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Biomedical subjects

J A Pierce

Publications and source records attributed to J A Pierce.

At least 19 recordsLinked to original sources
PubMed1992

Family study of alpha 1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits.

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin (alpha 1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV1), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25-75), total serum alpha 1AT, oxidized serum alpha 1AT, and total serum immunoglobulin E (IgE) were measured in alpha 1AT deficient individuals and their families. The effect of a known, measured genotype (the Pi type) was estimated for each quantitative trait; the influence of mode of case ascertainment on the measured genotype effect was also assessed. These analyses showed that total alpha 1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25-75, and oxidized alpha 1AT are moderately influenced by Pi type. The effect of genotype-by-environment interaction between Pi type and pack-years of cigarette smoking on the five quantitative phenotypes was studied using an analysis of covariance. Significant Pi x pack-years interaction was evident for FEV1, but this effect is confounded in this data set with the Pi x age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi x pack-years interaction effect of the Pi x pack-years subjects ascertained for other reasons demonstrate. The effect of the Pi x pack-years interaction on FEV1 was no longer significant on a transformed scale, (FEVf12,) thus providing an additive scale for future data analysis. The increased sensitivity of Pi MZ individuals in our sample to cigarette smoking reduced the Pi x packs-years interaction effect on FEF25-75 to borderline significance. This investigation has provided an opportunity to incorporate both measured genotype and genotype-by-environment interaction analyses into the study of the variable expression of lung disease in Pi Z individuals.

Family↗
PubMed1991

Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon.

Normal structure and function of the lung parenchyma depend upon elastic fibers. Amorphous elastin is biochemically stable in vitro, and may provide a metabolically stable structural framework for the lung parenchyma. To test the metabolic stability of elastin in the normal human lung parenchyma, we have (a) estimated the time elapsed since the synthesis of the protein through measurement of aspartic acid racemization and (b) modeled the elastin turnover through measurement of the prevalence of nuclear weapons-related 14C. Elastin purified by a new technique from normal lung parenchyma was hydrolyzed; then the prevalences of D-aspartate and 14C were measured by gas chromatography and accelerator-mass spectrometry, respectively. D-aspartate increased linearly with age; Kasp (1.76 x 10(-3) yr(-1) was similar to that previously found for extraordinarily stable human tissues, indicating that the age of lung parenchymal elastin corresponded with the age of the subject. Radiocarbon prevalence data also were consistent with extraordinary metabolic stability of elastin; the calculated mean carbon residence time in elastin was 74 yr (95% confidence limits, 40-174 yr). These results indicate that airspace enlargement characteristic of "aging lung" is not associated with appreciable new synthesis of lung parenchymal elastin. The present study provides the first tissue-specific evaluation of turnover of an extracellular matrix component in humans and underscores the potential importance of elastin for maintenance of normal lung structure. Most importantly, the present work provides a foundation for strategies to directly evaluate extracellular matrix injury and repair in diseases of lung (especially pulmonary emphysema), vascular tissue, and skin.

Adult↗
PubMed1990

Biochemical intermediates in alpha 1-antitrypsin deficiency: residual family resemblance for total alpha 1-antitrypsin, oxidized alpha 1-antitrypsin, and immunoglobulin E after adjustment for the effect of the Pi locus.

alpha 1-antitrypsin (alpha 1 AT) deficiency is variably associated with the development of pulmonary emphysema. To gain insight into the process which begins the Z point mutation at the Protease Inhibitor (Pi) locus and results in the variable development of emphysema, three quantitative phenotypes, including total alpha 1 AT, oxidized alpha 1 AT, and total immunoglobulin E (IgE), were measured in sera from alpha 1-antitrypsin-deficient individuals and their families. The mean and variance effects of the Pi locus on these biochemical phenotypes were removed, and path analysis of the residual phenotypes was performed by using a TAU model to investigate whether there was any additional multifactorial transmission. Significant transmission was demonstrated for total serum IgE and serum-oxidized alpha 1 AT, which could be due to major genes other than the Pi locus, polygenes, or familial environment. Segregation analysis of the residual phenotypes was performed to determine whether additional major gene effects, other than the Pi effect, influence these quantitative phenotypes. Convincing evidence for an additional major gene was not found for oxidized alpha 1 AT, total alpha 1 AT, or IgE.

