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Biomedical subjects

B P O'Sullivan

Publications and source records attributed to B P O'Sullivan.

18 recordsLinked to original sources
PubMed2001

Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications.

Cystic fibrosis (CF), an autosomal recessive disorder resulting from mutations in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene, is the most common lethal genetic illness in the Caucasian population. Gene transfer to airway epithelium, using adenoviruses containing normal CFTR cDNA, leads to transient production of CFTR mRNA and, in some studies, to correction of the airway epithelial ion transport defect caused by dysfunctional CFTR. Inflammatory responses to the adenoviral vector have been reported, particularly at high viral titers. We evaluated the effects of adenovirus-mediated CFTR gene transfer to airway epithelium in 36 subjects with CF (34 individuals, 2 of whom received two separate doses of vector), 20 by lobar instillation and 16 by aerosol administration. Doses ranged from 8 x 10(6) to 2.5 x 10(10) infective units (IU), in 0.5-log increments. After lobar administration of low doses there were occasional reports of cough, low-grade temperature, and myalgias. At the highest lobar dose (2.5 x 10(9) IU) two of three patients had transient myalgias, fever, and increased sputum production with obvious infiltrates on CT scan. After aerosol administration there were no significant systemic symptoms until the 2.5 x 10(10) IU dose, when both patients experienced myalgias and fever that resolved within 24 hr. There were no infiltrates seen on chest CT scans in any of the patients in the aerosol administration group. There were no consistent changes in pulmonary function tests or any significant rise in serum IgG or neutralizing antibodies in patients from either group. Serum, sputum, and nasal cytokines, measured before and after vector administration, showed no correlation with adenoviral dose. Gene transfer to lung cells was inefficient and expression was transient. Cells infected with the vector included mononuclear inflammatory cells as well as cuboidal and columnar epithelial cells. In summary, we found no consistent immune response, no evidence of viral shedding, and no consistent change in pulmonary function in response to adenovirus-mediated CFTR gene transfer. At higher doses there was a mild, nonspecific inflammatory response, as evidenced by fevers and myalgias. Overall, vector administration was tolerated but transfer of CFTR cDNA was inefficient and transgene expression was transient for the doses and method of administration used here.

Adenoviridae↗
PubMed2001

Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium.

A phase I clinical trial was conducted in which recombinant adenovirus containing the cystic fibrosis trans-membrane regulator (CFTR) (Ad2/CFTR) was administered by bronchoscopic instillation or aerosolization to the lungs of cystic fibrosis (CF) patients. In this paper, we evaluate the efficiency of Ad2/CFTR-mediated transduction of bronchial airway cells. The ability of an Ad2/CFTR vector to transduce airway cells was first evaluated in patients to whom the vector was administered by bronchoscopic instillation. Cells at the administration site were collected 2 days after treatment by bronchoscopic brushing. Ad2-specific CFTR DNA was detected in four of five individuals by PCR, and Ad2-specific CFTR RNA was detected in three of five individuals by RT-PCR. Ad2/CFTR-mediated transduction of airway epithelial cells was then determined in CF individuals receiving this vector by aerosol inhalation. Ad2-specific CFTR DNA was detected in 13 of 13 individuals 2 days after aerosolization, and in 3 of 5 individuals 7 days after aerosolization. Ad2-specific RNA was detected in 4 of 13 individuals on day 2, but was not detected in the 5 individuals tested on day 7. The percentage of airway epithelial cells containing nuclear-localized vector DNA was < or =2.4% as determined by fluorescence in situ hybridization (FISH). However, in some cases, a high percentage of nonepithelial mononuclear cells or squamous metaplastic epithelial cells was infected with the adenoviral vector. In conclusion, aerosol administration is a feasible means to distribute adenoviral vectors throughout the conducting airways, but improvements in adenovirus-mediated transduction of airway epithelial cells are necessary before gene therapy for CF will be effective.

Adenoviridae↗
PubMed1998

Tracheal bronchus: a cause of prolonged atelectasis in intubated children.

Tracheal bronchus is a common anomaly that occurs in approximately 2% of people. Two children with multiple medical problems which led to endotracheal intubation are described. The hospital course for each child was complicated by persistent right upper lobe atelectasis. The presence of a tracheal bronchus was not recognized in either case initially; identification of this anatomic variant allowed appropriate changes in airway management. The potential for tracheal bronchus to cause, or be associated with, localized pulmonary problems is reviewed. The diagnosis of tracheal bronchus should be considered early in the course of intubated patients with right upper lobe complications.

Bronchi↗
PubMed1995

Localized pneumothorax with lobar collapse and diffuse obstructive airway disease.

Localized pneumothorax adjacent to a collapsed lobe has been reported in children with bronchial obstruction. We present our findings in seven children with a similar phenomenon occurring in association with diffuse obstructive airway disease. The children, aged from 3 weeks to 17 years, were admitted for diffuse obstructive airway disease and, subsequently, developed lobar collapse with adjacent localized pneumothorax. In five of the seven patients there was a paradoxical shift of the mediastinum toward the side of the pneumothorax. In six cases, the pneumothorax resolved spontaneously with lobar reexpansion. A conservative treatment approach to patients with this constellation of radiographic findings appears justified.

