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Biomedical subjects

J E Gadek

Publications and source records attributed to J E Gadek.

At least 73 records · Page 4Linked to original sources
PubMed1981

Antielastases of the human alveolar structures. Implications for the protease-antiprotease theory of emphysema.

The current concepts of the pathogenesis of emphysema hold that progressive, chronic destruction of the alveolar structures occurs because there was in imbalance between the proteases and antiproteases in the lower respiratory tract. In this context, proteases, particularly neutrophil elastase, work unimpeded to destroy the alveolar structures. This concept has evolved from consideration of patients with alpha 1-antitrypsin deficiency, who have decreased levels of serum alpha 1-antitrypsin and who have progressive panacinar emphysema. To directly assess the antiprotease side of this equation, the lower respiratory tract of non-smoking individuals with normal serum antiproteases and individuals with PiZ homozygous alpha 1-antitrypsin deficiency underwent bronchoalveolar lavage to evaluate the antiprotease screen of their lower respiratory tract. These studies demonstrated that: (a) alpha 1-antitrypsin is the major antielastase of the normal human lower respiratory tract; (b) alpha 2-macroglobulin, a large serum antielastase, and the bronchial mucous inhibitor, an antielastase of the central airways, do not contribute to the antielastase protection of the human alveolar structures; (c) individuals with PiZ alpha 1-antitrypsin deficiency have little or no alpha 1-antitrypsin in their lower respiratory tract and have no alternative antiprotease protection against neutrophil elastase; and (d) the lack of antiprotease protection of the lower respiratory tract of PiZ individuals is a chronic process, suggesting their vulnerability to neutrophil elastase is always present.

Bronchi↗
PubMed1981

Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects.

The emphysema associated with the inherited serum deficiency of alpha 1-antitrypsin appears to result from an imbalance between neutrophil elastase and its major inhibitor within the alveolar structures. In the present study we assessed the feasibility of reversing this biochemical defect within the lung via parenteral replacement therapy with an alpha 1-antitrypsin concentrate of normal plasma. A 20--40% polyethylene glycol precipitate of pooled human donor plasma was used to obtain an enriched alpha 1-antitrypsin concentrate devoid of hepatitis B antigen and immunoglobulins. Using this material, five individuals with severe serum alpha 1-antitrypsin deficiency (PiZ phenotype) and advanced emphysema received 4 g of alpha 1-antitrypsin intravenously at weekly intervals for four doses. During this period of weekly replacement therapy alpha 1-antitrypsin serum levels were maintained at greater than or equal to 70 mg/dl, the level likely required for effective antielastase protection of the lung. In addition, assessment of lower respiratory tract antielastase activity by bronchoalveolar lavage demonstrated that parenteral replacement of alpha 1-antitrypsin resulted in establishment of effective antielastase activity within the alveolar structures. There were no untoward side effects consequent to this approach to the replacement therapy of alpha 1-antitrypsin. These results demonstrate that the parenteral replacement of alpha 1-antitrypsin provides a means of obtaining elastase-antielastase balance within the lung of individuals with this serum protease inhibitor deficiency.

Adult↗
PubMed1981

Oxidant injury of lung parenchymal cells.

Hyperoxia and paraquat ingestion are two clinical examples of lung injury thought to be mediated by oxidant mechanisms. An in vitro cytotoxicity assay using freshly explanted 51Cr-labeled lung tissue as the target was used to quantify the ability of hyperoxia and paraquat to directly injure lung parenchymal cells in an environment where indirect mechanisms such as recruitment of inflammatory cells were not possible. There are clear species differences in the susceptibility of lung parenchyma to direct injury by hyperoxia (95% O2) and paraquat (10 microM--10 mM) for 18 h at 37 degrees C, with human and rat lung being more sensitive than rabbit lung. Oxygen radical inhibitors, particularly catalase (1,100 U/ml) and alpha-tocopherol (10 micrograms/ml), reduced hyperoxia and paraquat-induced lung injury, although their ability to do so depended on the oxidant and the species. The simultaneous use of hyperoxia and paraquat accelerated the in vitro lung parenchymal cell injury in each species tested. These studies demonstrate that both oxygen and paraquat can directly injure the cells of the lower respiratory tract without enlisting the aid of additional blood-derived inflammatory cells. In addition, the 51Cr-labeled lung explant assay used for these studies allows for the quantitative assessment of direct lung cell injury and thus may prove useful as an in vitro model by which to investigate lung injury of other etiologies.

