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We studied alpha 1-antitrypsin deficiency in a large family of 10 siblings: 3 subjects had PiZZ phenotype, but only 1 had emphysema; 2 subjects had no respiratory complaint. The patient with emphysema was a heavy smoker. According to the literature, this case suggests that, in PiZZ phenotype, emphysema appears earlier and is more severe if the patients smoke.
alpha 1-Antitrypsin (alpha 1AT) deficiency is a hereditary disorder associated with reduced serum alpha 1AT levels and the development of pulmonary emphysema. An alpha 1AT gene is defined as "Null" when no alpha 1AT in serum is attributed to that alpha 1AT gene. Although all alpha 1AT Null genes have identical phenotypic consequences (i.e. no detectable alpha 1AT in the serum), different genotypic mechanisms can cause the Null state. This study defines the molecular basis for the alpha 1AT gene Nullmattawa, identified and cloned from genomic DNA of an individual with the Null-Null phenotype and emphysema resulting from the heterozygous inheritance of the Nullmattawa and Nullbellingham genes. Sequencing of exons Ic-V and all exon-intron junctions of the Nullmattawa gene demonstrated it was identical to the common normal M1(Val213) alpha 1AT gene except for the insertion of a single nucleotide within the coding region of exon V, causing a 3' frameshift with generation of a premature stop signal. Family analysis using oligonucleotide probes specific for the Nullmattawa sequence demonstrated the gene was inherited in an autosomal fashion. Examination of blood monocytes demonstrated that a normal-sized, 1.8-kb alpha 1AT mRNA transcript is associated with the Nullmattawa gene and in vitro translation of mRNA with the Nullmattawa mutation showed it translated at a normal rate but produced a truncated alpha 1AT protein. Additionally, retroviral transfer of the alpha 1AT Nullmattawa cDNA to murine fibroblasts demonstrated no detectable intracellular or secreted alpha 1AT, despite the presence of alpha 1AT Nullmattawa mRNA transcripts. These findings are consistent with the concept that the molecular pathophysiology of Nullmattawa is likely manifested at a posttranslational level. The identification of the Nullmattawa gene supports the concept that Null alpha 1AT alleles represent a heterogenous group in which very different mechanisms cause the identical phenotypic state.
Fibroblast growth factor (FGF) signaling has been shown to regulate lung epithelial development but its influence on mesenchymal differentiation has been poorly investigated. To study the role of mesenchymal FGF signaling in the differentiation of the mesenchyme and its impact on epithelial morphogenesis, we took advantage of Fgfr2c(+/Delta) mice, which due to a splicing switch express Fgfr2b in mesenchymal tissues and manifest Apert syndrome-like phenotypes. Using a set of in vivo and in vitro studies, we show that an autocrine FGF10-FGFR2b signaling loop is established in the mutant lung mesenchyme, which has several consequences. It prevents the entry of the smooth muscle progenitors into the smooth muscle cell (SMC) lineage and results in reduced fibronectin and elastin deposition. Levels of Fgf10 expression are raised within the mutant mesenchyme itself. Epithelial branching as well as epithelial levels of FGF and canonical Wnt signaling is dramatically reduced. These defects result in arrested development of terminal airways and an "emphysema like" phenotype in postnatal lungs. Our work unravels part of the complex interactions that govern normal lung development and may be pertinent to understanding the basis of respiratory defects in Apert syndrome.
OBJECTIVE AND BACKGROUND: The present study was performed to clarify the clinical characteristics of patients with COPD classified into phenotypes according to the dominancy of emphysema and the presence of bronchial wall thickening (BWT) evaluated by chest high-resolution CT. METHODS: A total of 172 patients with stable COPD (FEV1<80%) were examined by chest high-resolution CT. Emphysematous changes and BWT were evaluated visually, and COPD patients were classified into three phenotypes: absence of emphysema, with little emphysema with or without BWT (A phenotype), emphysema without BWT (E phenotype) and emphysema with BWT phenotype (M phenotype). The clinical characteristics were compared among the three phenotypes. RESULTS: The A phenotype showed a higher prevalence of those who had never smoked and patients with wheezing both on exertion and at rest, higher values of BMI and diffusing capacity for carbon mononide (DLCO), milder lung hyperinflation, and greater reversibility of airflow limitation responsive to beta2-agonist as compared with the E phenotype. The M phenotype showed a higher prevalence of patients complaining of a large amount of sputum, productive cough and wheezing, higher rate of exacerbation or hospitalization and greater reversibility of airflow limitation responsive to beta2-agonist as compared with the E phenotype. CONCLUSIONS: These findings suggest that the morphological phenotypes of COPD show several clinical characteristics and different responsiveness to bronchodilators.