Adolescent↗
PubMed1995

Acute lung injury in endotoxemic pigs: role of leukotriene B4.

The role of leukotriene B4 (LTB4) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB4-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB4 but had a much smaller effect on opsonin receptor upregulation induced by platelet-activating factor. In pigs treatment with LY-306669 prevented leukopenia induced by injection of authentic LTB4 but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxane-A2 mimetic. In a second study, pigs received an intravenous priming dose of lipopolysaccharide (LPS) at time (t) = -18 h and were randomized to receive 1) no further treatment (n = 5), 2) LPS (250 micrograms/kg over 1 h beginning at t = 0 h) and LY-306669 (10 mg/kg bolus and 3 mg.kg-1.h-1 infusion beginning at t = -15 min) (n = 7), or 3) LPS and vehicle (n = 6). Treatment with LY-306669 significantly ameliorated LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data suggest that LTB4 is an important mediator of pulmonary dysfunction and transendothelial migration of neutrophils in LPS-induced acute lung injury.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

The use of aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in children with leukemia.

We report our experience giving aerosolized pentamidine as prophylaxis for Pneumocystis carinii pneumonia (PCP) to 9 children (mean age, 7.33 years; range 3-17 years) with leukemia who were unable to tolerate trimethoprim-sulfamethoxazole (TMP-SMX) due to allergy or myelosuppression. The dose of pentamidine was modified for each child to correct for weight and approximate alveolar ventilation. We were able to administer the drug to younger children by using a cushioned face mask in place of the standard mouthpiece. One child experienced moderate coughing with administration of pentamidine. He and four others with a past medical history suggestive of reactive airways disease were pretreated with inhaled albuterol. No other adverse effects were noted. Treatment lasted an average of 8.11 +/- 4.1 months per child; no case of PCP occurred. We conclude that aerosolized pentamidine can be administered to even very young children and may be of benefit to all immunosuppressed children unable to use TMP-SMX prophylaxis. The adjusted dose used here appears to be safe, but further studies regarding drug delivery and efficacy are needed.

Adolescent↗
PubMed1994

Prior exposure to endotoxin exacerbates lipopolysaccharide-induced hypoxemia and alveolitis in anesthetized swine.

We sought to determine whether a standardized "priming" event, namely a small dose of LPS, would alter physiological responses to a subsequent larger "challenge" dose of endotoxin. Accordingly, four groups of pigs (N = 5-6) were studied. One group received neither priming nor challenge doses of LPS. A second group were not primed but were infused with a challenge dose (250 micrograms/kg) of LPS. A third group were pretreated 18 h before being studied with a priming dose of LPS (20 micrograms/kg), but were not infused with a second dose of LPS. A fourth group received both priming and challenge doses of LPS. Priming with LPS exacerbated endotoxin-induced arterial hypoxemia, and decreased animal-to-animal variability in the degree of hypoxemia induced by a challenge dose of endotoxin. Priming blunted the early phase (30 min) and exacerbated the delayed phase (120-210 min) of LPS-induced pulmonary hypertension. Priming blunted LPS-induced release of prostacyclin and thromboxane A2. The use of a priming dose of LPS increases the severity and reproducibility of LPS-induced acute lung injury in swine.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Bactericidal/permeability-increasing protein ameliorates acute lung injury in porcine endotoxemia.

Bactericidal/permeability-increasing protein (BPI), a cationic protein isolated from human neutrophils, binds lipopolysaccharide (LPS), kills gram-negative bacteria, and neutralizes many of the effects of LPS in vitro and in vivo. We hypothesized that a recombinant 23-kDa NH2-terminal fragment of BPI (BPI23) would reduce acute lung injury in endotoxemic pigs. At -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 4); 2) LPS (250 micrograms/kg over 50 min) and BPI23 (3-mg/kg bolus and 3 mg/kg over 60 min) (n = 6); or 3) LPS and thaumatin, a cationic protein devoid of LPS neutralizing activity that has a molecular mass and isoelectric point that are similar to that of BPI23 (n = 7). BPI23 treatment significantly ameliorated LPS-induced hypoxemia, functional upregulation of opsonin receptors on circulating phagocytes, and alveolitis but had no effect on the elaboration of tumor necrosis factor-alpha or thromboxane A2. The salutory effects of BPI23 on acute lung injury in endotoxemic pigs may be mediated, at least in part, by inhibition of direct activation of phagocytes by LPS.

Animals↗
PubMed1993

A novel leukotriene B4-receptor antagonist in endotoxin shock: a prospective, controlled trial in a porcine model.

