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PubMed2003

Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

Animals↗
PubMed1994

Longitudinal lung function study in heterozygous PiMZ phenotype subjects.

It is a matter of controversy whether subjects who are heterozygous (PiMZ) for alpha 1-antitrypsin deficiency are at risk of developing pulmonary emphysema. To assess the role of MZ phenotype in the development of abnormal lung function the authors performed a 10 year follow-up study of 28 PiMZ subjects, compared to 28 matched-paired normal PiMM subjects. Maximal expiratory flows and mechanical properties of the lungs were studied, in order to determine the changes of the lung function parameters characteristic of pulmonary emphysema. Total lung capacity and residual volume increased, whereas forced expiratory volume in one second, expiratory flows, diffusing capacity of the lungs for carbon monoxide, and static transpulmonary pressures decreased in the PiMZ patients. The majority of the controlled functional parameters were found to deteriorate significantly in PiMZ patients during the 10 year period. Trypsin inhibitory capacity in the PiMZ group (mean +/- SD) was 0.65 +/- 0.17 mg.ml-1 as compared to 1.52 +/- 0.3 mg.ml-1 in the PiMM group. These changes exceeded the values expected as physiological changes due to ageing. The findings in the present longitudinal study--especially the decrease in elasticity, which is the primary pathophysiological damage in alpha 1-antitrypsin deficiency--support the concept that the PiMZ phenotype is a risk factor for the development of pulmonary emphysema at younger age than in those without the deficiency.

Adult↗
PubMed1977

[Alpha-1-antitrypsin deficiency. Phenotype study of 60 members of the same family].

In two brothers treated for severe pulmonary emphysema, was demonstrated an alpha-1-antitrypsin deficiency associated with a ZZ phenotype (Pi system). The authors carried out a genetic study of the family including 60 members spread over 4 generations. In all, were demonstrated 4 subjects of phenotype ZZ, 29 of phenotype MZ, 3 of phenotype MS ; one subject had a phenotype SZ and 23 members of this family had normal levels of alpha-1-antitrypsin and were of phenotype MM. The disease was transmitted in all cases as an autosomic codominant. The interest of a study of the phenotype in alpha-1-antitrypsin deficiency is emphasized together with the practical steps to be taken on discovery of a subject with the allele responsible for a reduction in serum levels of alpha-1-antitrypsin.

Adult↗
PubMed1998

Long-range correlations of serial FEV1 measurements in emphysematous patients and normal subjects.

In obstructive lung disease the annual change in lung function is usually estimated from serial measurements of forced expiratory volume in 1 s (FEV1). Frequent measurements in each patient may not improve this estimate because data are not statistically independent; i.e., the measurements are autocorrelated. The purpose of this study was to describe the correlation structure in time series of FEV1 measurements. Nineteen patients with severe alpha1-antitrypsin deficiency (phenotype PiZ) and moderate to severe emphysema and two subjects with normal lungs were followed for several years with daily self-administered spirometry. FEV1 measurements fulfilling standard criteria were detrended, and the autocorrelation profile and the power spectrum were calculated. On average the subjects were followed for >3 yr and performed >1,000 acceptable spirometries. The autocorrelation of FEV1 measurements in the emphysematous patients was approximately 0.35 for short intervals and decreased almost exponentially with a half time of 38 days. Between 3 and 4 mo, the autocorrelation function became negative. It reached a minimum of -0.1 at approximately 8 mo and then increased toward zero over the following 12 mo. The autocorrelation function in the two normal subjects showed a similar pattern, but with a faster decay toward zero. In the patients, the power spectrum had a peak at 1 cycle/wk and showed a 1/f pattern, where f is frequency, with a slope of -0.88 at lower frequencies. We conclude that serial spirometric measurements show long-range correlations. The practical implication is that FEV1 need not be measured more often than once every 3 mo in studies of the long-term trends in lung function.

Adult↗
PubMed1998

Intermediate alpha 1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema?

