PubMed Health⌕ Search

Biomedical subjects

J E Gadek

Publications and source records attributed to J E Gadek.

At least 55 records · Page 3Linked to original sources
PubMed1986

Lung neutrophils in the adult respiratory distress syndrome. Clinical and pathophysiologic significance.

Although neutrophils are of pathogenetic importance in various animal models of acute lung injury, their role in the adult respiratory distress syndrome (ARDS) is unclear. To study the significance of lung neutrophils in this disorder, patients with ARDS (n = 11) were evaluated by bronchoalveolar lavage within 24 h of admission to the intensive care unit. Patients with non-ARDS respiratory failure requiring mechanical ventilation (n = 4) and normal volunteers (n = 12) were also studied. Neutrophils constituted 67.6 +/- 9.8% of recovered lavage cells in patients with ARDS compared with only 4.0 +/- 2.4% of cells in mechanically ventilated control patients and 0.8 +/- 0.2% in normal volunteers (p less than 0.005, both comparisons). Furthermore, in patients with ARDS (n = 6) evaluated serially by bronchoalveolar lavage at 72-h intervals, neutrophil percentages decreased from 91 +/- 3.2% (initial lavage) to 42.8 +/- 12% (final lavage) (p less than 0.005). Lung neutrophils also predicted the severity of abnormalities in gas exchange and lung protein permeability. That is, the percentage of neutrophils correlated directly with the alveolar-arterial Po2 difference (r = 0.69, p less than 0.01) and lavage fluid total protein concentrations (r = 0.62, p less than 0.01). Because large numbers of lung neutrophils were present in these patients, ARDS lavage fluid was assayed for neutrophil mediators relevant to the pathogenesis of acute lung injury. Neutrophil elastase activity was not detected in any ARDS lavages, although elastase was antigenically present in most samples and appeared to be complexed to alpha-1-antitrypsin. In contrast to elastase, neutrophil collagenase was readily detectable in ARDS fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Evaluation of danazol therapy for patients with PiZZ alpha-1-antitrypsin deficiency.

An inherited deficiency of alpha 1-antitrypsin with blood concentrations less than 80 mg/dl is associated with the accelerated development of emphysema. Current concepts of the pathogenesis of emphysema suggest that an imbalance between neutrophil elastase and alpha 1-antitrypsin in the lung allows neutrophil elastase to work unimpeded to destroy the alveolar structures. Because the common form of the inherited deficiency (homozygous Z) results from impaired hepatic release of alpha 1-antitrypsin, one therapeutic approach to increase plasma and hence lung alpha 1-antitrypsin concentrations is to enhance hepatic release or production of alpha 1-antitrypsin. In a preliminary trial with 6 alpha 1-antitrypsin-deficient subjects, we have previously shown that in 1 month, the impeded androgen danazol can augment serum alpha 1-antitrypsin concentrations by 37%. To evaluate the use of impeded androgens in alpha 1-antitrypsin deficiency on a broader scale, we have treated: 43 homozygous Z patients with danazol 200 mg given orally 3 times a day for 30 days; 6 homozygous Z patients with a similar danazol dose but given for 6 to 18 months; and 7 homozygous Z patients with stanazolol, another synthetic androgen, 2 mg given orally 3 times a day for 30 days. Of the 43 patients treated with danazol for 1 month, 23 (53%) responded with a serum alpha 1-antitrypsin concentration greater than or equal to 20% higher than baseline, an average increase of 52% over the pretreatment concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Protein permeability in the adult respiratory distress syndrome. Loss of size selectivity of the alveolar epithelium.

Small amounts of plasma protein normally reach the alveolar epithelial surface by a size-selective process that restricts the passage of very large molecules. Size selectivity may be compromised in the lungs of patients with the adult respiratory distress syndrome (ARDS). To assess this question, bronchoalveolar lavage fluid (BALF) from normal volunteers (n = 11), cardiac edema patients (n = 3), and ARDS patients (n = 8) was compared. Mean total protein in ARDS BALF was greater than 12 times the levels in normals or cardiac edema patients. BALF/plasma total protein ratios and measurements of epithelial lining fluid protein also separated the patients groups. The large proteins IgM and alpha 2-macroglobulin were found in ARDS BALF at greater than 90 times the concentrations of normal or cardiac edema fluid. The relationship of distribution coefficient vs. log molecular weight for seven proteins (54,000-900,000 mol wt) hyperbolically increased in normals but was flat in ARDS patients. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a paucity of high molecular weight proteins in normal and cardiac edema BALF, but demonstrated the full spectrum of plasma proteins in ARDS BALF. We conclude that normal size selectivity is preserved in cardiac edema but is destroyed by the alveolar-capillary injury of ARDS.