Alpha1,6-fucosyltransferase (Fut8) plays important roles in physiological and pathological conditions. Fut8-deficient (Fut8-/-) mice exhibit growth retardation, earlier postnatal death, and emphysema-like phenotype. To investigate the underlying molecular mechanism by which growth retardation occurs, we examined the mRNA expression levels of Fut8-/- embryos (18.5 days postcoitum [dpc]) using a cDNA microarray. The DNA microarray and real-time polymerase chain reaction (PCR) analysis showed that a group of genes, including trypsinogens 4, 7, 8, 11, 16, and 20, were down-regulated in Fut8-/- embryos. Consistently, the expression of trypsinogen proteins was found to be lower in Fut8-/- mice in the duodenum, small intestine, and pancreas. Trypsin, an active form of trypsinogen, regulates cell growth through a G-protein-coupled receptor, the proteinase-activated receptor 2 (PAR-2). In a cell culture system, a Fut8 knockdown mouse pancreatic acinar cell carcinoma, TGP49-Fut8-KDs, showed decreased growth rate, similar to that seen in Fut8-/- mice, and the decreased growth rate was rescued by the application of the PAR-2-activating peptide (SLIGRL-NH2). Moreover, epidermal growth factor (EGF)-induced receptor phosphorylation was attenuated in TGP49-Fut8-KDs, which was highly associated with a reduction of trypsinogens mRNA levels. The addition of exogenous EGF recovered c-fos, c-jun, and trypsinogen mRNA expression in TGP49-Fut8-KDs. Again, the EGF-induced up-regulation of c-fos and c-jun mRNA expression was significantly blocked by the protein kinase C (PKC) inhibitor. Our findings clearly demonstrate a relationship between Fut8 and the regulation of EGF receptor (EGFR)-trypsin-PAR-2 pathway in controlling cell growth and that the EGFR-trypsin-PAR-2 pathway is suppressed in TGP49-Fut8-KDs as well as in Fut8-/- mice.
OBJECTIVE: To investigate the association between the PiBsaskatoon variant of alpha-1 protease inhibitor (a1 Pi), present in the heterozygous state, and the development of emphysema. DESIGN: Twenty-year follow-up in the third generation of a family with the variant, naturally controlled with regard to both environmental influences and other genetic factors. SETTING: University teaching hospital. POPULATION STUDIED: Ten siblings, five with PiBsaskatoonM phenotype and five with PiM phenotype, 33 to 46 years of age. INTERVENTIONS: Respiratory symptoms and smoking histories; pulmonary function tests, including static lung volumes, dynamic lung volumes before and after salbutamol 200 mg, and diffusing capacity; allergen prick skin tests; serum a1 Pi level, chest radiographs and high resolution computerized tomography lung scans MAIN RESULTS: The two groups of siblings had similar mean ages, smoking histories and prevalence of current mild respiratory symptoms. Pulmonary function data showed normal mean values and no statistically significant differences for all the variables between the two groups. Chest radiographs were normal in all subjects. High resolution computerized tomography scans were normal in eight subjects, and demonstrated mild and very mild centrilobular emphysema in the two subjects with greatest smoking histories (approximately 30 pack-year each); both of these were PiBsaskatoonM phenotype. CONCLUSION: There is no evidence of an association between a1 Pi phenotype PiBsaskatoonM and the development of emphysema.