Animals↗
PubMed1980

Maintenance of granuloma formation in pulmonary sarcoidosis by T lymphocytes within the lung.

Pulmonary granulomata of sarcoidosis are composed primarily of mononuclear phagocytic cells that are probably derived from blood monocytes. To evaluate the concept that recruitment of blood monocytes to the sarcoid lung is mediated by chemoattractants produced by immune effector cells within the lung, we obtained mononuclear cells from lung and blood of six patients with active pulmonary sarcoidosis, six normal subjects, and six patients with active idiopathic pulmonary fibrosis and studied their ability to secrete a chemotactic factor for monocytes. Lung T lymphocytes from all sarcoidosis patients, but not from normal subjects or patients with idiopathic pulmonary fibrosis, spontaneously secreted such a mediator. Lung T lymphocytes from patients with sarcoidosis secreted more monocyte chemotactic factor than did blood T lymphocytes from the same patients. The accumulation of monocytes in the lung in patients with pulmonary sarcoidosis may be mediated by local production of monocyte chemotactic factor by lung T lymphocytes.

Adult↗
PubMed1980

Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor.

Although considerable progress has been made during the past two decades in the use of androgens to prevent attacks of hereditary angioedema, replacement of the deficient C1-inhibitor protein would provide a useful menas of treatment once an attack has begun. We studied the clinical use of C1 inhibitor that was partly purified on a large scale from pooled plasma. The in vivo efficacy and safety of this protein concentrate were evaluated during 11 intravenous infusions in eight patients with hereditary angioedema. Three patients received the C1-inhibitor preparation during an asymptomatic period. Increases in serum C4 activity provided evidence of the biologic activity of the infused inhibitor. Intravenous administration of the concentrate during acute abdominal or laryngeal attacks of hereditary angioedema in five patients resulted in abatement of symptoms in addition to increased serum C4 activity. No untoward effects of the intravenous administration of the C1 inhibitor were observed in these eight patients. Thus, this C1-inhibitor preparation seems to offer the potential for safe, effective replacement therapy and may provide a means of controlling an attack of hereditary angioedema that is in progress.

Angioedema↗
PubMed1980

Regulation of the release of alveolar macrophage-derived neutrophil chemotactic factor.

In order to further clarify the physiologic role of the neutrophil-directed chemotactic factor derived from alveolar macrophages, we evaluated those stimuli that possess the potential to regulate the quantity and kinetics of its release in vitro. In short-term culture, particulate stimuli (Staphylococcus albus, Micropolyspora faeni, zymosan, and Sepharose 4B) as well as IgG-immune complexes induced normal guinea pig alveolar macrophages to release significant quantities of this chemotactic factor. In addition, serum opsonization of particulate stimuli resulted in significant augmentation of release of the chemotactic factor from alveolar macrophages responding to these particles. This serum augmentation was associated with the fixation of C3b to the particle surface via the alternative complement pathway. Purified C3b, by itself, was also capable of inducing release of this macrophage-derived mediator. Partial characterization of this chemotactic factor revealed that it was a material of low molecular weight (400 to 600 daltons), and that it was antigenically and physically distinct from C5a. These studies suggested that the induction of chemotactic factor release from alveolar macrophages responding to microorganisms, noninfectious particulates, antigen-complexed IgG, and C3b may contribute to the pathophysiologic events observed in those lung diseases characterized by an influx of neutrophils into the pulmonary parenchyma.

Animals↗
PubMed1980

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↗
PubMed1980

Human alveolar macrophage-derived chemotactic factor for neutrophils. Stimuli and partial characterization.