Data Interpretation, Statistical↗
PubMed1990

Variability of pulmonary function in alpha-1-antitrypsin deficiency: residual family resemblance beyond the effect of the Pi locus.

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin deficiency, two pulmonary function tests, FEV1 and FEF25-75, were examined in alpha 1-antitrypsin-deficient individuals and their families. The mean and variance effects of Pi type, age, and sex on the pulmonary function variables were removed by stepwise multiple regression, and the residual phenotypes were analyzed. Path analysis of the residual phenotypes with environmental indices in 46 nuclear families demonstrated highly significant cultural inheritance. Significant polygenic inheritance was not demonstrated for FEV1 but was shown for FEF25-75. For FEV1, adjustment for the significant interaction between Pi type and pack-years of smoking tended to increase the estimated contribution of polygenic inheritance and to decrease the estimated contribution of cultural inheritance. Segregation analysis of the residual phenotypes in 44 nuclear families was carried out to determine whether another major gene, other than the Pi locus, may be influencing pulmonary function in this population. Statistical evidence was found for an additional major gene influencing FEV1; however, the evidence diminished after adjusting for the effects of pack-years and the interaction between Pi type and pack-years. This apparent drop in the importance of genetic factors would not be surprising if the effect of the putative major gene is to enhance susceptibility to effects of cigarette smoking. Finally, our investigation demonstrates the feasibility of dissecting residual familial effects on complex multifactorial traits.

Factor Analysis, Statistical↗
PubMed1990

A family study of the variability of pulmonary function in alpha 1-antitrypsin deficiency. Quantitative phenotypes.

A group of 52 alpha 1-antitrypsin-deficient individuals of phenotype Pi Z and 117 of their relatives underwent a protocol including pulmonary function testing, completion of a questionnaire, and blood donation. Our population permitted a minimum frequency estimate (7 x 10(-4)) for Pi null alleles. Five quantitative phenotypes were measured, including FEV1, FEF25-75, total serum alpha 1AT, oxidized serum alpha 1AT, and total serum IgE. We found that (1) total alpha 1AT levels were higher in Pi Z subjects with lung function impairment (FEV1 less than or equal to 65% of predicted) than in Pi Z subjects who were not impaired; (2) Pi Z subjects with lung function impairment had elevated serum levels of oxidized alpha 1AT; and (3) IgE levels were relatively elevated in first-degree Pi MZ relatives of impaired Pi Z subjects. Moreover, FEV1 tended to be relatively reduced in heterozygous parents of impaired Pi Z subjects, suggesting that a subset of Pi MZ individuals are at risk for development of lung disease because of familial factors. These results represent an initial step toward the development of intermediate phenotypes that will be predictive of a severe course in alpha 1AT deficiency; they suggest that, in addition to cigarette smoking, atopic predisposition and undetermined familial factors may be important codeterminants of lung disease progression.

Adult↗
PubMed1989

Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates.

STUDY OBJECTIVE: To determine the range of pulmonary function variability in alpha-1-antitrypsin-deficient persons and to identify epidemiologic factors and pulmonary symptoms and conditions associated with this variability. DESIGN: Case series ascertained through investigation of extant obstructive lung disease (index cases, 22 subjects) or by other means (non-index cases, 30 subjects). SETTING: Referral-based pulmonary division at a tertiary care medical center. PARTICIPANTS: Fifty-two alpha-1-antitrypsin-deficient persons of type Pi Z ascertained by: extant chronic obstructive pulmonary disease (22 cases), family studies (20 cases), liver disease (4 cases), population screening (4 cases), and other pulmonary problems (2 cases). MEASUREMENTS AND MAIN RESULTS: Pulmonary function tests and a version of the American Thoracic Society 1978 standard respiratory epidemiology questionnaire were used. Persons of type Pi Z who were not specifically ascertained with chronic obstructive pulmonary disease had values of forced expiratory volume in 1 second over 65% of predicted in 20 out of 30 cases and frequently had normal lung function. Univariate and multivariate analyses of possible causes of lung disease showed that the following factors were significant (P less than 0.05): pulmonary symptoms (effects associated with chronic obstructive pulmonary disease), including dyspnea and chronic cough; age and pack-years of smoking (epidemiologic correlates); and other pulmonary conditions (potential causes or effects) including asthma, pneumonia, and episodes of increased cough and phlegm. Finally, we found a striking excess of questionnaire-reported parental emphysema in families of type Pi Z persons with chronic obstructive pulmonary disease compared with families of type Pi Z persons without disease. CONCLUSIONS: Many persons with alpha-1-antitrypsin deficiency do not have clinically significant lung function impairment: the perceived natural history of antitrypsin deficiency has been distorted by ascertainment bias. In addition to cigarette smoking, it appears that asthma, lower respiratory infections, and possibly some familial factors contribute to a severe clinical course. Follow-up of our cohort with widely varying lung function will provide insights into the natural history of the emphysema associated with alpha-1-antitrypsin deficiency.

