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Biomedical subjects

J E Gadek

Publications and source records attributed to J E Gadek.

At least 19 recordsLinked to original sources
PubMed1992

Adverse effects of neutrophils on the lung.

Studies of both emphysema and adult respiratory distress syndrome (ARDS) support the premise that lung injury is due to unregulated host defense mechanisms. A major mediator of host defense and injury is the neutrophil, which is relatively incapable of regulating its own function. Accordingly, defects in regulatory mechanisms allow neutrophils to damage the lungs. Emphysema serves as a prime example of this link between host defense and injury. Hereditary emphysema is caused by a deficiency in alpha 1-antitrypsin (alpha 1-AT), a protease inhibitor. The decreased levels of this enzyme in affected individuals result in inadequate protection against neutrophil elastase and other proteolytic enzymes, leading to lung damage. Patients with acquired emphysema, associated with cigarette smoking, have normal levels of alpha 1-AT in their lungs. However, the alpha 1-AT in these patients has a reduced ability to associate with and inhibit the action of neutrophil elastase. Thus, both types of emphysema involve an alteration in the balance between proteases and antiproteases. The lung damage observed in patients with ARDS also appears to involve neutrophils, but in this case elastase may not be the culprit. In these patients, neutrophil elastase appears to be inactivated by high levels of alpha 1-AT, thus preventing excess protease action. It is hoped that a more complete understanding of the mechanisms involved in host defense and injury will enable the development of specific therapeutic interventions, such as the alpha 1-AT replacement therapy that is being used to treat patients with hereditary emphysema.

Emphysema↗
PubMed1991

Initial recruitment of neutrophils to alveolar structures in acute lung injury.

The adult respiratory distress syndrome and bacterial pneumonia are both characterized by an influx of neutrophils into the lung. The neutrophil has been implicated as having a "pathological" role in adult respiratory distress syndrome, in contrast to its role in bacterial pneumonia. We hypothesized that processes resulting in neutrophil recruitment to the lung are distinct, depending on whether the inflammatory stimulus arises in the intravascular or the alveolar compartment of the lung. Anesthetized sheep with lung lymph fistulas were utilized to access the three compartments of the lung relevant to studies of transpulmonary neutrophil migration. Serum, lung lymph, and bronchoalveolar lavage fluid were studied for neutrophil influx and chemotactic activity before and after administration of endotoxin by either an intravascular or inhaled alveolar route. Both groups developed significant neutrophil influx into the lymph and bronchoalveolar lavage fluid by 3 h postendotoxin. Those animals receiving intravascular endotoxin developed chemotactic gradients opposing neutrophil migration into the lung in contrast to animals receiving alveolar endotoxin, suggesting that neutrophil influx into the lung occurs by random migration.

Animals↗
PubMed1990

The protease-antiprotease balance within the human lung: implications for the pathogenesis of emphysema.

Critical elements of the mechanisms of emphysema remain to be clarified. However, taken together, the existing evidence supports the concept that alveolar matrix destruction ensues as the regulatory interplay between oxidant and protease expression is subverted. The final common pathway of matrix destruction links the inherited and acquired forms of emphysema through the ultimate expression of unimpeded neutrophil elastase.

Animals↗
PubMed1990

Analysis of airflow obstruction by bronchoalveolar lavage following bone marrow transplantation. Implications for pathogenesis and treatment.

The development of airflow obstruction, most often due to bronchiolitis, is a significant cause of morbidity and mortality in recipients of allogeneic BMT. Current consensus holds that this airways disease is the result of chronic GVHD and/or CMV infection. However, recent studies of idiopathic forms of BRO have demonstrated a striking influx of neutrophils into the lungs of affected individuals. Reasoning that the immune cell populations involved in tissue injury associated with either CGVHD or CMV infection would consist predominantly of lymphocytes, we tested this hypothesis by performing BAL in 12 adults with minimal or absent smoking histories who developed significant airflow obstruction (FEV1/FVC = 80.7 +/- 1 percent preBMT and 56.8 +/- 2.4 percent postBMT; p less than 0.001) following allogeneic BMT. Eleven of 12 patients had evidence of chronic, stable GVHD at the time of the study. In contrast to non-BMT patients with BRO, BAL defined two distinct patterns of lung inflammation in the BMT patients with airflow obstruction: (a) neutrophil predominance (five patients; neutrophil percentage = 20.2 +/- 6.6 percent); and (b) lymphocyte predominance (three patients; lymphocyte percentage = 35.9 +/- 12.1 percent). These data suggest that the pattern of inflammation in the lungs of BMT patients with BRO is not uniform and is not associated with active microbial infection. From these results, it is inferred that the airways injury in BMT patients may reflect diverse pathogenetic mechanisms initiated in the context of CGVHD and cytotoxic drug therapy.

