[Progression of pulmonary emphysema in severe alpha 1-PI deficiency. A retrospective, multicenter study of the Scientific Society for Therapy of Lung Diseases].
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Blood Proteins↗
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Results for “Emphysema Phenotype”
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Changes of volume of trapped gas after bronchodilation in subjects with suspected subclinical emphysema.
We studied the volume of trapped gas (VTG), using a nitrogen washout method, before and after bronchodilation in four groups with theoretically increasing risk of developing pulmonary emphysema: (1) nonsmoking healthy controls (PiMn), (2) nonsmoking subjects with an intermediate alpha 1-antitrypsin deficiency (PiMZn), (3) smoking subjects with normal concentration of alpha 1-antitrypsin, and (4) smoking PiMZ subjects. VTG was the only lung function variable that showed a significant difference between PiMZn and PiMn subjects but only after bronchodilation. Some conventional lung function tests also distinguished smokers from nonsmokers of both genotypes but VTG was the most sensitive test. VTG decreased after salbutamol inhalation in the control group but showed a consecutively larger increase with more risk factors of developing emphysema. An increase in VTG after bronchodilation may be a sign of alveolar abnormality preceding development of clinical lung emphysema.
Albuterol↗
Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase.
Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F alpha 1AT against human neutrophil elastase (HNE) was compared with that of common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1 respectively. F was found to have reduced activity much like that of Z, the alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. In conclusion, F alpha 1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.
Adult↗
Alpha 1-antitrypsin deficiency: the radiological features of pulmonary emphysema in subjects of Pi type Z and Pi type SZ: a survey by the British Thoracic Association.
In a multicentred survey of alpha 1-antitrypsin deficiency, radiological details have been obtained in 165 subjects homozygous for Pi type Z and in 23 subjects heterozygous for type SZ. Eight-five per cent of all type Z subjects had radiological evidence of pulmonary emphysema which was commoner in smokers than in those who had never smoked and which predominantly affected the lower zones of the lungs; 66% of the type Z subjects identified through family studies also had emphysema. Emphysema in subjects of Pi type SZ was limited to those who had smoked; this phenotype may not carry a specific risk of emphysema.
Adult↗
Epidemiology of alpha 1-protease inhibitor deficiency.
Alpha 1-protease inhibitor can exist as over seventy different biochemical variants (the Pi system) which are inherited as autosomal codominant alleles. The majority of these variants are of no clinical significance. Epidemiologically, the most abundant are Pi types M, S and Z. Homozygotes of type Z have only 10 to 20% of the normal serum concentration of the inhibitor and have an increased risk of developing pulmonary emphysema. Cigarette smoking is the most important risk factor. A minority of Pi Z homozygotes (10 to 20%) develop a form of neonatal hepatitis and a proportion of these suffer from cirrhosis in adult life. Heterozygotes of Pi type SZ have about one third of the normal serum alpha 1-protease inhibitor concentration but this phenotype does not in itself appear to be a significant emphysema risk factor. Heterozygotes of Pi type MZ are thought to have a moderately increased risk of developing emphysema but only if they smoke; there is also evidence for an increased risk of cirrhosis among subjects of type MZ. No excessive risk appears to be attached to the MS phenotype. Cumulative survival curves have suggested that type Z homozygotes have a poor prognosis but such estimates are based on clinic or hospital patients who already have respiratory symptoms. Calculations based on population frequencies however, suggest that about 90% of the total number of type Z subjects are not accounted for in such surveys. Their whereabouts remains unclear at present; some will undoubtedly have died of liver or lung disease but it is possible that the majority escape and live undetected among the general population.
Arthritis, Rheumatoid↗
[The current state of substitution treatment in congenital emphysema due to alpha-1-antitrypsin deficiency. The report of the National Registry].
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Adult↗
Intermediate alpha1-antitrypsin deficiency resulting from a null gene (M-phenotype).