Adult↗
PubMed1985

Hypoxia results in an increase in total systemic shunt flow in dogs.

There is considerable evidence to indicate that blood flow to many organs changes in response to hypoxia. However, since blood may traverse nutrient capillaries or be shunted through precapillary arteriovenous channels, measurements of total organ blood flow alone may not accurately reflect microcirculatory adaptations to hypoxia. To test this hypothesis, we determined the effect of controlled normoxic ventilation (PO2 = 86.4 +/- 2.8 Torr; N = 10) and controlled hypoxic ventilation (PO2 = 45.9 +/- 1.0 Torr; N = 5) on cardiac output, nutrient blood flow and total systemic shunt flow in dogs using radiolabelled 15 micrometers microspheres. The microspheres were injected from left heart catheters in each animal and total systemic shunt flow was estimated from the radioactivity present in pulmonary artery reference samples. Cardiac output, as well as nutrient blood flow to the heart and brain, was similar in both hypoxic animals and normoxic controls. Although we could detect no significant changes in nutrient blood flow to the remaining organs in response to hypoxia, total systemic shunt flow increased from a baseline value of 4.4% of cardiac output to a maximum value of 7.9% of cardiac output in hypoxic animals compared to 2.3% of cardiac output in normoxic animals at a similar time point (P less than 0.01). This hypoxia-induced increase in total systemic shunt flow may contribute to the overall decline in organ function often observed in this setting.

Animals↗
PubMed1985

Effects of breathing pattern on inspiratory muscle endurance in humans.

Endurance of the inspiratory muscles was measured in normal volunteers using a threshold resistance that produced a relatively constant mouth-pressure load, independent of inspiratory flow rate (VTI). Breathing pattern was controlled by visual feedback from an oscilloscope. Endurance was measured as the length of time (Tlim) a target VTI could be maintained with maximum effort. Effects of changes in breathing pattern on Tlim were compared with control measurements made the same day. Increases in VTI or in duty cycle (inspiratory time/total period) shortened Tlim, whereas decreases lengthened Tlim. However, effects of changes in VTI were less than equivalent changes in tidal volume produced by alterations in duty cycle. Furthermore, when two breathing pattern changes were altered simultaneously to keep the rate of external inspiratory work (Winsp) constant, significant effects due to changes in duty cycle were still observed. In conclusion, 1) both VTI and duty cycle have significant effects on measurements of inspiratory muscle endurance and 2) the effects of VTI are less than the effects of duty cycle for the same Winsp.

Adult↗
PubMed1985

Inspiratory muscle conditioning using a threshold loading device.

We demonstrate the effectiveness of a new conditioning technique for increasing the strength and endurance of the inspiratory muscles. The technique employs a threshold loading device which allows for maximization of exercise intensity with a minimum of exercise duration. After ten weeks, with approximately 25 minutes of exercise time per week, four test subjects showed an average increase in maximum inspiratory pressure (PImax) of 50 (+/- 9 SD) cm H2O (p less than 0.02), whereas four control subjects undergoing submaximal inspiratory muscle exercise showed no significant change. The time the test subjects could endure 65 percent of their prestudy PImax increased from an average of 3.58 +/- 1.65 SD min to over 10 min in all four subjects. No significant change was seen in control subjects. Further testing showed the test subjects could endure 100 percent of their prestudy PImax after conditioning for an average duration 5.15 +/- 1.65 min. This technique should be useful for conditioning the inspiratory muscles in subjects with pulmonary disease.

Adolescent↗
PubMed1985

Adult bronchiolitis. Evaluation by bronchoalveolar lavage and response to prednisone therapy.