Adult↗
PubMed1990

Multiple organ failure.

Diagnostic criteria for individual organ system failure are imprecise, a factor that adds a considerable amount of ambiguity to this area of clinical research. Nonetheless, multiple organ failure is a common sequela of ARDS and other catastrophic medical and surgical illnesses that continues to limit patient survival. The cumulative weight of investigative evidence currently supports the premise that concepts of acute respiratory failure must encompass the abnormal gas exchange in the systemic as well as the pulmonary microvasculature. In this context, we need not dispense with the term ARDS, as respiratory distress applies equally to the nonpulmonary organs as well as the lungs.

Bacterial Infections↗
PubMed1989

Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure.

Although chronic eosinophilic pneumonia is a well-known disorder, acute eosinophilic pneumonia has not been as well characterized. We describe the clinical features, results of bronchoalveolar lavage, and follow-up studies of four patients with acute eosinophilic pneumonia. The patients presented with an acute febrile illness, severe hypoxemia (partial pressure of arterial oxygen less than 60 mm Hg), diffuse pulmonary infiltrates, an increased number of eosinophils (mean +/- SEM, 42 +/- 4.8 percent) in bronchoalveolar-lavage fluid, and an absence of infection and previous atopic illness. The illness resolved rapidly after treatment with erythromycin and corticosteroids. The patients received doses of oral prednisone that were tapered over 10 days to 12 weeks, and none have relapsed since the steroids were discontinued. After a minimum follow-up period of five months, clinical evaluation, chest radiography, and pulmonary-function tests have shown no residual abnormalities attributable to the acute eosinophilic pneumonia. Follow-up bronchoalveolar lavage has demonstrated less than or equal to 1 percent eosinophils in all patients. We believe that we are describing an acute form of eosinophilic lung disease distinct from previously described syndromes. It can be diagnosed by bronchoalveolar lavage and seems to respond to treatment with corticosteroids.

Acute Disease↗
PubMed1989

Bronchiolitis in adults. A reversible cause of airway obstruction associated with airway neutrophils and neutrophil products.

In the past 4 yr, 16 adult patients were identified who had accelerated onset of a severe respiratory disorder (usually obstructive in nature) that was clinically distinct from the more commonly encountered chronic obstructive disorders (e.g., chronic bronchitis, emphysema, asthma, bronchiectasis, cystic fibrosis, and alpha 1-antitrypsin deficiency). These patients, termed patients with "bronchiolitis," underwent pulmonary function testing, bronchoscopy with bronchoalveolar lavage (BAL), and open lung biopsy. Although lung biopsy findings varied somewhat among the patients, each biopsy contained a prominent component of bronchiolitis. Pulmonary function testing and BAL were also repeated after 3 months of treatment with oral prednisone (1 mg/kg/day). Initial BAL neutrophil percentages were significantly higher in the bronchiolitis group (54 +/- 10%) than in smokers with chronic bronchitis (3.9 +/- 1.0%) or in normal nonsmoking volunteers (0.8 +/- 0.5%) (p less than 0.01, both comparisons). Eleven of 15 patients with bronchiolitis had significant improvement (greater than or equal to 15% increase in FEV1) in their lung function after prednisone treatment. Furthermore, this "responder" subgroup had a significant reduction in BAL neutrophil percentages after treatment with prednisone (46 +/- 15% to 6 +/- 3%, p less than 0.05). Finally, the neutrophil products collagenase and myeloperoxidase were detected in the BAL fluid of patients with bronchiolitis. These findings suggest a central role for the neutrophil in the pathogenesis of bronchiolitis and emphasize the utility of BAL in the identification of these patients.

