Alpha-1 Antitrypsin Deficiency Emphysema Research Articles

Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

SummaryBackgroundAlpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity.MethodsThe plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis.FindingsIn PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes.InterpretationUsing SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD.FundingThis work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency

IntroductionAlpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and...

Alpha-1 Antitrypsin Deficiency and Lung Transplantation: A Clinical Case

BACKGROUND: α1-antitrypsin deficiency is the most common hereditary disorder in adults and is associated to an increased risk of developing lung emphysema. METHODS: With this case report, we describe the case of a 54 years old patient, who underwent bilateral lung transplantation due to alpha-1 antitrypsin deficiency emphysema. RESULTS: The patient was diagnosed with partial alpha-1 antitrypsin deficiency (189 mg/dl) associated to PIMZ genotype; although he quitted smoking, lung disease progressively deteriorates to chronic respiratory failure. Now the patient is alive 10 months after lung transplant. CONCLUSIONS: We consider it an interesting clinical case regarding the opportunity to implement augmentation therapy, not only to preserve native lungs, but also to prevent chronic lung allograft dysfunction.

Anti-Proteases and Alpha-1 Antitrypsin Augmentation Therapy.

Alpha-1 antitrypsin deficiency is a genetic disease that first highlighted the importance of protease balance in normal lung homeostasis. Proteases such as neutrophil elastase are important in many pulmonary diseases. However, the first commercially licensed anti-protease therapy was used for emphysema in alpha-1 antitrypsin deficiency. The 4 commercial alpha-1 protease inhibitor preparations in the United States are currently given intravenously to augment the serum and alveolar epithelial lining fluid concentrations of alpha-1 antitrypsin. Since the discovery of alpha-1 antitrypsin deficiency in 1963, many genetic polymorphisms of the SERPINA1 gene have been discovered. Because neutrophilic inflammation is the hallmark of usual COPD, anti-protease therapy also has been explored in this disease. Further trials with different dosing schema, inhaled therapy, and in different disease states are all ongoing. These studies would be facilitated by having COPD outcomes that are independent of measurement of air flow and achievable in smaller populations over a short period of time.

Diagnosing alpha-1 antitrypsin deficiency: the first step in precision medicine.

Severe alpha-1 antitrypsin (AAT) deficiency is one of the most common serious genetic diseases in adults of European descent. Individuals with AAT deficiency have a greatly increased risk for emphysema and liver disease. Other manifestations include bronchiectasis, necrotizing panniculitis and granulomatosis with polyangiitis. Despite the frequency and potential severity, AAT deficiency remains under-recognized, and there is often a delay in diagnosis. This review will focus on three recent updates that should serve to encourage testing and diagnosis of AAT deficiency: first, the publication of a randomized clinical trial demonstrating the efficacy of intravenous augmentation therapy in slowing the progression of emphysema in AAT deficiency; second, the mounting evidence showing an increased risk of lung disease in heterozygous PI MZ genotype carriers; last, the recent publication of a clinical practice guideline, outlining diagnosis and management. Though it has been recognized for more than fifty years, AAT deficiency exemplifies the modern paradigm of precision medicine, with a diagnostic test that identifies a genetic subtype of a heterogeneous disease, leading to a targeted treatment.

Lung densitometry: why, how and when.