Nine patients with moderate pulmonary emphysema, six of PiZ phenotype and three of PiM phenotype, have received a single intravenous infusion of alpha-1-proteinase inhibitor (human) (A1PI), in a dose of 60 mg/kg over a 30-minute period. They also received a tracer dose (300 microCi) of 131I-labeled A1PI. No active or passive immunization against hepatitis was given. No acute toxicity was observed. Compared with baseline data, significant elevations of serum A1PI (measured both antigenically and as anti-elastase activity) occurred, with a serum half-life approximating 110 hours. Bronchoalveolar lavage fluid, obtained 48 hours after infusion, reflected a significant increase in A1PI concentration versus baseline bronchoalveolar lavage fluid values. Serial gamma camera images of the lungs confirmed persistence of enhanced lung radioactivity for several days. Urinary desmosine excretion did not change following A1PI infusion. During the period of follow-up thus far, no patient has had chronic toxicity, results of liver function tests have been stable, and there has been no development of hepatitis B antigen or antibodies to hepatitis B surface or core antigens.
The present study was performed to clarify the clinical characteristics of chronic obstructive pulmonary disease (COPD) patients classified into phenotypes according to the dominancy of emphysema and the presence of bronchial wall thickening evaluated by chest high-resolution computed tomography (HRCT). Eighty-five patients with stable COPD (FEV1 < or = 80%) were examined by chest HRCT. Emphysematous changes and bronchial wall thickening were evaluated visually, and COPD patients were classified into three phenotypes: absence of emphysema, with little emphysema with or without bronchial wall thickening (A phenotype), emphysema without bronchial wall thickening (E phenotype), and emphysema with bronchial wall thickening phenotype (M phenotype). Clinical characteristics were compared among the three phenotypes. The A phenotype group showed a higher prevalence of subjects who had never smoked and patients with wheezing, higher values of body mass index (BMI) and DLco, milder lung hyperinflation, and greater reversibility of airflow limitation responsive to inhaled beta2-agonist as compared with the other phenotypes. The degree of emphysema was significantly associated with Brinkman index, lower BMI, decrease in DLco, lower FEV1/FVC. The presence of bronchial wall thickening in A- and M- phenotype was significantly associated with reversibility responsive to treatment with inhaled corticosteroid and sputum eosinophilia. These findings suggest that the morphological phenotypes of COPD show several clinical characteristics and different responsiveness to treatment with bronchodilators and inhaled corticosteroids.
Eriksson's method was analysed and an attempt was made to determine the probability of the occurrence of phenotypes predisposing to emphysema and obstructive catarrhs, when low alpha-1-AT values were found using gelatinous film or immunochemical methods. The authoresses propose a three-stage system for the detection of all those susceptible to emphysema.
In one family three brothers were found to have a moderate deficiency of alpha 1-antitrypsin associated with the unusual Pi (protease inhibitor) phenotype FZ. The Pi phenotypes of their six living siblings were found to be FM (in three), M (in two) and MZ (in one). The three FZ brothers all had moderate to severe obstructive airways disease, and two had at least moderately severe pulmonary emphysema. Additional risk factors included moderate cigarette smoking in two and prolonged exposure to grain dust in all three. The same risk factors applied to the six non-FZ siblings, but they had only mild symptoms and pulmonary dysfunction or no lung problems at all; one, a female smoker with the MZ phenotype, had probable early emphysema demonstrated radiologically. The three FZ men may have had reduced fertility, as they produced only 1 child among them, as compared with 39 among the other eight siblings. This family study thus suggests that individuals with the FZ phenotype are at risk for pulmonary emphysema and chronic obstructive airways disease, particularly in the presence of other risk factors, such as cigarette smoking and grain dust exposure.