The presence of a null gene for alpha1-antitrypsin was detected in a family study by the inheritance of intermediate antitrypsin deficiency in association with a normal (PiM) phenotypic pattern. The proband, a 42-year-old man (M-phenotype), was a cigarette smoker and had physiologic evidence of pulmonary emphysema. Three female members of the family were receiving estrogenic medication but had deficient values for serum trypsin inhibitory capacity nevertheless, indicating an unresponsive gene. The mean serum trypsin inhibitory capacity for those with an M-phenotype was significantly lower than that found with an MZ phenotype, presumably due to the total noncontribution to serum antitrypsin activity by the null gene. A quantitative measurement of antitrypsin activity or concentration is necessary in an antitrypsin screening program, since phenotyping procedures alone cannot reveal the null gene.
Adult↗
Intermediate alpha1-antitrypsin deficiency, Pi M-.
A 50-year-old man was found to have 40% of the normal serum alpha1-antitrypsin concentration but subsequent electrofocusing showed a pattern indistinguishable from the ordinary M pattern. This finding and family studies suggested that he was a carrier of a null (-) allele. Heavy smoking and this Pi M- phenotype in interaction probably were responsible for the development of emphysema, documented by an extensive investigation of lung function. Two non-smoking offspring carrying the null allele had normal lung function. Normal karyotypes were found in all the Pi M- subjects.
Adolescent↗
HEREDITARY DEFICIENCY OF SERUM ALPHA-L-ANTITRYPSIN.
Deficiency of the serum alpha(1),-antitrypsin appears to be under genetic control. The level of this protein is reduced to less than 10 percent of the norm in individuals homozygous for the trait, who may suffer from pulmonary emphysema. Heterozygous individuals have a concentration of serum alpha(1)-antitrypsin between 50 and 60 percent of normal, but appear to be in good health. The estimated heterozygous frequency of the trait in a small white population in Georgia is 2.1 percent.
Blood Protein Disorders↗
Redo lung volume reduction surgery in a patient with alpha1-antitrypsin deficiency.
Lung volume reduction surgery is a palliative procedure that improves dyspnea and pulmonary function in selected patients with advanced emphysema. Postoperative benefit is sustained for an individual period and depends on the emphysema morphology, the surgical technique, and other not yet well-defined factors. The question whether lung volume reduction surgery can be performed a second time on the same thoracic cavity is often raised but experience in this regard is lacking. We describe a patient who has undergone a successful redo operation 2 years after the initial lung volume reduction surgery.
Humans↗
[Alpha 1-antitrypsin deficiency: a review with special reference to the significance of heterozygous deficiency].
Homozygous deficiency of alpha-1 antitrypsin is the most common inborn error or metabolism in Europe. Severe deficiency of this major protease inhibitor in serum is associated with chronic obstructive lung disease, chronic liver disease in adults and neonatal hepatitis. An overview is given of the role of heredity, and the diagnostic criteria and clinical and histological findings in this disorder. Emphysema seems to be caused by the free elastolytic activity of white cells, leading to the degradation of elastin. The pathophysiology of liver disease - less well understood - is discussed with special emphasis on the importance of heterozygous alpha-1 antitrypsin deficiency. Exogenous noxae seem to play an important role in the pathogenesis of heterozygous deficiency. In view of the 7% frequency of heterozygous alpha-1 antitrypsin deficiency in the European population and the role of noxae in the development of pulmonary and liver diseases, improved prophylaxis is mandatory.
Adult↗
Morphologic and phenotypic analysis of an outcross line of blotchy mouse.
