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Biomedical subjects

R A Robbins

Publications and source records attributed to R A Robbins.

At least 19 recordsLinked to original sources
PubMed1992

Pulmonary complications of transplantation.

Improved immunosuppressive regimens, advances in surgical proficiency and techniques, and improved supportive medical care have translated into dramatic increases in graft survival in organ transplantation and in patient outcome in bone marrow transplantation. Though effective immunosuppression has also led to an increase in infectious complications, several recent advances, including the development of effective surveillance protocols and antiviral therapy and the use of prophylactic antibiotics, appear to have made a significant positive impact on the management of infections and survival of transplant recipients. In addition, a clearer understanding of noninfectious pulmonary complications, such as bronchiolitis obliterans, and continued improvement in techniques for evaluating a host of posttransplant pulmonary disorders will likely further enhance posttransplant therapy and survival.

Bronchiolitis Obliterans↗
PubMed1992

Regional distribution of emphysema: correlation of high-resolution CT with pulmonary function tests in unselected smokers.

High-resolution computed tomography (CT) was correlated with pulmonary function tests in the evaluation of regional emphysema in 59 smokers. The lung was divided into upper (above the carina tracheae) and lower (below the carina tracheae) zones, and the degree of emphysema was graded with a subjective and an objective measurement. Functional emphysema was defined as a diffusion capacity less than 75% of predicted and forced expiratory volume in 1 second less than 80% of predicted. Three of 15 (20%) subjects with functional emphysema had no subjective evidence of emphysema at high-resolution CT, and 10 of 25 (40%) with emphysema at high-resolution CT had no functional abnormalities consistent with emphysema. Even though the upper lung zones were more severely affected by emphysema, the degree of emphysema in the lower zones had a stronger correlation with pulmonary function abnormalities. The upper lung zones are a relatively silent region where extensive destruction may occur before functional abnormalities become known.

Aged↗
PubMed1992

Acetylcholine stimulates bronchial epithelial cells to release neutrophil and monocyte chemotactic activity.

Bronchial asthma is accompanied by inflammatory cell infiltration in the airway. Increased bronchial reactivity to cholinergic stimulation is well recognized in patients with bronchial asthma. Thus, we postulated that acetylcholine (ACh) stimulates bronchial epithelial cells (BEC) to release neutrophil and monocyte chemotactic activity (NCA and MCA). To test this hypothesis, bovine BEC monolayers were tested for NCA and MCA by a blind-well chemotactic chamber technique. BEC released NCA and MCA in response to ACh in a dose-dependent and time-dependent manner. Molecular sieve column chromatography revealed that ACh induced a single low-molecular-weight peak (near 400) for NCA and two low-molecular-weight peaks (near 12,000 and 400) for MCA. The release of NCA and MCA was inhibited by the lipoxygenase inhibitors, nordihydroguaiaretic acid and diethylcarbamazine. Cigarette smoke is a well-recognized stimulus for airway inflammation. To determine whether smoke might activate BEC to release NCA by stimulating nicotinic ACh receptors, we further characterized the ACh receptors, using nicotine and nicotinic and muscarinic receptor antagonists. Nicotine, the nicotinic receptor antagonist d-tubocurarine, and the M2 receptor antagonist gallamine did not modulate the release of NCA in response to ACh. In contrast, atropine and the M1 receptor antagonist, pirenzepine, inhibited the release of NCA. These data demonstrate that ACh stimulates BEC to release lipoxygenase-derived NCA and MCA through the muscarinic receptor.

Acetylcholine↗
PubMed1992

Bronchial epithelial cells release neutrophil chemotactic activity in response to tachykinins.