Adolescent↗
PubMed1989

Comparison of smoker and nonsmoker lavage fluid for the rate of association with neutrophil elastase.

Cigarette smoking may impair the lung antiprotease screen. To test this hypothesis, the lung lining fluid from 10 smoking and 9 nonsmoking individuals was evaluated for its ability to inhibit neutrophil elastase and porcine pancreatic elastase. To eliminate the possibility of concentration- or purification-induced artifact, unconcentrated bronchoalveolar lavage fluid was used for all experiments. Smokers did not differ significantly from nonsmokers in the antigenic alpha-1-antitrypsin (alpha 1AT) concentrations (0.67 +/- 0.04 versus 0.73 +/- 0.09 nmol alpha 1AT/mg protein), in the neutrophil elastase inhibitory capacity (NEIC) (0.59 +/- 0.03 versus 0.52 +/- 0.05 nmol NEIC/mg protein), or in the porcine pancreatic elastase inhibitory capacity (PPEIC) (0.36 +/- 0.03 versus 0.42 +/- 0.05 nmol PPEIC/mg protein). In contrast, when the PPEIC/NEIC ratio was evaluated, smoker lung lining fluid exhibited a relative defect (0.64 +/- 0.06 smokers versus 0.80 +/- 0.05 nonsmokers, P less than 0.05). In agreement with the smokers' defect in the PPEIC/NEIC ratio, the kinetics of association (Ka) of lung lining fluid for neutrophil elastase was 0.38 +/- 0.3 x 10(7) M-1 s-1 from smokers and 0.58 +/- 0.05 x 10(7) M-1 s-1 from nonsmokers (P less than 0.002). Thus for a given amount of neutrophil elastase, smoker lung lining fluid took approximately 1.5 times longer to inhibit neutrophil elastase. These findings suggest that cigarette smoking is associated with a subtle defect in the antiprotease screen of the lower respiratory tract, recognizable by time-dependent measures of anti-neutrophil elastase function.

Bronchoalveolar Lavage Fluid↗
PubMed1989

Validity of bronchoalveolar lavage in acute lung injury: recovered cells accurately reflect changes in the lung parenchyma.

Bronchoalveolar lavage (BAL) has come into widespread use as a tool to diagnose and manage various lung diseases. However, the usefulness of BAL is based on the assumption that the cells recovered in BAL fluid accurately reflect cellular populations in the lung parenchyma. To test this hypothesis, random source (n = 16) dogs were given intravenous phorbol myristate acetate (PMA) to produce acute, diffuse lung inflammation. Dogs were divided into three groups. Group I animals (n = 2) underwent BAL and open lung biopsy at time zero. Group II (n = 7) animals underwent hourly BAL after PMA with open lung biopsy at 3 h. Group III (n = 7) animals underwent hourly BAL after PMA with open lung biopsy at 6 h. When BAL cell populations were compared with the corresponding biopsies, there was a direct correlation (r = 0.67) between BAL neutrophil percentages and neutrophils present in histologic sections. These findings suggest BAL accurately reflects changes in the lung parenchyma in acute lung disease.

Acute Disease↗
PubMed1988

Oxygen distribution and utilization after phorbol myristate acetate-induced lung injury.