Four adult patients with biopsy-proven bronchiolitis were identified and prospectively evaluated. Each patient presented with the rapid onset (weeks to months) of severe respiratory disease that was clinically distinct from asthma, chronic bronchitis, bronchiectasis, cystic fibrosis, and emphysema. Bronchiolitis patients were evaluated by pulmonary function testing and bronchoalveolar lavage (BAL) before and after two months of treatment with 1 mg/kg/day of prednisone. Initial BAL results of bronchiolitis patients were compared to those of cigarette smokers with chronic bronchitis (n = 4), asymptomatic cigarette smokers (n = 5), and normal nonsmoking volunteers (n = 5). Neutrophils comprised 53 +/- 13 percent of the cells recovered by BAL in bronchiolitis patients but only 3 +/- 2 percent of the cells in chronic bronchitis patients, 1.5 +/- 0.6 percent of the cells in asymptomatic smokers, and 0.3 +/- 0.3 percent of the cells in normal volunteers (p less than 0.01, all comparisons). Moreover, prednisone produced a striking decrease in lower respiratory tract neutrophils (53 +/- 13 percent to 8 +/- 3 percent, p less than 0.05) in all bronchiolitis patients while lung function either improved (two patients) or remained unchanged (two patients). These findings suggest a central role for the neutrophil in bronchiolitis and argue that BAL may be clinically useful in the diagnosis and management of these patients.

Adult↗
PubMed1984

Hereditary emphysema in the tight-skin mouse. Evaluation of pathogenesis.

The tight-skin (Tsk/+) mouse is a genetically determined model characterized by alveolar enlargement and physiologic evidence of emphysema. Morphologic evaluation of the lungs of these animals demonstrated increased numbers of potential protease-secreting cells (alveolar macrophages and neutrophils) in the lower respiratory tract prior to development of the emphysematous lesions. Quantitation of the neutrophils in the lungs of these animals was carried out by bronchoalveolar lavage. In the Tsk/+ mice, neutrophils constituted 3.5 +/- 2% of all inflammatory and immune effector cells present compared with 0.4 +/- 0.1% in control (+/+) mice (p less than 0.01). The Tsk/+ animals had no evidence of infection to explain the presence of the neutrophils and had normal proportions of lung T- and B-lymphocytes, suggesting that their lungs were immunologically normal. There was no evidence that the Tsk/+ mice have an antiprotease deficit; the capacity of serum of Tsk/+ mice to inhibit neutrophil elastase was no different from that of control +/+ animals. However, the fact that these animals have a persistent low level macrophage-neutrophil alveolitis prior to the development of the emphysematous lesion implies that the lung destruction may be associated, in part, with a chronic protease-antiprotease imbalance, similar to that hypothesized for human emphysema.

Animals↗
PubMed1984

Eosinophil-mediated injury to lung parenchymal cells and interstitial matrix. A possible role for eosinophils in chronic inflammatory disorders of the lower respiratory tract.

Eosinophils are a common component of the inflammation of the lower respiratory tract that characterizes the interstitial lung disorders. Bronchoalveolar lavage analyses (n = 680) of 251 patients with interstitial lung disease demonstrated that eosinophils represented greater than 5% of the effector cells comprising the alveolitis in 20% of all lavages. In contrast, lavage of normal individuals (n = 117) showed that eosinophils were never greater than 5% of the total effector cells recovered. To evaluate a possible role for eosinophils in mediating some of the cellular and connective tissue matrix derangements of the lung parenchyma found in interstitial disease, eosinophils were evaluated for the presence of proteases capable of cleaving connective tissue proteins found in the lung and for the ability to mediate cytotoxicity to lung parenchymal cells. Evaluation of guinea pig and human eosinophils demonstrated that eosinophil granules contained a collagenase that specifically cleaved human collagen types I and III, the two major connective tissue components of the human lung parenchyma. In contrast, the eosinophil did not contain an elastase or a nonspecific neutral protease. The eosinophil collagenase appeared to be a metalloprotease, as it was inhibited by ethylenediaminetetraacetate but not by phenylmethanesulfonyl-fluoride or alpha 1-antitrypsin. The eosinophil also has the capacity to injure lung parenchymal cells. Without further stimulation, eosinophils purified from peritoneal exudates of guinea pigs demonstrated spontaneous cytotoxicity for human lung fibroblasts (HFL-1), cat lung epithelial cells (AK-D) and rat lung mesothelial cells (I6B). Under identical conditions, the epithelial cells were more sensitive to eosinophil-mediated cytotoxicity than the fibroblasts or mesothelial cells (P less than 0.01), consistent with the clinical observation that in the interstitial disorders, the alveolar epithelial cells are damaged more commonly than fibroblasts or pleural cells. The eosinophil-mediated cytotoxicity could be partially inhibited by the antioxidants catalase and dimethylsulfoxide suggesting that toxic oxygen radicals play a role in mediating the cellular damage. Importantly, eosinophils purified from bronchoalveolar lavage of human interstitial lung disease also demonstrated spontaneous cytotoxicity for lung epithelial cells. These observations demonstrate that eosinophils are frequent participants of the alveolitis of the interstitial lung disorders and suggest that these cells have the potential to damage the parenchymal cells and collagen matrix of the lower respiratory tract.