The purpose of this study was to determine whether substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) induce the release of neutrophil chemotactic activity (NCA) from bovine bronchial epithelial cells (BBEC) and whether neutral endopeptidase (NEP), a membrane-bound metalloenzyme that hydrolyzes tachykinins, modulates these effects. BBEC monolayers were exposed to SP, NKA, and NKB in the absence or presence of phosphoramidon (10(-6) M), a selective NEP inhibitor, for 72 h. Using a modified blind-well in vitro neutrophil chemotaxis assay, we found that tachykinin-exposed BBEC culture supernatant fluids induced significant neutrophil chemotaxis compared with supernatants obtained from unstimulated BBEC. Maximal effect was observed after 48 h of incubation and at SP concentration of 10(-13) M [92 +/- 3 (SP) vs. 64 +/- 2 (media) cells/high-power field (HPF), mean +/- SE, n = 7, P less than 0.05]. Release of NCA was mediated by the COOH-terminal of the SP molecule. The rank order of potency of tachykinins in inducing release of NCA was SP greater than NKA = NKB. SP-induced response was significantly potentiated by phosphoramidon (109 +/- 3 vs. 92 +/- 3 cells/HPF, n = 7, P less than 0.05), whereas other proteinase inhibitors had no effect. The released NCA was composed of protein and lipid-soluble components. These data indicate that mammalian tachykinins induce the release of NCA from BBEC and that NEP modulates these effects. We suggest that tachykinins regulate neutrophil recruitment into the lower respiratory tract, in part, by inducing the release of NCA from airway epithelial cells.

Animals↗
PubMed1992

Demonstration of a keratan sulfate-containing proteoglycan in atherosclerotic aorta.

Proteoglycans were isolated from either grossly normal or atherosclerotic pigeon aortas after extraction with 4 M guanidine hydrochloride and purification by ion-exchange and size-exclusion chromatography. The small-size proteoglycans (Kav 0.4, on Sepharose CL-4B) from both normal and atherosclerotic tissue contained primarily a dermatan sulfate proteoglycan with an intact molecular size of 220-330 kd and a 45-kd core protein. In addition to the dermatan sulfate proteoglycan, the preparation contained a proteoglycan recognized by monoclonal antibody (MAb) 5-D-4, indicating the presence of sulfated poly-N-acetyllactosamine sequences common to corneal and cartilage keratan sulfate. Electrophoresis on sodium dodecyl sulfate-polyacrylamide gel revealed a polydisperse proteoglycan of 60-150 kd that was recognized by MAb 5-D-4. Significantly greater immunoreactivity with MAb 5-D-4 was observed for atherosclerotic compared with normal artery. After endo-beta-D-galactosidase treatment of the proteoglycan from atherosclerotic aorta, diminished MAb 5-D-4 reactivity observed by both Western blot analysis and enzyme-linked immunosorbent assay demonstrated that the material was keratan sulfate. Endo-beta-D-galactosidase treatment of the intact proteoglycan generated core proteins of 28 and 38 kd. These studies suggest the presence of one or more keratan sulfate proteoglycans in grossly normal and atherosclerotic arteries. Immunochemical data suggest that sulfation of the keratan sulfate proteoglycan may be greater in atherosclerotic aorta.

Amidohydrolases↗
PubMed1992

Airway inflammation predicts diffuse alveolar hemorrhage during bone marrow transplantation in patients with Hodgkin disease.

We determined risk factors present in patients with Hodgkin disease that predicted the development of diffuse alveolar hemorrhage syndrome (DAH) during autologous bone marrow transplantation (BMT). One hundred twenty-three patients with Hodgkin disease prospectively underwent bronchoscopy with bronchoalveolar lavage (BAL) before receiving BMT. The bronchitis index (BI) of the airways and bronchial and alveolar cell counts and differentials were determined in all patients and compared with 20 normal nonsmoking volunteers. Logistic regression analysis was used to determine factors that predicted for the development of DAH. Visual evidence of bronchial injury was observed regardless of smoking history (BI = 7.8 +/- 0.5 for BMT versus 2.3 +/- 0.5 for volunteers, p = 0.001). BMT patients who developed DAH (n = 14) had significantly greater numbers of bronchial neutrophils and eosinophils compared with DAH-negative (n = 109) patients (bronchial polymorphonuclear leukocytes (PMN), 33 +/- 7% versus 14 +/- 2%, p = 0.006; bronchial eosinophils, 0.9 +/- 0.3% versus 0.4% +/- 0.07%, p = 0.02). Logistic regression analysis revealed that the presence of bronchial PMN > 20% or bronchial eosinophils > zero% were predictive of DAH (p = 0.005 and 0.05, respectively). When both predictors were positive, the rate of DAH was 10 times greater than when both predictors were negative (43% versus 4% DAH occurrence). Survival was also significantly reduced when these predictors were positive. This study demonstrates that bronchial inflammation is present with or without intraluminal inflammatory cells in the majority of patients with Hodgkin disease before BMT. The subgroup of these patients with increased bronchial inflammatory cells are at greatly increased risk for development of DAH and death.

