There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT. CONCLUSION: These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.
Assuntos
Células Epiteliais Alveolares/enzimologia , Pulmão/enzimologia , Macrófagos Alveolares/enzimologia , Metaloproteinase 1 da Matriz/análise , Enfisema Pulmonar/enzimologia , Fumar/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/fisiopatologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Fumar/efeitos adversos , Fumar/fisiopatologia , Tomografia Computadorizada por Raios X , Regulação para CimaRESUMO
Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.
Assuntos
Enfisema/tratamento farmacológico , Receptores do Ácido Retinoico/agonistas , Adulto , Idoso , Animais , Método Duplo-Cego , Enfisema/metabolismo , Feminino , Volume Expiratório Forçado , Gases , Genótipo , Humanos , Inflamação , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Placebos , Pirazóis/uso terapêutico , Fumar , Estilbenos/uso terapêutico , Tomografia Computadorizada por Raios X , Receptor gama de Ácido RetinoicoRESUMO
BACKGROUND: Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects. METHODS: We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated. RESULTS: We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages. CONCLUSIONS: We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.
Assuntos
Heme Oxigenase-1/genética , Pulmão/fisiopatologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Sequência de Bases , Primers do DNA/genética , Feminino , Volume Expiratório Forçado/genética , Volume Expiratório Forçado/fisiologia , Expressão Gênica , Estudo de Associação Genômica Ampla , Haplótipos , Heme Oxigenase-1/metabolismo , Humanos , Macrófagos Alveolares/enzimologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Doença Pulmonar Obstrutiva Crônica/enzimologiaRESUMO
OBJECTIVES: The primary objective of this retrospective study was to evaluate whether abnormal predicted postoperative variables and predicted postoperative product are useful in predicting postoperative complications. The secondary objective was to assess whether an abnormal diffusion heterogeneity index is associated with increased postoperative complications. METHODS: In this retrospective study we evaluated the medical records of 57 patients who underwent lung resection for lung cancer. Calculations of the predicted postoperative variables were done using preoperative testing data, including the extent of the resected lung segments. Predicted postoperative product was obtained by multiplying the predicted postoperative percent-of-predicted FEV(1) by the predicted postoperative percent-of-predicted single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)). The measured product was obtained by multiplying FEV(1) by D(LCO). We derived diffusion heterogeneity index from measurements of the single-breath D(LCO) with the 3-equation method, as a measure of the heterogeneity of the distribution of gas exchange in the lung. RESULTS: Patients with complications had lower predicted postoperative FEV(1) (P < .001), lower predicted postoperative D(LCO) (P < .001), lower predicted postoperative maximal oxygen uptake (P < .001), lower predicted postoperative increase in percent-of-predicted D(LCO) at 70% work load from at-rest percent-of-predicted D(LCO) (ΔD(LCO)%) (P < .001), lower predicted postoperative product (P < .001), and lower measured product (P = .004). Interestingly, diffusion heterogeneity index increased with exercise in [corrected] patients with complications but decreased with exercise in [corrected] patients without complications. CONCLUSIONS: The predicted postoperative variables, predicted postoperative product, measured product, and diffusion heterogeneity index are potentially useful predictors of complications in candidates for lung resection.
Assuntos
Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/fisiopatologia , Distribuição de Qui-Quadrado , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Pneumonectomia , Valor Preditivo dos Testes , Capacidade de Difusão Pulmonar , Curva ROC , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de RiscoRESUMO
Pulmonary emphysema is a major cause of mortality and morbidity in chronic obstructive pulmonary disease (COPD). Cigarette smoking is a major risk factor in the development of pulmonary emphysema. In this study, we investigated the acute effect of cigarette smoke in vitro on the production of tumour necrosis factor-alpha (TNF-alpha) using differentiated U937 cells, a macrophage model system. We found that stimulation of the macrophages with cigarette smoke media (CSM) leads to a rapid activation of extracellular-regulated kinases 1 and 2 (erk1/2), p90RSK and a transient decrease in phosphorylation of PKB/akt. The CSM also caused the subsequent induction of TNF-alpha release. Our studies revealed that U0126, an inhibitor of the erk1/2 pathway, markedly suppressed CSM-induced TNF-alpha release. Consistent with this finding, U0126 blocked CSM-stimulated erk1/2 phosphorylation, as well as phosphorylation of the downstream kinase, p90RSK. On the other hand, the PI3-K inhibitor, LY294002, and epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, did not suppress the release of TNF-alpha. Thus, CSM induction of TNF-alpha production by differentiated macrophages is regulated primarily via the erk1/2 pathway.