Lung densitometry assesses with computed tomography (CT) the X-ray attenuation of the pulmonary tissue which reflects both the degree of inflation and the structural lung abnormalities implying decreased attenuation, as in emphysema and cystic diseases, or increased attenuation, as in fibrosis. Five reasons justify replacement with lung densitometry of semi-quantitative visual scales used to measure extent and severity of diffuse lung diseases: (I) improved reproducibility; (II) complete vs. discrete assessment of the lung tissue; (III) shorter computation times; (IV) better correlation with pathology quantification of pulmonary emphysema; (V) better or equal correlation with pulmonary function tests (PFT). Commercially and open platform software are available for lung densitometry. It requires attention to technical and methodological issues including CT scanner calibration, radiation dose, and selection of thickness and filter to be applied to sections reconstructed from whole-lung CT acquisition. Critical is also the lung volume reached by the subject at scanning that can be measured in post-processing and represent valuable information per se. The measurements of lung density include mean and standard deviation, relative area (RA) at -970, -960 or -950 Hounsfield units (HU) and 1st and 15th percentile for emphysema in inspiratory scans, and RA at -856 HU for air trapping in expiratory scans. Kurtosis and skewness are used for evaluating pulmonary fibrosis in inspiratory scans. The main indication for lung densitometry is assessment of emphysema component in the single patient with chronic obstructive pulmonary diseases (COPD). Additional emerging applications include the evaluation of air trapping in COPD patients and in subjects at risk of emphysema and the staging in patients with lymphangioleiomyomatosis (LAM) and with pulmonary fibrosis. It has also been applied to assess prevalence of smoking-related emphysema and to monitor progression of smoking-related emphysema, alpha1 antitrypsin deficiency emphysema, and pulmonary fibrosis. Finally, it is recommended as end-point in pharmacological trials of emphysema and lung fibrosis.

Serum Proteins Associated with Emphysema Progression in Severe Alpha-1 Antitrypsin Deficiency.

Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV1). QUANTitative lung CT UnMasking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV1 post-bronchodilator values (Post-BD) ≥ 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15th percentile density (PD15) which was indexed to CT-derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP® panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson's product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies.

Treatment of Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that creates multiple unique phenotypes of chronic obstructive pulmonary disease. While bronchospasm, cough, dyspnea, and sputum production all occur with AATD, the phenotypic differences require a computed tomographic (CT) scan to decipher. The availability of augmentation therapy in the United States since 1989 has generated both controversy and evidence that informs the science of usual chronic obstructive pulmonary disease (COPD). Because of the predominance of emphysema in AATD, much of the best evidence concerning biomarkers of emphysema progression comes from this population. Imaging measurement of emphysema progression, impact of emphysema phenotypes on hyperinflation and dynamic hyperinflation, and correlation with traditional spirometric measures of COPD progression are required to understand the impact of AAT therapies. These studies are important for better understanding of usual COPD pathogenesis. Significantly, there are no adequately powered research studies to determine if augmentation therapy is helpful for the non-emphysema phenotypes of AATD. Specifically, phenotypes of chronic bronchitis, asthma predominant disease, and bronchiectasis will require targeted research studies to define optimal therapy.

Characteristics of Candidates for Lung Transplantation Due to Chronic Obstructive Pulmonary Disease and Alpha-1 Antitrypsin Deficiency Emphysema

IntroductionCOPD and emphysema due to alpha-1 antitrypsin deficiency (AATD) are the first and fourth indications for lung transplantation worldwide, respectively. Despite this, there is little information regarding the health status of these patients at the time of transplantation. MethodsPatients who received a lung transplant in the Hospital Vall d’Hebron between July 1993 and August 2013 were identified and data from the evaluation prior to the transplant were collected. ResultsA total of 217 patients who received a lung transplant for COPD and 19 in whom the indication was AATD were included. These patients were severely impaired at the time of the evaluation for lung transplantation, although the trend in recent years has been to evaluate patients at earlier stages of the disease.Baseline characteristics were similar in both groups except that patients with AATD were younger [43 (7.7) vs 53.6 (6.1) years old, P<.001], with less exposure to tobacco [23.9 (15) vs 50 (29) packs-year, P<.002] and lower PCO2 [41.7 (7.6) vs 47.9 (9.7) mmHg, P<.004]. ConclusionsThe number of patients receiving a lung transplant for COPD has progressively increased and the tendency is to perform the evaluation in earlier stages of the disease. Patients receiving transplants for COPD and AATD had similar characteristics at the time of the evaluation, although AATD patients were younger and had less exposure to tobacco and lower PCO2.

Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency

BackgroundComputed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD).MethodsPatients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin®) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment.ResultsWhole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression.ConclusionPD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis.Trial registrationRegistered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

Isolated lung transplantation. Analysis of 17 consecutive operations. Munich Lung Transplant Group

16 patients (nine men, seven women; mean age 45 [23-62] years) with end-stage pulmonary disease underwent lung transplantation, 14 unilateral, three bilateral (one bilateral retransplantation). The diagnoses were: emphysema (n = 5), idiopathic pulmonary fibrosis (n = 5), emphysema in alpha 1-antitrypsin deficiency (n = 1), mucoviscidosis (n = 1), drug-induced fibrosis (n = 1), chronic lung rejection after heart-lung transplantation (n = 1), secondary pulmonary hypertension with persistent ductus arteriosus (n = 1), sarcoidosis (n = 1) and chronic transplant failure after unilateral transplantation (n = 1). Eleven patients survived long-term (mean follow-up period 247 [8-585] days). Ten of these patients have been independent of additional oxygen after an average of 8 months postoperatively, eight are physically active according to their age. Three patients died of reperfusion damage intraoperatively or in the early postoperative period. The two other patients died from septicaemia 5 1/2 and 7 months postoperatively. It is concluded that lung transplantation in end-stage pulmonary disease provides the only therapeutic means with any expectation of physical rehabilitation.

Lung and Heart-Lung Transplantation: Overview of Results

During the last decade, activity in lung transplantation increased rapidly to a plateau of approximately 900 transplants per year in the United States, and it is unlikely to increase further unless the supply of usable donor organs can be expanded. However, the demand for lung transplantation has continued to rise, and the median waiting time for lung transplantation in the United States is approaching 2 years. The main indications for lung transplantation have been chronic obstructive pulmonary disease, alpha1-antitrypsin deficiency emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, primary pulmonary hypertension, and Eisenmenger's syndrome. Overall, survival after lung transplantation has been good, with 1-, 3-, and 5-year survival rates of 75, 58, and 44%, respectively, and the results have been improving. Chronic rejection and infection have been the main causes of medium-term mortality, and the high prevalence of chronic rejection remains a barrier to better outcomes. Quality of life has been enhanced by lung transplantation, but the posttransplantation immunosuppressive regimen has been associated with considerable morbidity.

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in alpha 1-antitrypsin deficiency.

Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in alpha 1-antitrypsin (AAT) deficiency. Millimolar concentrations of leukocyte elastase, when released from single azurophil granules of activated neutrophils, lead to evanescent quantum bursts of proteolytic activity before catalysis is quenched by pericellular inhibitors. Herein, we tested the possibility that quantum proteolytic events are abnormal in AAT deficiency. We incubated neutrophils on opsonized fluoresceinated fibronectin in serum from individuals with various AAT phenotypes, and then measured and modeled quantum proteolytic events. The mean areas of the events in serum from heterozygous individuals (Pi MZ and Pi SZ) were slightly, but significantly, larger than those in serum from normal patients (Pi M). In marked contrast, mean areas of events in serum from AAT-deficient individuals were 10-fold larger than those in serum from normal patients. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for less than 20 milliseconds and for more than 80 milliseconds in Pi M and Pi Z individuals, respectively. Thus, quantum proteolytic events are abnormally large and prolonged in AAT deficiency, leading directly to an increased risk of tissue injury in the immediate vicinity of activated neutrophils. These results have potentially important implications for the pathogenesis and prevention of lung disease in AAT deficiency.