It is well documented that the severe hereditary disorder alpha 1-antitrypsin deficiency (alpha 1ATD) PiZZ is a strong risk factor for emphysema, especially among smokers, but the role of intermediate alpha 1ATD PiMZ and PiSZ in the development of emphysema remains uncertain. In this study, we have evaluated mortality and lung function of 94 persons with intermediate alpha 1ATD PiSZ of whom 66 were non-index cases, i.e. persons ascertained through family studies. The index cases and the non-index cases were similar with respect to sex, age and follow-up time, but differed in smoking habits and FEV1. Among the smokers there was no significant difference in pack-years between index cases and non-index cases. The overall Standardized Mortality Ratio (SMR) was 1.6 (95% confidence intervals (CI): 0.8-2.7). For the index cases the SMR was 4.3 (95% CI: 1.9-8.5) and for the non-index cases it was 0.8 (95% CI: 0.3-1.8). In the index group six patients died of pulmonary emphysema, one of pulmonary fibrosis, and one of colon cancer. In the non-index group two died of pulmonary emphysema, two of pneumonia, and one of cerebral haemorrhage. The mean initial FEV1% predicted among the index cases was 59% compared with 94% among the non-index cases. Based on the analysis of the non-index cases it is concluded that only a small fraction of persons with the PiSZ phenotype are at increased risk of developing pulmonary emphysema, and at an older age than persons with the PiZ phenotype.

Adult↗
PubMed1997

Progress of emphysema in severe alpha 1-antitrypsin deficiency as assessed by annual CT.

PURPOSE: To assess serial CT as a measure of the progress of emphysema in patients with severe alpha 1-antitrypsin deficiency (phenotype PiZ). MATERIAL AND METHODS: In a randomized placebo-controlled study of alpha 1-antitrypsin augmentation therapy, 22 patients with moderate emphysema were followed for 2-4 years with an annual lung CT. The images were analysed by means of semiautomatic lung detection, and the degree of emphysema was quantitated by the density-mask and the percentile methods. The influence of lung volume was standardised by a regression model. RESULTS: A highly significant decline in Hounsfield units (HU) was found in low-density areas, corresponding to a mean (SE) annual loss of lung tissue of 2.1 (0.4) g/l lung volume. Analysis of a single slice at 5 cm below the level of the carina gave comparable results: 2.4 (0.4) g/l. CONCLUSION: Serial CT is a sensitive measure of the progress of emphysema in patients with severe alpha 1-antitrypsin deficiency.

Acute Disease↗
PubMed1981

Protease inhibitor phenotypes and pulmonary disease in patients with Sjögren's syndrome.

The incidence of pulmonary emphysema in patients with alpha-1-antitrypsin (alpha-1-AT) deficiency associated with the protease inhibitor (Pi) phenotype ZZ is increased. To determine whether less severe deficiency states of alpha-1-AT (i.e. Pi phenotypes other than ZZ and MM) might predispose to the development of pulmonary disease, Pi phenotypes were determined in a group of patients in whom the incidence of chronic pulmonary disease is high. The proportion of 52 patients with Sjögren's syndrome who had Pi phenotypes other than ZZ and MM was not significantly greater than that for populations of normal subjects. Mean values for tests of pulmonary function, including estimates of both restrictive lung disease and airway obstruction in patients with the MM phenotype were not significantly different from corresponding means for patients with non-MM phenotypes. These findings suggest that the increased susceptibility of patients with Sjögren's syndrome to develop chronic obstructive pulmonary disease is not attributable to an abnormally high frequency of non-MM phenotypes and associated moderately reduced serum levels of alpha-1-AT.

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↗
PubMed1983

Alpha 1 antitrypsin deficiency: clinical and physiological features in heterozygotes of Pi type SZ. A survey by the British Thoracic Association.