Animals↗
PubMed1984

Role of connective tissue proteases in the pathogenesis of chronic inflammatory lung disease.

The normal structure and function of the human lung is dependent on the maintenance of the connective tissue matrix. These structural macromolecules provide the template for normal parenchymal cell architecture on which efficient gas exchange depends. In addition, the organization and amount of this extracellular matrix accounts for much of the mechanical behavior of the lung parenchyma during the respiratory cycle. The preservation of this intricate connective tissue scaffold depends on the lung's capacity to prevent enzymatic disruption of the component matrix proteins. Specifically, the integrity of the normal connective tissue skeleton of the lung is determined by the maintenance of a balance between proteases capable of cleaving these structural elements and the specific protease inhibitors. The normal extracellular matrix is preserved when the local concentrations of protease inhibitors prohibits expression of active connective tissue proteases within the lung parenchyma. Conversely, the disruption of lung structure during the course of acute and chronic inflammatory diseases of the lung is often associated with an imbalance of protease-antiprotease activity. The consequence is the expression of unimpeded proteolytic attack on the connective tissue matrix of the lung. In this context, the nature of the pulmonary lesion and its physiologic consequences, reflect the specificity of the expressed proteases for the individual connective tissue components. Experimental evidence suggests that the differential expression of collagenase and elastase, prototypes of connective tissue proteases, may determine whether the pathologic outcome is fibrosis (e.g., idiopathic pulmonary fibrosis) or destruction (e.g., emphysema) of the alveolar structures.

Animals↗
PubMed1983

Cleavage of membrane-bound C3b and C3bi by viable human neutrophils (PMN).

Cleavage of C3 by purified leukocyte enzymes and crude extracts of human polymorphonuclear leukocyte (PMN) granules has been reported. We demonstrate that viable PMN mediate the cleavage of erythrocyte-bound C3b and C3bi via cell-associated proteases. Greater than 50% of 125IC3(x) was released from EAC43bix during a 5-min incubation with viable PMN at 37 degrees C. More than a 30-min incubation was required for substantial release from EAC43bx. Culture fluids from PMN suspensions had limited cleaving ability; cleavage of cell-bound C3bx and C3bix was only partially reduced when PMN were preincubated with high levels of soluble C3 which completely blocked EAC43b rosettes. Thus, cell-to-cell contact between opsonized erythrocytes and viable PMN with surface-associated proteases are responsible for cleavage of these opsonic sites. The effect of defined protease inhibitors on PMN cleaving activity as well as on purified leukocyte elastase was examined. Phenylmethylsulfonyl fluoride (PMSF) and the leukocyte elastase inhibitor, methoxy-succinate-alanine-alanine-valine-chloromethyl ketone (MeO) each inhibited cleavage of C3b by 90% and C3bi by 60%. In contrast, the cathepsin-G inhibitor, benzyloxy-carbonyl-glycine-leucine-phenylalanine-chloromethyl ketone (Z) inhibited C3b and C3bi cleavage by less than 20 and less than 5%, respectively. Ethylenediaminetetra-acetate (EDTA), which had a minimal effect on soluble leukocyte elastase, also inhibited PMN-related release. Thus, elastase appeared to be the principle but not the only enzyme responsible for cleavage of C3b and C3bi. PMSF and MeO had a minimal effect on the activity of purified C3bINA (Factor I); and PMN-mediated release of C3b fragments was not inhibited by anti-Factor I and anti-beta 1H (Factor H) IgG and Fab. Thus, these control proteins are not involved in the PMN-mediated cleavage under study. PMN-mediated cleavage of C3b was also inhibited when PMSF- and MeO-treated PMN were washed to remove the fluid phase phase protease inhibitor before adding EAC43b. This suggests that proteases localized in the PMN membrane, prior to the adherence of EAC43b, are responsible for C3b cleavage. Normal human serum was effective in blocking PMN-mediated release activity, while serum from alpha 1 antitrypsin-deficient patients was minimally effective. This suggests a mechanism for the in vivo regulation of PMN-mediated release of C3b and C3bi from opsonized particles by the natural plasma protease inhibitors.