EPOC y trasplante pulmonar: resultados en España

To determine the outcome of lung transplantation in patients with chronic obstructive pulmonary disease (COPD) in Spain. In all COPD patients transplanted at four Spanish hospitals over a period of seven years, we studied actuarial survival rates retrospectively using the Kaplan Meier test in relation to demographic characteristics, type of transplant, underlying disease, lung function evolution in terms of forced vital capacity (FVC), maximum expiratory flow in 1 second (FEV1) and gasometric evolution (PaO2 and PaCO2). Seventy-four transplants were performed in COPD patients over a five-year period. Mean age was 47 +/- 7 years (26-61) and 77% of the patients were men. A diagnosis of emphysema was made in 58%, alpha-1 antitrypsin deficiency emphysema in 14% and chronic bronchitis in 28%. The likelihood of survival was 75% for the first year, 63% for two years and 41% for the third year. Lung function and blood gases improved significantly by the third month after transplantation: FVC was 1677 +/- 637 ml before transplantation and 2631 +/- 670 ml afterwards; FEV1 was 585 +/- 189 ml before transplantation and 2118 +/- 673 ml afterwards (p < 0.001). Double lung transplants achieved significantly greater improvement in function variables than did single-lung transplants (FVC 2843 +/- 681 ml and FEV1 2543 +/- 620 ml by the third month in DLT patients versus FVC 2402 +/- 587 ml and FEV1 1659 +/- 350 ml for SLT), with no significant differences in blood gases after the two types of transplant. Half the sing-lung transplant patients developed hyperinflation of the native lung and reached maximum lung function values, which tended to be lower than those for patients who did not experience this complication (FEV1 1638 +/- 349 ml versus 1930 +/- 307 ml, p = 0.051). First-year mortality in patients with COPD undergoing lung transplantation in Spain is similar to that described in the International Transplant Registry. We found no differences between double- and single-lung transplant patients. Functional change is good for both types of transplantation, although this aspect of outcome is significantly better when two lungs are transplanted.

Lung Transplantation for COPD

In appropriately selected patients with COPD and alpha1-antitrypsin deficiency emphysema, lung transplantation prolongs life, improves functional capacity, and enhances quality of life. However, rejection remains an obstacle to better medium-term results, and lung transplantation is a treatment, not a cure and not a panacea.

Right and Left Ventricular Dysfunction in Patients With Severe Pulmonary Disease

To determine the prevalence of right and left ventricular dysfunction in a prescreened population of patients with severe pulmonary disease, and to analyze the relationship between right and left ventricular function. Retrospective record review of 434 patients with severe pulmonary disease. Patients with end-stage pulmonary disease, including alpha1-antitrypsin deficiency emphysema, COPD, cystic fibrosis (CF), idiopathic pulmonary fibrosis, and pulmonary hypertension (primary and Eisenmenger's syndrome), who were evaluated for lung transplantation between January 1993 and December 1995. Pulmonary function tests, arterial blood gases, radionuclide ventriculography, two-dimensional transthoracic echocardiography, pulmonary hemodynamics, coronary angiography. Right ventricular dysfunction (right ventricular ejection fraction [RVEF] <45%) was present in 267 patients (66%), but the prevalence was highest (94%) in patients with pulmonary vascular disease. Among the patients with airway or parenchymal lung disease, the prevalence ranged from 59% in COPD to 66% in CF. In contrast, left ventricular dysfunction (left ventricular ejection fraction [LVEF] <45%) was present in only 6.4%, but it, too, was most common in the group with pulmonary hypertension (19.6%). In the groups with parenchymal or airway disease, the prevalence was 3.6%, and there was no statistical difference among the four diagnoses (alpha1-antitrypsin deficiency emphysema; COPD; CF; idiopathic pulmonary fibrosis). LVEF showed a significant correlation with RVEF (r=0.44; p<0.05), and left ventricular dysfunction was associated with the presence of moderate-to-severe tricuspid regurgitation but not with coronary artery disease. In a subset of patients with both right and left ventricular dysfunction who subsequently underwent lung transplantation, RVEF and LVEF increased pari passu after transplantation. The prevalence of right ventricular dysfunction is high in patients with end-stage pulmonary disease, but the prevalence of left ventricular dysfunction is relatively low. Left ventricular dysfunction appears to be related to right ventricular dysfunction, perhaps through ventricular interdependence.

The Washington University-Barnes Hospital experience with lung transplantation. Washington University Lung Transplantation Group