Blotchy is an X-linked recessive mutation at the "Mottled" locus in the mouse. The affected blotchy male (Blo/Y) mouse from an inbred genetic background demonstrates morphologic and physiologic abnormalities consistent with emphysema in adult life. Breeding of Blo/Y mice has been difficult because the inbred Blo/Y males are sterile. We report the successful development of a line of outbred Blo/Y male and Blo/Blo female nice by the controlled outcross mating of the inbred heterozygous Blo/+ female with the Argonne hybrid B6CF1 male mouse. The subsequent outcross Blo/Y progeny breed vigorously with the outcrossed Blo/+ female. The lungs of the outbred Blo/Blo female and inbred Blo/Y male mice demonstrate mild to moderate panacinar emphysema with a significant decrease in internal surface area (p less than 0.005) and an increase in mean linear intercept (p less than 0.005). In contrast, the lungs of the outbred Blo/Y is structurally normal. Despite the absence of emphysema-like changes in the outbred Blo/Y males, there were phenotypic features that suggest inherited abnormalities in connective tissue proteins including 1) high incidence of aortitis leading to premature death from aneurysmal rupture, and 2) significant decrease in the morphometrically determined parenchymal elastic fiber length in the lung (p less than 0.01). The outbred blotchy strain may be a useful experimental animal model in determining the pathogenesis of emphysema.
Animals↗
Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease.
Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.
Adult↗
Involvement of leukocytic proteases in emphysema and antitrypsin deficiency.
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Animals↗
Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
Amino Acid Sequence↗
Alpha 1-antitrypsin deficiency. Impact of genetic discovery on medicine and society.
An increasing body of molecular information resulting from advances in basic research is being incorporated into clinical practice by medical genetics. The process by which these research advances progress from the laboratory to the bedside and their medical, social, and legal impact is a topic of intense current interest. Some authors have claimed that new genetic information may lead to discrimination in insurance and employment; change the way courts allocate responsibility for injury and resultant damages; and be inappropriately interpreted by the medical profession. To address some of these issues, we chose, as a model, to review alpha 1-antitrypsin deficiency, described over 30 years ago. At this time, such concerns with respect to alpha 1-antitrypsin deficiency have not yet been realized, perhaps for the following reasons: (1) knowledge of alpha 1-antitrypsin deficiency, while common among geneticists and pulmonologists, has not been well disseminated in the medical community; (2) insurers, employers, lawyers, and judges are not generally aware of the deficiency and its implications; (3) insurers, if they are aware of the deficiency, have not found it cost-effective to screen for the condition; and (4) in the legal context, case law involving other types of preexisting conditions is being applied to genetic predispositions.
Biomedical Research↗
Quantitative computed tomography of chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is described as airflow limitation that is not fully reversible. Quantitative assessment of structural changes within the lung that are responsible for this airflow limitation has relied on the examination of tissue obtained from surgical or postmortem specimens. However, in the past two decades, researchers have developed novel and robust tools to measure the structure of the lung parenchyma and airway wall by using computed tomographic (CT) scans, which do not require the removal of lung tissue. These techniques are extremely important because they allow longitudinal studies of the pathogenesis of COPD and the assessment of therapeutic interventions. Another application of this approach is that it potentially allows phenotyping of individuals who predominately have emphysema or small-airway disease, which may be important for the evaluation of pathogenesis and prescription of treatment options. This review describes some of these CT techniques for quantitative assessment of lung structure.
Humans↗
Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor.
Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease. To further explore the role of PDGF in these processes, we have developed transgenic mice that express the PDGF-B gene from the lung-specific surfactant protein C (SPC) promoter. Adult SPC-PDGFB transgenic mice exhibited lung pathology characterized by enlarged airspaces, inflammation, and fibrosis. Emphysematous changes frequently occurred throughout the lung, but inflammation and fibrotic lesions were usually confined to focal areas. The severity of this phenotype varied significantly among individual mice within the same SPC-PDGFB transgenic lineage. A pathology similar to that observed in adult mice was noted in lungs from transgenic mice as young as 1 week of age. Neonatal transgenic mice exhibited enlarged saccules and thickened primary septa. Results of these studies indicated that overexpression of PDGF-B induced distinct abnormalities in the developing and adult lung and led to a complex phenotype that encompassed aspects of both emphysema and fibrotic lung disease.
Age Factors↗