SERU Pi TYPES IN PATIENTS WITH PULMONARY DISEASES

Fagerhol, Magne K.; Hauge, Hilde

doi:10.1111/j.1398-9995.1969.tb03760.x

Cited by 82 publications

(27 citation statements)

References 12 publications

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“…COLP et al [5] found a significant increase in the rare alleles among Puerto Rican children with asthma compared to nonasthmatic controls with the same ethnic background. Other studies have found MS to be associated with asthma [20] and MZ has also been associated with asthma in some studies [6,7]. Together with the present study, this indicates that the changes in the airways associated with heterozygosity for rare alleles are inflammatory in origin, giving rise to asthmatic symptoms.…”

Section: Discussionsupporting

confidence: 70%

S and Z alpha1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction

Sigsgaard¹,

Brandslund²,

Omland³

et al. 2000

Eur Respir J

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Several studies have found an association between the rare Pi-alleles and asthma or bronchial hyperresponsiveness (BHR). This study deals with the effect of Pi-type on BHR among 2,308 young Danish people living in rural areas with a meanSD age of 19.72.4 yrs.Interviews, pulmonary function testing, bronchial histamine provocation and skinprick tests were performed. Serum a 1 -antitrypsin levels were determined and phenotyping was performed by means of isoelectric focusing and the subjects categorized into four groups: 1) MM and MX; 2) MS; 3) MZ; and 4) rare, i.e. SZ, SS and ZZ.Among the farmers, a significant positive trend for sensitization towards house dust mites was found, ranging from 12% in the MM group to 22% in the rare Pi-group. A positive test for trend was found within the Pi-groups in a one-sided test for doctordiagnosed asthma with a peak prevalence of 40% for these symptoms among smokers in the rare Pi-group. On multiple logistic regression analysis, an increased odds ratio (OR) for BHR was found among farming school attendants with the rare Pi-alleles. The OR (95% confidence interval) was 1.71 (0.84±3.49) for MS, 1.93 (1.10±3.39) for MZ and 4.34 (1.19±15.8) for the rare Pi-group. Such a relationship was not found among the conscripts.These results show that a gene/environment interaction may exist between the farming occupation and the rare Pi-alleles, leading to a higher proportion of bronchial hyperresponsiveness related to the rare Pi-alleles in farming school attendants, in contrast to what is found among other young people living in rural areas. Eur Respir J 2000; 16: 50±55. The antiprotease a 1 -antitrypsin (a 1 -AT) has, since 1963, been known to be involved in the pathogenesis of chronic obstructive lung diseases and emphysema [1]. Since then several studies have investigated a possible link between asthma, bronchial hyperresponsiveness (BHR) and Piphenotypes. The most-studied alleles with low a 1 -AT levels are the two most common types, S and Z. COLE et al.[2] and studied the association between a 1 -AT phenotype and pulmonary symptoms in the working population. They found no association with respiratory symptoms, for either S or Z heterozygous persons, whereas, in a study of cotton workers, an increased risk of respiratory symptoms among the MZ heterozygous was found, after control for other factors, i.e. smoking, sex and exposure [4].A history of asthma among close relatives was found to be more common among the heterozygous in one study [5], and, in another study, the odds ratio (OR) for familial atopy was increased among persons with the Pi-MZ phenotype [4].Asthma has been found to be associated with the Z allele in some studies and the S allele in others [5±7]. However, the association between asthma and the S or Z alleles could not be confirmed in other studies. A recent study of a 1 -AT and BHR found the S allele to be associated with hyperresponsiveness [8], indicating that the underlying mechanism for the association with asthma might be inflammation.Allergy measured a...

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Section: Discussionsupporting

confidence: 70%

S and Z alpha1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction

Sigsgaard¹,

Brandslund²,

Omland³

et al. 2000

Eur Respir J

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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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“…Because the emphysema accelerates to deteriorate pulmonary function of the silicotic patients, we are looking for the factors con tributing to it. Since Laurell and Eriksson (1963) first reported the relationship between inherited serum alpha-1-antitrypsin deficiency and pulmonary em physema, numerous lines of evidence have documented that not only the deficiency but also intermediate level (Fagerhol and Hauge 1969) of this serum protein could associate the pulmonary emphysema significantly. To understand this relation ship, the following hypothesis may be presented that various kinds of proteolytic enzymes released from the leukocyte, macrophage and bacteria into the pulmonary tissue can digest the structural protein in the lung, if antiprotease activity is reduced, for instance, in the case of lowered alpha-1-antitrypsin level in the serum.…”

Section: Methodsmentioning

confidence: 99%

Low Serum Alpha-l-Antitrypsin Level as a Contributory Factor of Combined Emphysema in Silicosis

Tokita

Ikeda

Kanno

et al. 1975

Tohoku J. Exp. Med.

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SERU Pi TYPES IN PATIENTS WITH PULMONARY DISEASES

Cited by 82 publications

References 12 publications

S and Z alpha1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction

S and Z alpha1-antitrypsin alleles are risk factors for bronchial hyperresponsiveness in young farmers: an example of gene/environment interaction

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

Low Serum Alpha-l-Antitrypsin Level as a Contributory Factor of Combined Emphysema in Silicosis

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