--To review our experience with lung transplantation, emphasizing recipient selection, choice of procedure, functional results, and outcome. --Retrospective review of patients who received lung transplants at Barnes Hospital, St Louis, Mo, between July 1, 1988, and January 31, 1991. --Washington University School of Medicine, St Louis, Mo, and Barnes Hospital, a medical school and its affiliated referral hospital, respectively. --Sixty-nine lung transplant procedures were performed in 66 recipients. Patients with clinically and physiologically severe lung disease were selected according to predetermined guidelines. Underlying diseases in the recipients included chronic obstructive pulmonary disease, alpha 1-antitrypsin deficiency emphysema, cystic fibrosis, pulmonary fibrosis, primary pulmonary hypertension, Eisenmenger's syndrome associated with an atrial septal defect, bronchiectasis, eosinophilic granuloma, and lymphangiomyomatosis. --Double-lung, bilateral sequential, and single-lung transplantations were performed. Eight patients underwent en bloc double-lung transplantations or a modification of this procedure with separate bronchial anastomoses. Thereafter, the bilateral sequential approach to replacement of both lungs was performed in 26 patients. Thirty-two patients underwent single-lung transplantations. --Pulmonary function tests, arterial blood gas levels, pulmonary artery pressure, pulmonary vascular resistance, and actuarial survival. --Actuarial survival at 1 year for the 66 lung transplant recipients was 79%. Actuarial survival at 1 year was 82% for the bilateral lung transplant recipients and was 90% for the single-lung transplant recipients. In patients with either restrictive or obstructive lung disease, pulmonary function tests and arterial blood gas levels improved markedly after lung transplantation. In patients with primary pulmonary hypertension or Eisenmenger's syndrome, the pulmonary artery pressure decreased and the cardiac index increased into the normal range after single-lung transplantation. --In carefully selected patients with end-stage lung disease, single-lung and bilateral lung transplantations can significantly improve functional capacity, with promising early actuarial survival statistics after 1 year.

The Washington University— Barnes Hospital Experience With Lung Transplantation

--To review our experience with lung transplantation, emphasizing recipient selection, choice of procedure, functional results, and outcome.--Retrospective review of patients who received lung transplants at Barnes Hospital, St Louis, Mo, between July 1, 1988, and January 31, 1991.--Washington University School of Medicine, St Louis, Mo, and Barnes Hospital, a medical school and its affiliated referral hospital, respectively.--Sixty-nine lung transplant procedures were performed in 66 recipients. Patients with clinically and physiologically severe lung disease were selected according to predetermined guidelines. Underlying diseases in the recipients included chronic obstructive pulmonary disease, alpha 1-antitrypsin deficiency emphysema, cystic fibrosis, pulmonary fibrosis, primary pulmonary hypertension, Eisenmenger's syndrome associated with an atrial septal defect, bronchiectasis, eosinophilic granuloma, and lymphangiomyomatosis.--Double-lung, bilateral sequential, and single-lung transplantations were performed. Eight patients underwent en bloc double-lung transplantations or a modification of this procedure with separate bronchial anastomoses. Thereafter, the bilateral sequential approach to replacement of both lungs was performed in 26 patients. Thirty-two patients underwent single-lung transplantations.--Pulmonary function tests, arterial blood gas levels, pulmonary artery pressure, pulmonary vascular resistance, and actuarial survival.--Actuarial survival at 1 year for the 66 lung transplant recipients was 79%. Actuarial survival at 1 year was 82% for the bilateral lung transplant recipients and was 90% for the single-lung transplant recipients. In patients with either restrictive or obstructive lung disease, pulmonary function tests and arterial blood gas levels improved markedly after lung transplantation. In patients with primary pulmonary hypertension or Eisenmenger's syndrome, the pulmonary artery pressure decreased and the cardiac index increased into the normal range after single-lung transplantation.--In carefully selected patients with end-stage lung disease, single-lung and bilateral lung transplantations can significantly improve functional capacity, with promising early actuarial survival statistics after 1 year.

Degradation of tropoelastin and elastin substrates by human neutrophil elastase, free and bound to alpha2-macroglobulin in serum of the M and Z (Pi) phenotypes for alpha1-antitrypsin.

Human neutrophil elastase degraded tropoelastin approximately 9 times faster than it did solubilized elastin and approximately 19 times faster than it did lung elastin. When bound to alpha2-M, the enzyme retained approximately 6 per cent of its activity toward tropoelastin and solubilized latter observations suggest that alpha2-M--bound elastase, cleared slowly from lung extracellular tissue space, may participate normally in the turnover of soluble precursor (s) of elastin and may contribute to the development of emphysema in alpha1-antitrypsin deficiency.