Adolescent↗
PubMed1989

The alpha 1-antitrypsin gene and emphysema.

alpha 1-Antitrypsin (alpha 1-AT) is the major endogenous inhibitor of neutrophil elastase. Individuals with alpha 1-AT deficiency are susceptible to premature development of emphysema. Thus a greater understanding of this serine proteinase inhibitor (serpin) has been a major objective of research on the pathogenesis of emphysema. In this article, we review recent literature on the alpha 1-AT gene and its relationship to other members of the serpin supergene family, particularly as it pertains to the function of alpha 1-AT. We also discuss the current literature on biosynthesis of alpha 1-AT and how its synthesis may be tightly regulated by the net balance of neutrophil elastase and alpha 1-AT at sites of inflammation/tissue injury. The net functional activity of alpha 1-AT in complex biological fluids is also affected by interaction with other enzymes, inhibitors, matrix proteins, and endogenous oxidants. Finally, we discuss the pathogenesis, clinical manifestations, and treatment of injury to the lung associated with deficiency variants of the alpha 1-AT gene.

Emphysema↗
PubMed1989

Alpha-1-antitrypsin deficiency. High prevalence in the St. Louis area determined by direct population screening.

Considerable attention has been focused upon alpha-1-antitrypsin deficiency because of the insights into the pathogenesis of human pulmonary emphysema that may derive from study of deficient subjects, and because of evolving therapeutic strategies that may slow the progression of lung disease in affected persons. We have applied an automated immunoassay for alpha-1-antitrypsin to plasma samples from 20,000 blood donors. Seven PI Z antitrypsin-deficient persons were identified and confirmed; this is more than twice the number predicted from previous estimates of the Z allele frequency in the St. Louis area. Five of the subjects were further evaluated. We anticipate that this assay, if utilized to screen large populations, could identify many alpha-1-antitrypsin-deficient persons for study of the natural history of lung and liver disease associated with the deficiency. These subjects would be potential candidates for early intervention strategies to prevent the development of lung disease. The surprisingly high prevalence of deficient persons indicates that direct screening is the best method for prevalence estimation of genetic disorders.

Adolescent↗
PubMed1989

Synthesis of stress proteins is increased in individuals with homozygous PiZZ alpha 1-antitrypsin deficiency and liver disease.

Individuals who are homozygous for the protease inhibitor phenotype Z (PiZ) genetic variant of alpha 1-antitrypsin (alpha 1-AT) have reduced plasma concentrations of alpha 1-AT, and are susceptible to premature development of pulmonary emphysema. A subset of this population develops chronic liver disease. The reduction in plasma concentrations of alpha 1-AT results from a selective defect in secretion as the abnormal PiZ alpha 1-AT protein accumulates within the cell. It has recently been shown in several experimental systems that the heat shock/stress response, a response characterized by the synthesis of a family of highly evolutionarily conserved proteins during thermal or chemical stress, may also be activated by the presence of abnormal proteins within the cell. Therefore, we predicted that the heat shock/stress response would be induced in the absence of thermal or chemical stress in alpha 1-AT-synthesizing cells of PiZZ individuals. In the following study, however, we show that net synthesis of proteins in the heat shock/stress gene family (SP90, SP70, ubiquitin) is increased only in a subset of the population, PiZZ individuals with liver disease. It is not significantly increased in PiZZ individuals with emphysema or in those without apparent tissue injury. Net synthesis of stress proteins is not increased in individuals with another variant of the alpha 1-AT gene (PiS alpha 1-AT) and is not increased in individuals with severe liver disease but a normal alpha 1-AT haplotype (PiM alpha 1-AT). These results demonstrate that the synthesis of stress proteins is increased in a subset of individuals with homozygous PiZZ alpha 1-AT deficiency, those also having liver disease.