Academic Medical Centers↗
PubMed1992

Modulation of neutrophil and mononuclear cell adherence to bronchial epithelial cells.

Neutrophils and mononuclear cells have been associated with the lower respiratory tract inflammation observed in both acute and chronic bronchitis. In order to transit into and remain within the airways, neutrophils and mononuclear cells would likely need to adhere to bronchial epithelium. To test this hypothesis, bovine bronchial epithelial cells (BBECs) were isolated and cultured on a round coverslip. After 7 to 10 days, 51Cr-labeled neutrophils and mononuclear cells were evaluated for their capacity to adhere to the BBEC monolayer. Both neutrophils and mononuclear cells readily bound to the BBEC monolayer (10.8 +/- 1.2% bound neutrophils; 40.5 +/- 2.8% bound mononuclear cells). Stimulation of the neutrophils and mononuclear cells with phorbol 12-myristate 13-acetate (PMA) increased the adherence (45.8 +/- 10.6% bound neutrophils, P less than 0.01 compared with unstimulated cells; 58.7 +/- 6.2% bound mononuclear cells, P less than 0.01 compared with unstimulated cells). Importantly, stimulating the BBEC monolayer with PMA, bacterial lipopolysaccharide, or a cigarette smoke extract for 4 to 72 h also increased the adherence of both cell types (P less than 0.01, all comparisons at 24 h). The adherence was not decreased by exposure of either the BBEC monolayer, the neutrophils, or the mononuclear cells to cycloheximide or to the anti-CD11/CD18 monoclonal antibody 60.3 (P greater than 0.05). However, exposure of the BBEC monolayer to trypsin before addition of the neutrophils significantly decreased adherence (P less than 0.05). Because neutrophils and mononuclear cells are thought to mediate cell cytotoxicity by adhering to the target cells, BBECs were labeled with 51Cr, and 51Cr release was measured as an index of cytotoxicity. There was a modest increase in 51Cr release by the addition of unstimulated neutrophils and mononuclear cells, and culturing the BBEC monolayer with PMA before the addition of the neutrophils or mononuclear cells resulted in a further modest enhancement of 51Cr release (P less than 0.05). Similar results were obtained using lactate dehydrogenase release as a measure of cytotoxicity. These results demonstrate that inflammatory cells can adhere to BBECs and may be capable of mediating cytotoxicity and adherence and cytotoxicity can be increased by stimulating BBECs.

Animals↗
PubMed1991

Endotoxin stimulates bronchial epithelial cells to release chemotactic factors for neutrophils. A potential mechanism for neutrophil recruitment, cytotoxicity, and inhibition of proliferation in bronchial inflammation.

To test the effect of endotoxin on bronchial epithelial cells (BEC), BEC were isolated from bovine lungs and cultured in the presence of bacterial endotoxin. The BEC culture supernatant fluids were harvested, and neutrophil chemotactic activity (NCA) was determined with a blindwell chamber technique; cytotoxicity determined by lactate dehydrogenase release and BEC proliferation determined by Coulter counting. Endotoxin caused a dose- and time-dependent release of NCA from BEC cultures compared with media alone (82.3 +/- 8.1 vs 12.0 +/- 3.1 cells/high power field, p less than 0.001). To further characterize this activity, reverse phase HPLC analysis of release eicosanoid metabolites after [3H]arachidonic acid incorporation was performed. Endotoxin stimulated the release of the neutrophil chemoattractants, leukotriene B4 and 12-hydroxyeicosatetraenoic acids. Endotoxin also resulted in a dose and time dependent release of lactate dehydrogenase (42.9 +/- 4.2 vs 20.2 +/- 2.2 U/liter, p less than 0.001) although higher doses were required to cause cytotoxicity than to stimulate chemotaxis. Finally, endotoxin resulted in a dose dependent inhibition of BEC proliferation (176 x 10(3) +/- 16 x 10(3) vs 1,080 x 10(3) +/- 38 x 10(3) cells/ml measured at day 14, p less than 0.001). These data suggest that bacterial release of endotoxin may contribute to the pathophysiologic changes observed in bronchial inflammation by stimulating BEC to release NCA, denuding airway epithelium by causing cytotoxicity of BEC, and inhibiting epithelial repair by inhibiting BEC proliferation.

