Smoking and intermediate alpha1-antitrypsin deficiency and lung function in middle-aged men.

Larsson, Christer; Eriksson, Sten; Dirksen, H

doi:10.1136/bmj.2.6092.922

Cited by 56 publications

(24 citation statements)

References 14 publications

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“…Some studies (7,(27)(28)(29), but not all (30)(31)(32), have suggested a slightly increased risk of lung disease in heterozygotes for AAT deficiency. It is likely that, in the presence of cigarette smoking and familial or other additive risk factors, some heterozygotes do experience an increased risk of developing pulmonary emphysema (6,33).…”

Section: Discussionmentioning

confidence: 99%

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency

Campbell¹,

Campbell²,

Boukedes³

et al. 1999

J. Clin. Invest.

117

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IntroductionDeficiency of α 1 -antitrypsin (AAT) is the most common, potentially lethal hereditary disease seen in Caucasians. AAT is a highly polymorphic serine proteinase inhibitor and is the major inhibitor of human leukocyte elastase (HLE) in plasma and in the lower respiratory tract. Individuals with AAT deficiency have a markedly increased risk of severe, early-onset pulmonary emphysema (1). HLE is contained at high concentrations within the azurophil granules of polymorphonuclear neutrophils (PMNs) (2) and within the peroxidase-positive granules of proinflammatory (P) monocytes (3). It is thought that the increased risk of lung tissue injury in AAT-deficient individuals is due to inadequately controlled HLE activity that is released from activated inflammatory cells within the lower respiratory tract (4).Individuals with Pi Z phenotype have plasma concentrations of AAT (5) Traditional enzyme kinetics have failed to provide a satisfactory explanation for the strikingly increased risk of lung tissue injury that occurs in Pi Z individuals, because (a) even in Pi Z individuals, the mean AAT concentration in plasma (∼5.3 µM) is more than 7 orders of magnitude greater than its K I for HLE (3.3 × 10 -14 M) (8); and (b) only subtle abnormalities in the function of the Z variant have been described (9, 10). In this respect, it is noteworthy that recent studies from our laboratory (11) have demonstrated that evanescent, quantized bursts of HLE-mediated proteolytic activity are associated with the extracellular release of high concentrations of HLE from single azurophil granules of PMNs. Our diffusion-based theoretical model (2) predicts that obligate HLE catalytic activity persists until HLE diffuses away from the site of granule release and the molar ratio of enzyme to extracellular inhibitor decreases to less than 1:1.Herein, we have tested the possibility that the quantum proteolytic events associated with PMN degranulation are markedly abnormal in Pi Z individuals and thereby directly contribute to the excess risk of lung tissue injury that is observed in AAT deficiency. To accomplish this, we directly measured and modeled quantum events occurring while PMNs were bathed in serum from donors having different AAT phenotypes. Our results confirmed that quantum proteolytic events can be expected to be greatly different, both in Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in α 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 ...

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Section: Discussionmentioning

confidence: 99%

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency

Campbell¹,

Campbell²,

Boukedes³

et al. 1999

J. Clin. Invest.

117

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“…Again, following a classical pattern of codominant genetic expression, quantitative AAT levels in the homozygotes (Pi ZZ) were about one-quarter those seen in normals (Pi MM). The homozygotes are at definite risk for developing clinical pulmonary and/or hepatic disease, and heterozygotes are at a somewhat smaller risk of developing clinical disease, especially if other cofactors are present (17).…”

Section: Discussionmentioning

confidence: 99%

“…Once detected, immediate careful testing for occult disease in family members is mandatory, and the initiation of preventive measures to either reduce the morbidity or prevent the expression of disease can be instituted. For example, abstinence from smoking has been established to be clearly useful (17) and abstinence from alcohol might be prudent, although not established in such individuals. Further, genetic counseling is important, especially pertaining to the likelihood of bearing children with AAT deficiency (18,19).…”

Section: Discussionmentioning

confidence: 99%

Idiopathic Hemochromotosis and Alpha-1-Antitrypsin Deficiency: Coexistence in a Family with Progressive Liver Disease in the Proband

et al. 1983

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A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed.

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“…These results suggest either that: 1) PiMZ is not a risk factor for the development of lung emphysema [5, 9, 15-17, 19, 21, 24, 25, 30, 35]; or that 2) PiMZ individuals are at increased risk [6,7,10,18,22,23,26,27,29,31,33,36]; or that 3) in addition, cigarette smoking may be an important co-determinant for the development of early onset pulmonary emphysema [20,32,37].…”

mentioning

confidence: 95%

“…Large surveys of various populations (from a community or from a working population) have been analysed to identify persons with intermediate deficiency, and to compare their respiratory status to control groups with the normal MM type selected from the same population; in some studies, matched-pairs were used [5,8,9,[15][16][17][18][19][20][21][22][23]. Other cross-sectional studies have addressed the question of whether the prevalence of heterozygotes among patients with emphysema or related disease is higher than among control populations [6,7,19,22,[24][25][26][27][28][29].…”

mentioning

confidence: 99%

Longitudinal lung function study in heterozygous PiMZ phenotype subjects

et al. 1994

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L Lo on ng gi it tu ud di in na al l l lu un ng g f fu un nc ct ti io on n s st tu ud dy y i in n h he et te er ro oz zy yg go ou us s P Pi iM MZ Z p ph he en no ot ty yp pe e s su ub bj je ec ct ts s 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.

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Smoking and intermediate alpha1-antitrypsin deficiency and lung function in middle-aged men.

Cited by 56 publications

References 14 publications

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in α1-antitrypsin deficiency

Idiopathic Hemochromotosis and Alpha-1-Antitrypsin Deficiency: Coexistence in a Family with Progressive Liver Disease in the Proband

Longitudinal lung function study in heterozygous PiMZ phenotype subjects

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