In a multicentre survey of alpha 1 antitrypsin deficiency 25 heterozygotes of type SZ were identified. Fourteen index cases were identified through chest clinics and 11 non-index cases through family studies. Emphysema was largely confined to index males who had smoked and there was little evidence of the disease among the non-index cases. It appears that the SZ phenotype may carry little or no extra risk of emphysema.

Adult↗
PubMed2002

[PiSZ-phenotype alpha 1-antitrypsin deficiency: a rare cause of bronchiectasis].

Panacinar emphysema is the most characteristic pulmonary disease in patients with alpha1-antitrypsin deficiency (AAT). Bronchiectasis can also arise with AAT deficiency, although the association is much less common and no clear cause-effect relationship has yet been established. We report the case of a woman who presented with bronchiectasis and PiSZ-phenotype ATT deficiency, without emphysema. A review of the literature showed that the case is exceptional.

Bronchiectasis↗
PubMed1979

Tryptic and elastolytic inhibitory capacities of serum from various Pi phenotypes.

Alpha-1-antitrypsin deficiency is responsible for emphysema in adults. The genetic polymorphism of this protein (Pi system) is used to detect these deficiencies. The relationship between the serum protease inhibitory capacities and M, MZ and Z Pi phenotypes was investigated. 120 sera including 31 M, 33 MZ and 56 Z were studied. The alpha-1-antitrypsin concentration varied according to the Pi phenotype, the sex and the health of the subject. The alpha-2-macroglobulin level did not depend on the Pi phenotype. The trypsin inhibitory capacity fluctuated with the age and the health of the subject, but did not faithfully represent the Pi phenotype. In contrast, the elastase inhibitory capacity depended only on the Pi phenotype. The relationship between alpha-1-antitrypsin levels and the serum elastase inhibitory capacities was linear. Canonical analysis was employed to determine the relative contributions of each antiprotease to the two inhibitory capacities. It appeared that the elastase inhibitory capacity was influenced more by the alpha-1-antitrypsin level while the trypsin inhibitory capacity was more sensitive to alpha-2-macroglobulin.

Adult↗
PubMed2006

External validity of randomized controlled trials in COPD.

BACKGROUND: COPD is a heterogeneous disease comprising a wide range of clinical phenotypes, depending on the degree to which emphysema, chronic bronchitis, reversible bronchospasm and small airways inflammation are present. Not all of these phenotypes may be represented among the subjects included in randomized controlled drug trials (RCTs) in COPD, making it difficult for doctors to know to what extent RCT evidence applies to individual patients. From a respiratory health survey of adults randomly selected from the community, we have estimated the proportion of subjects with COPD who would have been eligible for inclusion in major COPD RCTs. METHODS: A postal survey was sent to 3500 randomly selected individuals aged 25-75 years. Respondents were invited to complete a detailed respiratory questionnaire and pulmonary function tests. Subjects with COPD defined by post-bronchodilator spirometry were assessed against the eligibility criteria of 18 major RCTs cited in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. FINDINGS: Of 749 subjects completing the full survey, 117 had COPD. Of these, a median of 5% (range 0-20%) of subjects met inclusion criteria for the major RCTs. Of 55 subjects with COPD receiving treatment, 0-9% (median 5%) met inclusion criteria for the major RCTs. INTERPRETATION: The major COPD RCTs on which the GOLD treatment guidelines are based may have limited external validity. Over 90% of the COPD subjects in the community who were taking medication, did so on the basis of RCTs for which they would not have been eligible.

Adult↗
PubMed1980

The role of alpha 1 protease inhibitor (alpha 1 antitrypsin) in the regulation of immunologic and inflammatory reactions.