The presence of neutrophils within the lung is a characteristic feature of a variety of lung diseases. To evaluate the potential role of alveolar macrophages in modulating the migration of neutrophils to the lung, normal human alveolar macrophages obtained from volunteers by bronchopulmonary lavage, were exposed for various periods of time in vitro to heat-killed microorganisms, and noninfectious particulates, immune complexes, and the macrophage supernates were evaluated for chemotactic activity. The microorganisms, noninfectious particulates, and immune complexes were chosen as stimuli for alveolar macrophages because these stimuli are representative of a spectrum of pathogenic agents that cause neutrophil accumulation in the lower respiratory tract. After incubation with each of these stimuli, alveolar macrophages released low molecular weight (400-600) chemotactic factor(s) (alveolar macrophage-derived chemotactic factor[s] [AMCF]) with relatively more activity for neutrophils than monocytes or eosinophils. Checker-board analysis of the AMCF revealed that the factor was primarily chemotactic and not chemokinetic for neutrophils. The selectivity for neutrophils vs. monocytes could not be explained by a selective deactivation of monocytes, because the AMCF was more potent in deactivating neutrophils than monocytes. Partial characterization of AMCF demonstrated it was heterogeneous with the following features: (a) stable to heating at 56 and 100 degrees C for 30 min; (b) stable over a pH range of 1.0 to 12.0 for 60 min; (c) stable after exposure to trypsin, papain, chymotrypsin, collagenase, and elastase; (d) partially inhibited by serum chemotactic factor inhibitor(s); (e) two major isoelectric points (pI 7.6 and 5.2); and (f) partially extractable into ethyl acetate, ether, and hexane. Although AMCF was, at least, partially lipid in nature, it did not appear to be similar to previously described lipid chemotactic factors (e.g., hydroxy-derivatives of 5,8,10,14-eicosatetraenoic acid); analysis by gas chromatography-mass spectrophotometry of AMCF extracted into ethyl acetate did not reveal the presence of 5,8,10,14-eicosatetraenoic acid. The macrophage supernates containing the AMCF also stimulated normal human neutrophils to release lysozyme and lactoferrin but not lactate dehydrogenase. These studies suggest that a wide variety of potentially pathogenic stimuli induce normal alveolar macrophages to generate a low molecular weight chemotactic factor(s) that preferentially attracts neutrophils. Because alveolar macrophages are normal residents of alveoli, it is likely that by releasing this factor(s) macrophages play a significant role in amplifying the inflammatory processes seen in many acute and chronic lung diseases.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1980

Distribution of complement receptors on human normal and malignant mononuclear cells.

Mononuclear cells from normal human subjects and patients with chronic lymphocytic leukemia (CLL), chronic lymphosarcoma cell leukemia (LCL), and hairy cell leukemia (HCL) were labeled with fluoresceinated, purified human C3b (FI-C3b) and analyzed using the fluorescence-activated cell sorter (FACS). FI-C3b labeled 17.6% +/- 6.0% of peripheral blood mononuclear cells (PBM) from 20 normal subjects, which, when separated by the FACS, consisted of B lymphocytes and approximately 5% monocytes. Analyses in which either monocytes or B lymphcoytes were excluded from consideration demonstrated that both these cell types were labeled by the FI-C3b with a heterogeneous distribution of fluorescence intensity, indicating either heterogeneity of CR density or variable avidity of individual CR for the FI-C3b. FACS profiles of PBM ( < 5% monocytes) from 14 of 15 patients with CLL showed a homogeneous distribution of very low fluorescence intensity, with > 60% of the cells being slightly more fluorescent than unlabeled controls. This low, homogeneous distribution of fluorescence is strikingly similar to profiles of CLL cells labeled with anti-Ig reagents and suggests homogeneity of low CR density and/or avidity. Similarly, CR+ mononuclear cells from five patients with HCL and three patients with LCL displayed more homogeneous FI-C3b labeling than normal CR+ PBM. Homogeneity of FI-C3b binding to CLL, LCL, and HCL cells further supports the concept for a clonal origin for these disorders.

Blood Cells↗
PubMed1979

Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans.

Current concepts of the pathogenesis of emphysema suggest that it results from an imbalance of elastase and antielastase activity within the alveolar structures. Although emphysema that is associated with hereditary deficiency of serum alpha 1-antitrypsin conforms to this scheme, the major risk factor in the more common form of emphysema is cigarette smoking. A study was designed to evaluate the premise that cigarette smoking may be associated with an acquired, functional defect in lung alpha 1-antitrypsin. Determination of the antielastase activity of alpha 1-antitrypsin obtained from the lungs of smoking and nonsmoking individuals revealed a nearly twofold reduction in the functional activity of this elastase inhibitor in the lungs of cigarette smokers. These data suggest that cigarette smokers may lose some of the normal antielastase protective screen of the lower respiratory tract, making them more vulnerable to destructive lung disease.

Adult↗
PubMed1979

Collagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis.