There is considerable evidence suggesting that substrate (e.g., oxygen) distribution and utilization are abnormal in the setting of acute respiratory failure from the adult respiratory distress syndrome (ARDS). The mechanisms that may explain this anomalous relationship include: redistribution of cardiac output resulting in the nonuniform delivery of substrate to regional vascular beds; increases in flow through anatomic precapillary arteriovenous channels; increased organ metabolic demand; and direct injury to the regional microvasculature. To test these hypotheses, we used radiolabeled 15-mu microspheres to measure cardiac output, regional blood flow, total systemic shunt flow, oxygen uptake (VO2), and oxygen delivery (QO2) in dogs after phorbol myristate acetate (PMA: 30 micrograms/kg; n = 5)-induced neutrophil activation and acute lung injury. These studies demonstrated that neutrophil activation and acute lung injury was accompanied by an increase in the level of QO2 (e.g., 19.1 ml/min.kg) necessary to maintain a constant level of VO2. Although PMA-induced acute lung injury did not result in an increase in the fraction of cardiac output comprising total systemic shunt flow or in an increase in whole body metabolic demand compared to control animals (e.g., PMA = 0 micrograms/kg; n = 10), it did result in a significant decrease in cardiac output. In addition, there were significant reductions in blood flow to most organs after PMA-induced acute lung injury that were not reversible with intravascular volume expansion (80 ml isotonic saline/kg; n = 5). The exclusion of reversible volume depletion, anatomic shunts, and increased metabolic demand suggest a role for microvascular injury in the development of the regional blood flow abnormalities and the supply dependence of oxygen uptake observed in this study. In the context of the mechanisms of lung injury known to be operative in this model, these microcirculatory abnormalities may be mediated through the intravascular activation of circulating neutrophils.

Acute Disease↗
PubMed1988

Alveolar fluid neutrophil elastase activity in the adult respiratory distress syndrome is complexed to alpha-2-macroglobulin.

We characterized the elastase and antielastase activity of the alveolar fluid of seven patients with the adult respiratory distress syndrome (ARDS) and thirteen normal volunteers. Alpha-1-antitrypsin (A1AT) concentrations were 60-fold higher in ARDS as compared to normal lavage fluid (2,140 +/- 498 nM; 36.1 +/- 4.2 nM, respectively). ARDS fluid antineutrophil elastase activity was also considerably higher than that of normals (979 +/- 204 nM; 31.3 +/- 2.9 nM, respectively). Despite the antineutrophil elastase excess, 5 of 7 ARDS lavage samples contained elastase activity (mean, 6.1 +/- 2.4 pM) as assayed using low-molecular-mass substrate, while only 1 of 13 normal subjects had detectable elastase activity (0.2 pM) (P less than 0.01, compared with ARDS). That this activity was due to alpha-2-macroglobulin (A2MG)-complexed neutrophil elastase was evidenced by (a) the Sephadex G-75 elution profile; (b) the inactivity against insoluble [3H]elastin; (c) the inhibitory profile with phenylmethylsulfonyl fluoride, methoxy-succinyl-alanyl-alanyl-prolyl-valyl-chloromethylketone, ethylene diamine tetraacetic acid, and A1AT; and (d) the immobilization by A2MG antibody bound to polystyrene plates. Furthermore, in agreement with the predicted affinity of A1AT and A2MG for neutrophil elastase, the ratio of A2MG to A1AT in the fluid (0.57%) coincided with the ratio of the A2MG- to A1AT-complexed elastase (0.36%). These findings suggest that the net lung protease-antiprotease balance in ARDS is shifted largely in favor of the antiproteases (chiefly A1AT), and that the antiproteases, A1AT and A2MG, have similar affinities for neutrophil elastase in vivo.

Adolescent↗
PubMed1988

Relationships of oxygen uptake and oxygen delivery in respiratory failure not due to the adult respiratory distress syndrome.

Previous studies have suggested that oxygen uptake (VO2) may be dependent on oxygen delivery (QO2) at most levels of QO2 in patients with the adult respiratory distress syndrome (ARDS); however, the adequacy of substrate delivery in patients with non-ARDS respiratory failure is unclear. The purpose of the present study was to examine the relationship between VO2 and QO2 in a group of critically ill patients (n = 10) with non-ARDS respiratory failure (ie, cardiac pulmonary edema, chronic obstructive pulmonary disease [COPD], or pneumonia). For comparison, these relationships were also examined in a group of patients (n = 6) with ARDS. The data indicate that VO2 is dependent on QO2 in both patients with ARDS and non-ARDS respiratory failure. In contrast, regional venous oxygen tension differences varied considerably between the two groups of patients, indicating differences in local adaptations to critical reductions in QO2. Finally, over a similar range of QO2, oxygen extraction was greater in patients with ARDS compared to patients with non-ARDS respiratory failure (r = -0.67 and slope = -0.62 vs r = -0.45 and slope = -0.35; p less than 0.05). These data suggest that a linear relationship between VO2 and QO2 is not unique to patients with ARDS and may not predict regional adaptations to critical reductions in substrate availability.