Assuntos
Sistema de Sinalização das MAP Quinases , Macrófagos/enzimologia , Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Nicotiana/efeitos adversos , Fumaça/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Butadienos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Nitrilas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: To evaluate the effect of lung resection on lung function and exercise capacity values, including diffusion capacity of the lung for carbon monoxide (Dlco), during exercise, and to determine whether postoperative lung function, including exercise capacity and Dlco during exercise, could be predicted from preoperative lung function and the number of functional segments resected. DESIGN: Prospective study. SETTING: Clinical pulmonary function laboratory in a university teaching hospital. PATIENTS: Twenty-eight patients undergoing lung resection at Vancouver General Hospital from October 1998 to May 1999, were studied preoperatively and 1-year postoperatively. INTERVENTIONS: We determined FEV(1) and FVC, and maximal oxygen uptake (Vo(2)max) and maximal workload (Wmax) achieved during incremental exercise testing. We used the three-equation modification of the single-breath Dlco technique to determine Dlco at rest (RDlco) and during steady-state exercise at 70% of Wmax, and the increase in Dlco from rest to exercise (ie, the mean increase in Dlco percent predicted at 70% of Wmax from resting Dlco percent predicted [(70%-R)Dlco]). We calculated the predicted postoperative (PPO) values for all the above parameters using the preoperative test data and the extent of functioning bronchopulmonary segments resected, and compared the results with the actual 1-year postoperative results. RESULTS: Following lung resection, there was a significant reduction in FEV(1), FVC, and Dlco with decreases of 12%, 13%, and 22% predicted, respectively. There were also significant decreases in Vo(2)max per kilogram of 2.1 mL/min/kg (8% of predicted Vo(2)max) and in Wmax of 12 W (7% of predicted Wmax). However, (70%-R)Dlco did not significantly decrease after lobectomy but decreased after pneumonectomy. The calculated PPO values significantly underestimated postoperative values after pneumonectomy but were acceptable for lobectomy. CONCLUSIONS: Exercise tests may be better indicators of functional capacity after lung resection than measurements of FEV(1) and FVC or RDlco. PPO results calculated by estimating the functional contribution of the resected segments, are comparable with those obtained using ventilation-perfusion lung scanning and significantly underestimate postoperative lung function after pneumonectomy, but are acceptable for lobectomy.
Assuntos
Monóxido de Carbono/metabolismo , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Tolerância ao Exercício/fisiologia , Neoplasias Pulmonares/fisiopatologia , Pneumonectomia , Capacidade de Difusão Pulmonar/fisiologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Teste de Esforço , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Severe alpha(1)-antitrypsin (AAT) deficiency is an inherited disorder that leads to the development of emphysema in smokers at a relatively young age; most are disabled in their forties. Emphysema is caused by the protease-antiprotease imbalance when smoking-induced release of neutrophil elastase in the lung is inadequately inhibited by the deficient levels of AAT, the major inhibitor of neutrophil elastase. This protease-antiprotease imbalance leads to proteolytic damage to lung connective tissue (primarily elastic fibers), and the development of panacinar emphysema. AAT replacement therapy, most often applied by weekly intravenous infusions of AAT purified from human plasma, has been used to partially correct the biochemical defect and raise the serum AAT level above a theoretically protective threshold level of 0.8 g/L. A randomized controlled clinical trial was not considered feasible when purified antitrypsin was released for clinical use. However, AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. There was a suggestion of a slower progression of emphysema by computed tomography (CT) scan in a small randomized trial. Two nonrandomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV(1) before and after replacement therapy, suggested a possible benefit for selected patients. Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, we recommend reserving AAT replacement therapy for deficient patients with impaired FEV(1) (35-65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV(1) after a period of observation of at least 18 months. A randomized placebo-controlled trial using CT scan as the primary outcome measure is required. Screening for AAT deficiency is recommended in patients with chronic irreversible airflow obstruction with atypical features such as early onset of disease or disability in their forties or fifties, or positive family history, and in immediate family members of patients with AAT deficiency.
Assuntos
Enfisema Pulmonar/tratamento farmacológico , Inibidores da Tripsina/uso terapêutico , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/uso terapêutico , Testes Genéticos , Humanos , Infusões Intravenosas , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/fisiopatologia , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/fisiopatologiaRESUMO
To determine whether lung transfer factor for carbon monoxide (T(L(CO))) alters during menstrual phase and if steroid hormone levels relate to these changes, T(L(CO)) and T(L(CO)) adjusted for both alveolar volume (T(L)/V(A)) and haemoglobin concentration, were measured at five predefined and hormonally confirmed menstrual phases in 13 women. No difference between phases was observed in T(L(CO)) or adjusted values. Moreover, there was no association between the maximal change in oestradiol, progesterone, or oestradiol:progesterone ratio and the change in T(L(CO)) measured at the same time. When the first five chronological measurements, regardless of the menstrual phase at which they were measured, were analysed, T(L(CO)) changed significantly (p<0.05) with a maximal change between the first and fourth test (-2.69+/-2.53, 95% confidence interval). Although these results indicate that the first in a series of T(L(CO)) measurements may be higher, we found neither menstrual cycle phase nor ovarian hormone-related changes in T(L(CO)), and conclude that its adjustment for menstrual phase may not be necessary.