To test the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated through collagenase present in the lower respiratory tract, we used the fiberoptic bronchoscope to obtain fluid from the lower respiratory tract of 24 patients with IPF, 18 controls and nine patients with sarcoidosis. The fluid was analyzed for a variety of enzymes, including collagenase. Fifteen of 21 patients with IPF showed collagenase activity, whereas normal controls and patients with sarcoidosis showed none (P greater than 0.001, for all comparisons). In two patients with IPF who were re-evaluated after eight to 24 months, the collagenase activity was persistent. Fluid from patients with IPF also contained elevated levels of a non-specific neutral protease (P greater than 0.01 compared with controls), but there was no elastase activity in fluid from patients with IPF or from controls. The collagenase found in lavage fluid in IPF cleaved lung collagen into collagenase-specific TCA and TCB fragments. We conclude that in IPF the collagen of the lung is subjected to sustained lysis, followed by disordered resynthesis, and that the presence of active collagenase in the lower respiratory tract is a specific feature of the alveolitis associated with this disease.

Adult↗
PubMed1979

Localization of the immune response in sarcoidosis.

Pulmonary sarcoidosis is an interstitial disease characterized by granulomas within the lung parenchyma, anergy to a variety of skin tests, and decreased numbers of circulating T-lymphocytes. To evaluate the effector cell populations present at sites of disease in patients with active pulmonary sarcoidosis, inflammatory and immune effector cells were isolated from lung via bronchoalveolar lavage and compared to comparable cell populations from the peripheral blood of the same patients and similar cell populations of normal subjects and patients with idiopathic pulmonary fibrosis. Patients with sarcoidosis had a marked increase in the percentage of T-lymphocytes in the lung despite a significant peripheral blood T-lymphocytopenia. In addition, many of these T-lymphocytes demonstrated surface marker characteristics associated with lymphocyte activation, and they spontaneously secreted leukocyte inhibitory factor. In contrast to patients with sarcoidosis, normal subjects and patients with idiopathic pulmonary fibrosis had similar percentages of T-lymphocytes in lung and blood, and there was no evidence for T-lymphocyte activation. Analysis of lymphocytes in uninvolved marrow from 7 of 8 patients with sarcoidosis revealed proportions of T-lymphocytes similar to those in the marrows of normal subjects and patients with idiopathic pulmonary fibrosis. In comparison, one patient with sarcoidosis had large numbers of T-lymphocytes in bone marrow, but only in areas where there were granulomas in the marrow. These studies suggest that: (1) the alveolitis of pulmonary sarcoidosis is characterized by large numbers of activated T-lymphocytes, and (2) there is an anatomic localization of the immune response in sarcoidosis in that analysis of uninvolved tissues such as peripheral blood may not reflect local immune responses at sites of granuloma formation.

Adult↗
PubMed1979

Acute hypersensitivity pneumonitis: serial changes in lung lymphocyte subopulations after exposure to antigen.

The earliest lesion in hypersensitivity penumonitis is an acute inflammatory alveolitis characterized by parenchymal hemorrhage and accumulations of polymorphonuclear leukocytes within the lung. In many instances, this initial lesion is replaced by a more chronic alveolitis, with development of mononuclear cell interstitial infiltrate, granuloma formation, and interstitial fibrosis. To help define the mechanisms by which the early polymorphonuclear leukocyte alveolitis of acute hypersensitivity pneumonitis evolves into a chronic mononuclear-cell process, an animal model of the disease was developed using guinea pigs sensitized by footpad injeection with either ovalbumin (OVA) in complete Freund's adjuvant (CFA), CFA alone, or phosphate-buffered saline. Ten days after sensitization, the animals were challenged by intratracheal injection of either particulate OVA, particulate human serum albumin, or phosphate-buffered saline alone, and their lungs were evaluated sequentially for changes in histologic appearance and lymphocyte subpopulations. After challenge, only animals sensitized with CFA plus OVA and challenged with particulate OVA developed pulmonary lesions consistent with acute hypersensitivity pneumonitis. Within 4 h after challenge, these animals developed an acute hemorrhagic alveolitis that persisted for more than 24 h. By 48 to 96 h, the alveolitis evolved into a predominantly mononuclear-cell infiltrate. This change in the histologic appearance of the lungs in these animals was preceded by a rapid increase in the proportions of T-lymphocytes within the lungs, noted by 24 h after intratracheal challenge with specific antigen. Before intratracheal challenge with antigen, lung lymphocytes from only the group of animals immunized with CFA plus OVA were capable of proliferating on exposure to OVA in vitro. In the same group, lymphocytes recovered from the lung after intratracheal particulate OVA demonstrated blast transformation in vivo, a phenomenon not found in any other group. These studies suggest that the alveolitis of acute hypersensitivity pneumonitis is rapidly associated with changes in populations of immune effector cells before development of the mononuclear cell alveolitis characteristic of the chronic disease.

Alveolitis, Extrinsic Allergic↗