Hemodynamics↗
PubMed1987

Alterations in regional blood flow during positive end-expiratory pressure ventilation.

PEEP improves the gas-exchange abnormalities that accompany adult respiratory distress syndrome (ARDS). However, since PEEP decreases cardiac output, it may also alter regional blood flow and therefore, substrate delivery to specific organs. To test this hypothesis, radiolabeled 15-mu microspheres were used to directly quantify the effects of mechanical ventilation with PEEP on regional blood flow to individual organs in animals. Mechanical ventilation alone produced a -21.2 +/- 3.6% and a -28.1 +/- 5.2% decrease in cardiac output at 30 and 60 min, respectively. The addition of 14 cm H2O PEEP resulted in little further reduction in cardiac output at 30 and 60 min (-28 +/- 2.3% and -36.4 +/- 4.9%, respectively). However, 25 cm H2O PEEP reduced markedly (p less than .01) cardiac output (-59.2 +/- 6.1% at 30 min and -55.1 +/- 4.0% at 60 min). Although blood flows to the kidney and brain were maintained, decreases in cardiac output were invariably accompanied by proportional decreases in blood flow to the heart. Intravascular volume expansion with saline (20 ml/kg) during 14 cm H2O PEEP significantly improved cardiac output (3.23 +/- 0.34 to 4.22 +/- 0.13 L/min; p less than .01) and proportionately increased blood flow to several regional vascular beds, including the heart. These data suggest that PEEP decreases cardiac output to produce reversible alterations in blood flow to a number of regional vascular beds. These PEEP-induced alterations in regional blood flow may have important implications for the development of multiple-organ failure in ARDS patients.

Animals↗
PubMed1987

Effects of swim training on lung volumes and inspiratory muscle conditioning.

Lung volumes and inspiratory muscle (IM) function tests were measured in 16 competitive female swimmers (age 19 +/- 1 yr) before and after 12 wk of swim training. Eight underwent additional IM training; the remaining eight were controls. Vital capacity (VC) increased 0.25 +/- 0.25 liters (P less than 0.01), functional residual capacity (FRC) increased 0.39 +/- 0.29 liters (P less than 0.001), and total lung capacity (TLC) increased 0.35 +/- 0.47 (P less than 0.025) in swimmers, irrespective of IM training. Residual volume (RV) did not change. Maximum inspiratory mouth pressure (PImax) measured at FRC changed -43 +/- 18 cmH2O (P less than 0.005) in swimmers undergoing IM conditioning and -29 +/- 25 (P less than 0.05) in controls. The time that 65% of prestudy PImax could be endured increased in IM trainers (P less than 0.001) and controls (P less than 0.05). All results were compared with similar IM training in normal females (age 21.1 +/- 0.8 yr) in which significant increases in PImax and endurance were observed in IM trainers only with no changes in VC, FRC, or TLC (Clanton et al., Chest 87: 62-66, 1985). We conclude that 1) swim training in mature females increases VC, TLC, and FRC with no effect on RV, and 2) swim training increases IM strength and endurance measured near FRC.

Adolescent↗
PubMed1987

Neutrophil collagenase in rheumatoid interstitial lung disease.

Ten patients with rheumatoid arthritis were evaluated by bronchoalveolar lavage. Five patients (group I) had interstitial lung disease by physiological and radiographic criteria, whereas five (group II) had no evidence of lung disease. Lavage fluid from four of the five group I patients contained an active collagenase which by inhibitory profile and substrate specificity appeared to be of neutrophil origin. None of the group II patients demonstrated lavage fluid collagenase. Treatment of lavage fluid with trypsin failed to uncover latent collagenase activity in either group, suggesting that the collagenase is present entirely in an active form. These findings parallel those observed in idiopathic pulmonary fibrosis and suggest a potential pathogenetic role for collagenase in rheumatoid interstitial lung disease.

Arthritis, Rheumatoid↗