Twenty-six different alleles have been identified for alpha 1 protease inhibitor (alpha 1 antitrypsin), each designated by a letter of the alphabet. In any individual two alleles codominantly determine the characteristics of alpha 1 protease inhibitor (Pi), including mobility on electrophoresis, serum concentration and acute phase response. Recent evidence has linked some mildly deficient phenotypes of Pi with a variety of chronic immunologic and inflammatory disorders, such as rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, asthma and fibrosing alveolitis, in addition to the well recognised association of severe deficiency with emphysema and chronic liver disease. This disease susceptibility in phenotypes associated with reduced serum levels may be due to alteration in lymphocyte responses, complement activation and leukocyte migration. Pi can also influence the autolytic effects of leukocytic enzymes on tissues and may inhibit some aspects of coagulation and fibrinolysis. Therefore patients with deficient Pi phenotypes are likely to have exaggerated immunologic and inflammatory responses.

Asthma↗
PubMed2026

Proteomic Mediators of Chronic Obstructive Pulmonary Disease Phenotypes and Coronary Artery Calcification Burden in Ever Smokers.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) increases cardiovascular disease risk. Coronary artery calcification (CAC) predicts cardiovascular events and mortality in COPD. We hypothesized that plasma proteins linked to pulmonary phenotypes mediate CAC burden. METHODS: Pulmonary function, emphysema, airway wall thickening, Agatston CAC scores (inverse normal transformed), and relative abundance of 1305 plasma proteins (log-transformed) were assessed in 989 Phase 1 COPDGene (Genetic Epidemiology of COPD) participants. Proteins associated with both pulmonary phenotypes (FEV1[forced expiratory volume in 1 second]%predicted, FVC [forced vital capacity], FEV1/FVC, emphysema, airway wall thickness, wall area percentage) and CAC (false discovery rate P&#x2264;0.20) were evaluated using multivariable mediation. Model adjustments included sex, age, race, body mass index, smoking, comorbidities, and medications. Adjustment for pulmonary artery-to-aortic diameter ratio-a marker of pulmonary vascular pressure-was also explored. The95% bootstrap CIs that excluded zero were considered significant. RESULTS: FEV1%predicted (P=0.026) and FEV1/FVC (P=0.010) were associated with CAC. After adjusting for FEV1, visual emphysema, and visual airway wall thickening remained associated with CAC. Five proteins (TSP2 [thrombospondin-2], renin, MMP-7 [matrix metalloproteinase-7], ERBB1 [epidermal growth factor receptor], MIC-1 [macrophage inhibitory cytokine-1]) mediated the FEV1%predicted and CAC association. All except MIC-1 mediated FEV1/FVC and CAC. All except renin mediated quantitative airway wall thickness or wall area percentage and CAC. Additionally, &#x3b1;2-antiplasmin (alpha-2 antiplasmin) mediated airway wall thickness and CAC. ERBB1 mediated visual paraseptal emphysema and CAC. Pulmonary artery-to-aortic diameter ratio adjustment reduced or eliminated some mediation effects. ERBB1 remained an independent mediator across multiple phenotypes. CONCLUSIONS: Six plasma proteins mediated associations between COPD phenotypes and CAC burden. These effects were partially influenced by pulmonary artery-to-aortic diameter ratio A, suggesting shared molecular pathways linking lung dysfunction to cardiovascular risk in COPD.

Humans↗
PubMed1997

The effect of inhaled glucocorticosteroids in emphysema due to alpha1-antitrypsin deficiency.

Despite the success of inhaled steroids in controlling asthma, the benefit in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Five subjects with moderate to severe emphysema due to alpha 1-antitrypsin deficiency (phenotype PiZ) were followed with daily home spirometry in a 2 x 8 weeks, randomized double-blind, placebo-controlled, crossover study of inhaled budesonide 0.8 mg b.i.d. In three of the five patients, there was a statistically significant increase in the mean forced expiratory volume in 1 s (FEV1), and in two of these patients, there was also a statistically significant increase in the mean forced vital capacity (FVC) during budesonide treatment. A significant diurnal variation in FEV1 and FVC was found in three and two patients, respectively, but did not change significantly during treatment. These findings emphasize the need for renewed evaluation of inhaled steroids in the treatment of patients with emphysema, and indicate that individual patients may have significant clinical improvement.

Administration, Inhalation↗