Animals↗
PubMed1991

Bronchial epithelial cells release monocyte chemotactic activity in response to smoke and endotoxin.

An increase in mononuclear phagocytes occurs within the airways during airway inflammation. Bronchial epithelial cells could release monocyte chemotactic activity and contribute to this increase. To test this hypothesis, bovine bronchial epithelial cells were isolated and maintained in culture. Bronchial epithelial cell culture supernatant fluids were evaluated for monocyte chemotactic activity. Epithelial cell culture supernatant fluids attracted significantly greater numbers of monocytes compared to media alone and the number of monocytes attracted increased in a time dependent manner. Endotoxin and smoke extract induced a dose and time dependent release of monocyte chemotactic activity compared with cells cultured in media (52.5 +/- 2.6 (endotoxin), 30.5 +/- 2.3 (smoke) vs 20.5 +/- 2.2 cells/high power field (HPF) p less than 0.001). The released activity was chemotactic by checkerboard analysis. Stimulation of the epithelial cells by opsonized zymosan, calcium ionophore (A23187), and PMA also resulted in an increase in monocyte chemotactic activity (p less than 0.01). Because the release of activity was blocked by the lipoxygenase inhibitors, nordihydroguaiaretic acid and diethycarbamazine, epithelial cell monolayers were cultured with 3 microCi [3H]arachidonic acid for 24 h and then exposed to A23187, PMA, or both stimuli, for 4, 8, and 24 h. Analysis of the released 3H activity was performed with reverse-phase HPLC and revealed that the major lipoxygenase product was leukotriene B4. These data suggest that monocytes may be recruited into airways in response to chemotactic factors released by bronchial epithelial cells.

Animals↗
PubMed1991

Death anxiety, death competency and self-actualization in hospice volunteers.

A total of 248 hospice volunteers completed the Personal Orientation Inventory, the Templer/McMordie Death Anxiety Scale, the Bugen Coping with Death Scale, and a Death Self-Efficacy Scale constructed for this research. Death anxiety significantly negatively correlated with four Personal Orientation Inventory scales, Coping with Death Scale positively correlated with seven of the twelve Personal Orientation Inventory Scales, and the Self-Efficacy Scale significantly correlated with eleven of them. These findings suggest that death competency constructs may be more useful than the concept of death anxiety in conceptualizing people's emerging self-actualization in the process of confronting mortality.

Adaptation, Psychological↗
PubMed1991

Protease injury in airways disease.

In summary, proteases are present in the airway in inflammatory airways disease. These enzymes can damage the airway epithelium. As a consequence, airway function can be altered, and long-term changes in airway anatomy can result. Although the exact cellular and biochemical mechanisms that lead to these changes are incompletely described, it seems likely that they will play important roles in clinical airways disease. As such, these pathways may represent novel opportunities for therapeutic intervention.

Animals↗
PubMed1991

Complement activation by cigarette smoke.

Lung disease secondary to cigarette smoking is associated with an influx of neutrophils and monocytes into the lower respiratory tract. To determine whether cigarette smoke can generate chemotactic activity, human serum was exposed to cigarette smoke and evaluated for neutrophil and monocyte chemotactic activity. Serum exposed to cigarette smoke attracted significantly greater numbers of neutrophils and monocytes compared with normal human serum exposed to air (P less than 0.01, both comparisons). The increase in chemotactic activity was partially attenuated by EDTA but not by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and MgCl2 (P greater than 0.05, both comparisons), suggesting activation of the alternate complement pathway. To evaluate the capacity of cigarette smoke to activate the complement system, smoke-exposed serum was evaluated for cleavage of properdin factor B and C3 using immunoelectrophoresis and for C5a using a radioimmunoassay. Cleavage of properdin factor B and C3 was observed in the smoke-exposed serum and C5a was detected in the smoke-exposed serum (112 +/- 31 ng/ml). These data suggest that complement activation may play a role in directing the influx of neutrophils and monocytes into the lungs of cigarette smokers.