Amino Acid Chloromethyl Ketones↗
PubMed1983

Fibronectin mediates cell attachment to C1q: a mechanism for the localization of fibrosis in inflammatory disease.

Chronic inflammatory processes frequently lead to the abnormal replacement of normal tissue elements by increased numbers of fibroblasts and fibrous connective tissue, i.e., fibrosis. Since the growth of fibroblasts requires that these cells be attached to an extracellular support, the current study was designed to determine if the interaction between the fibroblast attachment factor fibronectin and the C1q component of complement could support fibroblast attachment and growth and thus could form a basis for the attachment of fibroblasts in abnormal tissue locations in those inflammatory states where C1q is bound. Fibronectin purified from human plasma supported attachment of both Chinese hamster ovary cells and of normal fetal lung fibroblasts (HFL-1) to C1q coated substrates. The attachment activity was approximately twice that of attachment to collagen, and was specific, as no attachment occurred to albumin coated substrates. Cells attached to C1q substrates demonstrated characteristic 'spreading' similar to those on collagen. Moreover, the C1q substrate resembled collagen in its ability to support fibroblast growth. Further, the ability of the interaction between C1q and fibronectin to mediate attachment of fibroblasts to immune complexes was demonstrated by the formation of fibroblast-red blood cell-immune complex rosettes, a process that was dependent on both fibronectin and C1q. Thus, the interaction between fibronectin and C1q could serve as the basis for fibroblast attachment and growth in abnormal tissue sites where immune complexes are formed and could be a contributing factor to the development of fibrosis.

Antigen-Antibody Complex↗
PubMed1981

Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema.

This study suggests one mechanism by which alveolar macrophages accumulate in the lung in pulmonary emphysema: elastin fragments generated at the diseased sites are potent chemoattractants for monocytes, the precursors of the macrophages. The most chemotactic elastin fragments have a molecular weight between 10,000 and 50,000 and are active at concentrations as low as 3 nanograms per milliliter. By comparison, elastin fragments with higher molecular weights and desmosines are active at concentrations greater than 0.3 microgram per milliliter. In addition, preincubation of monocytes with the 10,000- to 50,000-dalton elastin impairs the ability of the cells to migrate toward elastin fragments but not toward activated serum. Fragments of tropoelastin are not chemotactic for monocytes. Because elastin, but not tropoelastin, contains lysyl-derived cross-links, these structures may be the active chemotactic site on the elastin fragments.

Cells, Cultured↗
PubMed1981

Mechanisms of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis.

Neutrophils are a characteristic feature of the alveolitis of idiopathic pulmonary fibrosis (IPF). a chronic disorder limited to lung. One mechanism by which neutrophils may be selectively attracted to lung and not other tissues is via the secretion of the neutrophil-specific chemotactic factor by alveolar macrophages. To evaluate the role of alveolar macrophages in modulating the migration of neutrophils to he lung in IPF, alveolar macrophages, obtained by bronchoalveolar lavage of patients with IPF, were evaluated for their ability to release a chemotactic factor for neutrophils. Unstimulated alveolar macrophages from normal individuals did not release the factor. In patients with IPF, there was a significant correlation between the proportions of neutrophils in lavage fluid and the release of a chemotactic factor for neutrophils by alveolar macrophages (p less than 0.001). The chemotactic factor released by IPF alveolar macrophages was of low molecular weight (400-600), at least partially lipid in nature, and preferentially attracted neutrophils compared with monocytes. Several lines of evidence suggested that immune complexes in the lung stimulated alveolar macrophages of patients with IPF to release the chemotactic factor. First, immune complexes stimulated normal macrophages to release the factor.Second, there was a significant correlation between the release of the chemotactic factor by IPF alveolar macrophages and the levels of immune complexes in bronchoalveolar lavage fluid. Third, bronchoalveolar lavage fluid containing immune complexes stimulated normal macrophages to release the factor. Fourth, IPF alveolar macrophages that released large amounts of the chemotactic factor had an apparent suppression of their immunoglobulin (Ig)G Fc receptor function, suggesting that immune complexes were bound to their surface. In contrast, the IgG Fc receptor function of IPF alveolar macrophages that released only small amounts of the factor was similar to that of normal macrophages. These studies suggest that neutrophils are attracted to the lung in patients with IPF by a potent chemotactic factor released by alveolar macrophages that have been stimulated, in vivo, via their IgG Fc receptor by immune complexes.

Adult↗