Adolescent↗
PubMed1987

Lipopolysaccharide modulates the expression of alpha 1 proteinase inhibitor and other serine proteinase inhibitors in human monocytes and macrophages.

alpha 1 Proteinase inhibitor (PI) is the principle inhibitor of neutrophil elastase, an enzyme that degrades many components of the extracellular matrix. Expression and regulation of alpha 1 PI, therefore, affects the delicate balance of elastase and antielastase, which is critical to turnover of connective tissue during homeostasis, tissue injury, and repair. In this study we show that expression of alpha 1 PI in human monocytes and macrophages is regulated during activation by LPS. LPS mediates a concentration- and time-dependent increase in the rate of synthesis of alpha 1 PI in mononuclear phagocytes. There is a 4.5-8.7-fold increase in functionally active inhibitor delivered to the cell culture fluid of monocytes. The effect of LPS is specific in that it is neutralized by an mAb to the lipid A moiety. The increase in expression of alpha 1 PI mediated by LPS occurs in the context of other specific changes in the expression of serine proteinase inhibitor genes in mononuclear phagocytes. There is an increase in the rate of synthesis of C1 inhibitor and a decrease in synthesis of alpha 2 macroglobulin. Regulation of alpha 1 PI by LPS is distinctive in that it is largely determined by a change in the efficiency of translation of alpha 1 PI mRNA. LPS has no effect on the rate of posttranslational processing and/or secretion of alpha 1 PI and, therein, causes greater intracellular accumulation of alpha 1 PI in mononuclear phagocytes from individuals with homozygous PiZZ alpha 1 PI deficiency.

Blood Proteins↗
PubMed1987

Effects of alkyl grafting on surface properties and blood compatibility of polyurethane block copolymers.

In order to probe the factors which affect the interaction between the surface of a multiphase polyurethane material and blood, a series of butanediol-chain-extended polyetherurethanes was synthesized. These polyurethanes contained different levels of phase separation, produced by systematically varying the hard segment chemical structure by grafting ethyl and octadecyl groups to the urethane nitrogen atom. Surface characterization using high vacuum, air-equilibrated, and water-equilibrated methods was performed. A canine ex vivo arteriovenous series shunt was used to monitor initial platelet and fibrinogen deposition on these polymers. The ex vivo response to these materials, along with contact angle and ESCA surface chemistry, was found to vary with the degree of alkyl derivatization. This study demonstrated that an increase in the degree of phase separation and also the incorporation of long chain (C18) alkyl groups can affect surface properties and improve the short-term blood compatibility of the underivatized polyurethane.

Animals↗
PubMed1986

Ex vivo interactions and surface property relationships of polyetherurethanes.

Despite the use of polyurethanes in a number of blood-contacting applications, little is known about the contributing effects of the various polyurethane components in thrombogenesis. In order to investigate blood-polyurethane interactions, a number of different polyurethanes were examined in an acute canine ex vivo series shunt experiment. Multiprobe surface characterization techniques, including contact angle measurements, ESCA, ATR-IR, and SEM were used to obtain surface property information on the materials studied. The polyurethanes examined included several with different soft segment types, a series of materials with different hard segment diisocyanates and chain extenders, a series consisting of the same polymer cast from different solvents, a zwitterionomer, and a hard segment analog. Two commercial urethanes were also examined, and the effect of methanol extraction on these materials was studied. The blood-contact and surface characterization results indicated that both the surface concentration and type of hard segment were of importance in determining blood response. The relative concentration of hard segment on the polymer surface was found to affect the observed blood-material interaction, although the extent of this effect was found to depend on the hard and soft segment components of the copolymer system. Both the surface properties and thrombogenicity of a particular polyurethane were changed by casting from different solvents, indicating the need to optimize and control fabrication conditions. Methanol extraction was found to improve the thromboresistance of the commercial polyurethanes.

Animals↗
PubMed1983

Alpha-1-antitrypsin-deficient phenotype is not maintained by segregation distortion.

Recent reports have suggested that the alpha-1-antitrypsin allele PiZ, which in homozygotes results in severe deficiency of this important protease inhibitor, is maintained at a relatively high gene frequency through the mechanism of segregation distortion. We report here on 121 nuclear families selected because only one parent was segregating the Z allele. After correcting for ascertainment, no evidence of preferential transmission was observed in 278 informative offspring.

Crosses, Genetic↗