To evaluate the concept that lung elastin degradation is accelerated in homozygous alpha-1-antitrypsin (AAT) deficient persons, we prepared acid hydrolysates of urine and used a radioimmunoassay for desmosine to measure urine concentrations of this elastin-specific cross-link in such persons and in control subjects. Excretion of desmosine in 17 homozygous AAT-deficient (PiZZ) patients with emphysema was compared with that in 27 patients with interstitial lung diseases (16 sarcoid, 5 idiopathic pulmonary fibrosis, 6 other interstitial lung diseases) and 26 healthy subjects. Both smokers and nonsmokers were present in all groups. Urinary desmosine concentration (microgram/100 mg creatinine) was 2.35 +/- 0.93 in the PiZZ patients, 2.49 +/- 1.01 in those with interstitial lung disease, and 2.05 +/- 0.54 in the healthy control subjects (p greater than 0.1, all comparisons). Because abnormal pulmonary elastolysis may be largely completed before symptoms of emphysema develop in AAT-deficient persons, we also tested 6 asymptomatic adults with homozygous AAT deficiency (PiZZ) and 5 PiZZ children. Urine desmosine (microgram/100 mg creatinine) was not significantly elevated in either group compared with that in the age-matched control subjects, although children (PiZZ and age-matched controls) showed higher excretions than did adults (6 asymptomatic PiZZ adults, 2.60 +/- 0.91; 5 PiZZ children, 3.27 +/- 0.62; 10 control children, 3.61 +/- 0.62). These data suggest that pathologic lung elastolysis in the PiZZ subject may constitute too small a fraction of total-body elastin turnover to be detected by this method.(ABSTRACT TRUNCATED AT 250 WORDS)
A case of alpha-I-antiproteinase (AIPI) hereditary deficiency (serum concentration 34 mg%, determined by NOR-Partigen Assay F-my Behringer) in 41 years old patient with premature emphysema, confirmed by phenotyping (isoelectrofocusing in polyacrylamide gel) phenotype PiZ is presented. Lung function tests showed considerable decrease (FEV1 = 1,2 l., i.e. 34% pred., FEF50% = 0.55 l., i.e. 12% pred., diffusing capacity DLCO = 12.8 ml/min/mmHg, i.e. 43% pred.). Computed tomography revealed huge emphysematous bullae mainly in supradiaphragmatic parts of the lungs. The authors discuss the difficulties in diagnosing homozygotes with A1P1 deficiency. They suggest screening of severe hereditary deficiency in persons with emphysema in age interval 30-55 years. The presented case of premature emphysema and AIPI deficiency (confirmed by phenotyping variant Z) is the first in the polish literature.
Pi phenotypes have been studied in a group of 433 patients. Patients with panacinar emphysema and/or bullae were identified from careful analysis of their clinical, physiological, radiological and anatomical characteristics. Twenty-five p.cent of the emphysematous patients were MZ; there was no significant difference in the alpha-1-antitrypsin plasmatic levels between the groups. The HLA antigens were studied in order to try to identify the possible cofactors in the development of emphysema. The role of occupational pollutants and/or of tobacco is discussed. The frequency of the MZ phenotype in our series differs from previous publications. This discrepancy is discussed on the basis of the criterious used to identify the emphysematous patients.
We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.
Severe lung disease and liver disease are not recognised features of the PiMZ phenotype, which is associated with alpha 1 antitrypsin deficiency. A 31 year old woman with this phenotype was found to have emphysema and complete heart block and showed evidence of hepatic cirrhosis, although her three sisters, all of whom had the same phenotype, were clinically normal. This case supports the possibility of a causal relation between the PiMZ phenotype and chronic lung and liver disease, but an association between alpha 1 antitrypsin deficiency and complete heart block could not be proved in this patient.
For plethysmographic studies of lung mechanics and measurement of pulmonary diffusing capacity, 62 subjects were drawn from a randomly selected population sample. Data obtained from the 24 subjects of heterozygous phenotype for alpha-1-antitrypsin deficiency (PiMZ) were compared by age group with data from 38 normal (PiM) subjects matched for sex, age, and smoking history. Comparison of mean values by age group for lung volumes, diffusing capacity, lung elastic recoil, maximum expiratory flow, and the occurrence of frequency dependence of dynamic compliance revealed no differences between phenotype groups. There was no evidence of an accelerated effect of aging among PiMZ subjects when compared with normal counterparts nor was there evidence of an increased effect of smoking. From these data it appears that the PiMZ phenotype per se is not a risk factor in the development of emphysema.
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