Assuntos
Monóxido de Carbono/sangue , Hemoglobinas/metabolismo , Ciclo Menstrual/fisiologia , Capacidade de Difusão Pulmonar/fisiologia , Adolescente , Adulto , Estradiol/sangue , Feminino , Humanos , Medidas de Volume Pulmonar/métodos , Progesterona/sangue , Testes de Função Respiratória/métodos , Fatores de TempoRESUMO
A multicentre, cross-sectional study was carried out in six centres across Canada to establish a national standard for pulmonary function tests using healthy, lifetime nonsmokers, with each centre aiming to test 10 men and 10 women from each decade from 20 to 80 years of age. Data from each centre were used to derive prediction equations for each centre, and pooled data from all centres (total: 327 women and 300 men) were used to derive Canadian predicted equations. The predictive models were compared with three widely used published models for selected tests. It was found that, in general, the equations modelled for each centre could be replaced by the models obtained when pooling all data (Canadian model). Comparisons with the published references showed good agreement and similar slopes for most tests. The results suggest that pulmonary function test results obtained from different centres in Canada were comparable and that standards currently used remain valid for Canadian Caucasians.
Assuntos
Testes de Função Respiratória/normas , População Branca , Adulto , Idoso , Canadá/etnologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Padrões de Referência , Valores de ReferênciaRESUMO
AIMS: Alpha(1)-antitrypsin deficiency (AATD) is a clinically under-diagnosed genetic disorder that originates from deleterious mutations in the alpha(1)-antitrypsin (AAT) gene, SERPINA1. Severe deficiency is associated with significant pulmonary and hepatic malfunctions. Conventional clinical diagnosis involves the evaluation of serum AAT level and detection of diseased protein isoforms. In this communication, we describe the investigations of a case of severe AATD in which the AAT levels were well below those expected from the MZ phenotype determined by isoelectric focusing for protease inhibitor type (IEF PI-typing). METHODS: In addition to the traditional diagnostic method that combines the assessment of serum AAT concentration and IEF PI-typing, we investigated the SERPINA1 gene of the proband and participating family members for mutations using Sanger sequencing. RESULTS: We identified a novel mutation (M409T) in the proband, initially missed by the standard diagnostic approach. The novel mutation was present in 4 out of 8 family members who participated in the study. CONCLUSIONS: This report illustrates the diagnostic value of incorporating exon sequencing of the AAT gene into the algorithm for evaluating AATD, particularly when the AAT serum level is significantly lower than expected from IEF PI-typing.
Assuntos
Mutação de Sentido Incorreto , Análise de Sequência de DNA , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/etiologia , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/etiologia , Radiografia , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicaçõesRESUMO
Severe α1-antitrypsin deficiency (AATD) is an inherited disorder, leading to development of emphysema in smokers at a relatively young age with disability in their forties or fifties. The emphysema results from excessive elastin degradation by neutrophil elastase as a result of the severe deficiency of its major inhibitor α1-antitrypsin (AAT). The AAT expression is determined by the SERPINA1 gene which expresses codominant alleles. The three most common alleles are the normal M, the S with plasma levels of 60% of normal, and the severely deficient Z with levels of about 15% of normal. Homozygosity for the Z mutant allele is associated with retention of abnormal AAT in the liver, which may lead to neonatal hepatitis, liver disease in children, and liver disease in adults. Regular intravenous infusions of purified human AAT (AAT augmentation therapy) have been used to partially correct the biochemical defect and protect the lung against further injury. Two randomized controlled trials showed a trend of slower progression of emphysema by chest computerized tomography. Integrated analysis of these two studies indicated significantly slower progression of emphysema. AAT is quantified by immunologic measurement of AAT in serum, the phenotype characterized by isoelectric focusing, the common genotypes by targeted DNA analysis, and by sequencing the coding region of the gene when the AAT abnormality remains undefined. AATD is often unrecognized, and diagnosis delayed. Testing for AATD is recommended in patients with chronic irreversible airflow obstruction, especially in those with early onset of disease or positive family history. Testing is also recommended for immediate family members of those with AATD, asthmatics with persistent airflow obstruction, and infants and older subjects with unexplained liver disease. There are over 100 different AAT gene variants; most are rare and only some are associated with clinical disease.
RESUMO
An abnormal increase in proteolytic enzymes is thought to play a key role in pulmonary emphysema. Alveolar macrophage proteolytic enzymes include cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12, and a number of studies have implicated these proteinases in the alveolar destruction that characterizes emphysema. The aim of this study was to investigate cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12 mRNA expression in alveolar macrophages isolated from patients with varying degrees of emphysema and to correlate their level of expression with measures of emphysema. Alveolar macrophages were isolated from fifty-four patients who underwent surgical resection for lung carcinoma. The level of mRNA expression was determined using real-time PCR. Emphysema was quantified using high-resolution CT scans. Alveolar macrophages were also cultured for 24 h and 48 h; the effect of proinflammatory mediators and promoter polymorphisms on expression was analyzed. There was a significant correlation between matrix metalloproteinase 1 mRNA expression and emphysema. A higher level of matrix metalloproteinase 1 mRNA was associated with more severe emphysema. Matrix metalloproteinase 12 mRNA expression was increased in current smokers as compared with former smokers. Furthermore, there was a negative correlation between matrix metalloproteinase 12 gene expression and carbon monoxide diffusing capacity. The matrix metalloproteinase 9 C-1562T polymorphism significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. These results suggest that alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. Furthermore, these data provide evidence to support the concept that multiple proteinases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.