Chemotaxis, Leukocyte↗
PubMed1991

Dibutyryl cAMP, prostaglandin E2, and antioxidants protect cultured bovine bronchial epithelial cells from endotoxin.

Acute bronchitis secondary to bacterial infection in the airway is accompanied by an acute inflammatory response composed predominantly of neutrophils. Mucosal injury with denudation of the airway epithelium to basement membrane frequently occurs. We postulated that endotoxin might explain this cytotoxicity and neutrophil influx. To test this hypothesis, bovine bronchial epithelial cells were cultured, and the culture supernatant fluids were evaluated for neutrophil chemotactic activity (NCA) and lactate dehydrogenase (LDH) after exposure to endotoxin. Escherichia coli endotoxin stimulated the release of NCA and LDH in a dose-dependent manner. Because intracellular augmentation of adenosine 3',5'-cyclic monophosphate (cAMP) has anti-inflammatory effects, we postulated that dibutyryl cAMP (DBcAMP) and prostaglandin E2 (PGE2) might modulate the effect of endotoxin. DBcAMP and PGE2 decreased the release of NCA and LDH. Because cAMP might exert its effect by decreasing intracellular release of oxidants, we investigated the capacity of the antioxidants dimethyl sulfoxide (DMSO) and allopurinol to attenuate the effects of endotoxin. DMSO and allopurinol alone or in combination attenuated the effects of endotoxin-induced NCA and LDH release. These data suggest that endotoxin may account for the pathophysiological changes seen with bronchial bacterial infection or endotoxin inhalation and that the inflammatory responses may be attenuated by DBcAMP, PGE2, and antioxidants.

Allopurinol↗
PubMed1991

Bronchoalveolar lavage fluid obtained from smokers exhibits increased monocyte chemokinetic activity.

Alveolar macrophages, which are cells derived from blood monocytes, accumulate within the lower respiratory tract of cigarette smokers. One mechanism to account for this accumulation of alveolar macrophages may be an increase in the migration of blood monocytes into the lungs of smokers. To evaluate this hypothesis, bronchoalveolar lavage fluid (BALF) was obtained from 15 smokers and 16 nonsmokers. The smokers' BALF possessed a significantly increased capacity to attract normal blood monocytes when evaluated using a blind-well chamber technique (26.2 +/- 7.6 vs 14.8 +/- 6.9 cells/high-power field, P less than 0.01). Checkerboard analysis of the activity revealed that it was predominantly chemokinetic. Partial characterization of the activity in smokers' BALF revealed that it was lipid soluble but only partially sensitive to trypsin and heat. The chemokinetic activity correlated with alveolar macrophage numbers in the BALF (r = 0.4391, P = 0.009). Furthermore, both the chemokinetic activity and alveolar macrophage number correlated with alterations of respiratory function (forced expiratory volume in 1 s, diffusing capacity for carbon monoxide, and forced expiratory flow at 75% of the vital capacity). These results suggest that the increase in alveolar macrophage number present in the BALF of cigarette smokers may be due, at least in part, to an increased amount of chemokinetic factor(s) in the smokers' BALF, and these factor(s) may participate in the decline of respiratory function associated with cigarette smoking, probably by recruiting monocytes into lung.

Adult↗
PubMed1991

Role of neutrophils in endotoxin-mediated microvascular injury in hamsters.

The purpose of this study was to examine the role of circulating neutrophils in endotoxin-induced increase in microvascular permeability in vivo. Fifteen hamsters were anesthetized, and a plastic chamber was placed in each cheek pouch to observe the microvasculature. Fluorescein-labeled dextran (FITC-D, 150 kDa) was injected intravenously, and changes in leaky sites and FITC-D clearance were measured in three groups: control (saline, n = 4), endotoxin suffusion (n = 6), and endotoxin suffusion after neutropenia induction (n = 5). We found a significant increase in leaky sites and FITC-D clearance with endotoxin (45 +/- 18/cm2 and 20 +/- 6 x 10(-6) ml/min, respectively; mean +/- SD, P less than 0.05) in comparison to control (7 +/- 6/cm2 and 7 +/- 5 x 10(-6) ml/min) and endotoxin suffusion in neutropenic animals (19 +/- 11/cm2 and 12 +/- 4 x 10(-6) ml/min). There was a significant correlation between the number of leaky sites and FITC-D clearance (r = 0.91, P less than 0.01) and between the number of circulating neutrophils and FITC-D clearance (r = 0.87, P less than 0.01). We conclude that endotoxin-mediated increase in microvascular permeability in the peripheral circulation is dependent in part on circulating neutrophils.

Animals↗
PubMed1991

Gcglobulin functions as a cochemotaxin in the lower respiratory tract. A potential mechanism for lung neutrophil recruitment in cigarette smokers.

Activation of the complement pathway with generation of the potent chemotaxin C5a may play a significant role in the neutrophil accumulation seen in the lungs of patients with smoking-associated diseases. Although C5a is rapidly degraded to the less potent chemotaxin C5a des Arg, binding of this peptide with its cochemotaxin Gcglobulin (GcG) can restore its chemotactic potency. Therefore, modulation of Gcglobulin levels in smoking-induced lung disease could affect the accumulation of neutrophils seen in this disorder. To test this hypothesis GcG was measured by an enzyme-linked immunosorbent assay in bronchoalveolar lavage fluids (BALF) obtained from non-smokers, asymptomatic smokers, and patients with chronic obstructive pulmonary disease (COPD). Antigenic amounts of GcG in BALF were increased in COPD patients and asymptomatic smokers compared with nonsmokers (6.35 +/- 1.02 and 5.15 +/- 1.07 versus 2.82 +/- 0.37 micrograms/mg albumin, p less than 0.05). In addition, we found that BALF enhanced C5a des Arg-mediated chemotaxis (48.3 +/- 5.6 versus 11.2 +/- 1.6 cells/high power field, p less than 0.05), an effect that was not seen in the presence of GcG antibody. Furthermore, BALF GcG was similar to serum GcG using Western blot analysis, and the interaction of GcG with C5a des Arg was not inhibited by cigarette smoke. These data demonstrate that elevation of BALF GcG levels occurs in smoking-associated lung disease and that this protein is biologically active and capable of increasing C5a des Arg-mediated chemotaxis. This suggests that modulation of GcG levels may be important in smoking-associated lung diseases.

Adult↗
PubMed1991

Bronchoscopy with bronchoalveolar lavage causes neutrophil recruitment to the lower respiratory tract.

Bronchoscopy with bronchoalveolar lavage (BAL) is a technique now widely utilized for both clinical and investigational purposes. At times, it is useful to perform bronchoscopy with BAL in a serial fashion. However, previous work in animals indicates that bronchoscopy with BAL can cause lower respiratory tract inflammation. To determine if BAL also causes lower respiratory tract inflammation in humans, sequential bronchoscopy with BAL was performed in 30 human subjects. Inflammation was evaluated using a quantitative visual assessment of bronchitis and by BAL. BAL was performed by instilling and aspirating five 20-ml aliquots of saline in each of three areas of the lung. The fluid returned from the first aliquot from each site was pooled as the bronchial fraction, and that from the remaining four aliquots was pooled as the alveolar fraction. Each volunteer was restudied at 2, 7, 24 or 72 h. Findings at the second bronchoscopy with BAL included an elevation in visual signs of large airways inflammation, which was greatest at 24 h. Bronchial neutrophils increased significantly, with the greatest effect seen at 7 h (5.3 +/- 2.0 versus 59.5 +/- 11.0%, SEM). The effect was most pronounced in the area of the lung previously lavaged, but was also seen in lobes that had not received BAL at the first bronchoscopy. Alveolar neutrophils also increased, with the maximal effect also seen at 7 h. Visible bronchial inflammation, bronchial neutrophils, and alveolar neutrophils returned to the normal range by 72 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