OBJECTIVE: To evaluate the hypothesis that treatment with LY255283, a novel leukotriene B4-receptor antagonist, is beneficial in an animal model of the adult respiratory distress syndrome induced by endotoxin. DESIGN: Prospective, randomized, controlled trial. SETTING: Laboratory at a large university medical center. SUBJECTS: Twenty-five, immature, random-bred swine. INTERVENTIONS: Four groups of pigs were studied: the LPS group of animals (n = 6) were infused with Escherichia coli lipopolysaccharide (strain 0111:B4, 250 micrograms/kg) from 0 to 60 mins; the LPS + 255283 group of animals (n = 6) were infused with lipopolysaccharide as above, but were also treated with LY255283 (30 mg/kg, then 10 mg/kg/hr), beginning at -15 mins; the 255283 group of animals (n = 6) were infused with the same dose of LY255283, but were not challenged with lipopolysaccharide; and the RL control group of subjects (n = 7) received only the lactated Ringer's solution vehicle. Beginning at 30 mins, all groups were infused with dextran-70 solution as needed to maintain cardiac output at 90% to 110% of baseline value. MEASUREMENTS AND MAIN RESULTS: Treatment with LY255283 significantly (p < .05) ameliorated lipopolysaccharide-induced systemic arterial hypotension, pulmonary arterial hypertension, and arterial hypoxemia. Treatment with this drug also abrogated lipopolysaccharide-induced increases in pulmonary extravascular water content and bronchoalveolar lavage fluid protein concentration. CONCLUSIONS: These data suggest that leukotriene B4 may be an important mediator of acute lung injury in this porcine model of septic shock and acute lung injury. Further studies to assess the specificity of LY255283 as a leukotriene B4 antagonist are necessary in order to exclude the possibility that the beneficial effects of this compound are due to pharmacologic actions other than the blockade of LTB4 receptors.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Effect of granulocyte colony-stimulating factor on systemic and pulmonary responses to endotoxin in pigs.

Granulocyte colony-stimulating factor (G-CSF) stimulates the production and function of neutrophils (PMNs). Administration of G-CSF to non-neutropenic animals has been shown to improve survival in experimental models of infection, but PMNs have been implicated as mediators of acute lung injury induced by lipopolysaccharide (LPS) or bacteremia. Thus G-CSF-induced neutrophilia might be deleterious in sepsis. To investigate this possibility, we studied four groups of pigs: G+E50 (n = 6) were pretreated for 5 days with recombinant bovine (rb) G-CSF (5 micrograms/kg/day) and then challenged with LPS (50 micrograms/kg); NS+E50 (n = 6) were similarly pretreated with saline and challenged with LPS (50 micrograms/kg); E250 (n = 6) were not pretreated and were infused with a larger dose of LPS (250 micrograms/kg); RL (n = 7) were controls infused with lactated Ringer's solution. Pretreatment with rbG-CSF increased the peripheral absolute neutrophil count approximately fivefold (p < 0.05 vs. RL group). Comparisons of the NS+E50 and G+E50 groups showed that pretreatment with rhG-CSF did not affect LPS-induced alterations in mean arterial blood pressure or arterial oxygenation. Indices of pulmonary injury also were similar in these two groups, although pulmonary edema and protein leakage into alveoli were greater in the E250 group. We conclude that G-CSF-induced neutrophilia does not adversely effect physiologic responses to LPS in pigs.

Animals↗
PubMed1993

LY255283, a novel leukotriene B4 receptor antagonist, limits activation of neutrophils and prevents acute lung injury induced by endotoxin in pigs.

BACKGROUND: Polymorphonuclear neutrophils (PMNs) have been implicated in the pathogenesis of the adult respiratory distress syndrome (ARDS). Because leukotriene B4 (LTB4) is a potent activator of PMNs, we sought to determine whether LY255283, an LTB4 receptor antagonist, could block PMN activation and lung injury in a porcine model of lipopolysaccharide-induced ARDS. METHODS: Eighteen hours before being studied, pigs were injected with lipopolysaccharide (20 micrograms/kg). From 0 to 60 minutes, pigs received either Ringer's lactate solution (n = 5) or lipopolysaccharide (250 micrograms/kg). Among the pigs that were infused with lipopolysaccharide, nine received no other treatment, six received a low dose of LY255283 (30 mg/kg loading dose; 3 mg/kg-hr infusion), and six received a high dose of LY255283 (30 mg/kg loading dose; 30 mg/kg-hr). In vivo PMN activation was assessed with an automated chemiluminescence assay wherein results are expressed as CORE/MORE (i.e., the ratio of complement-opsonized zymosan receptor expression on circulating cells [CORE] divided by the maximal complement-opsonized zymosan receptor expression induced by incubating the cells in vitro with LTB4 or platelet-activating factor [MORE]). RESULTS: In control pigs, lipopolysaccharide induced hypoxemia, pulmonary hypertension, and neutrophil activation (increased CORE/MORE ratio). These changes were attenuated by LY255283, particularly when pigs were infused with the higher dose of the compound. The drug also blunted lipopolysaccharide-induced recruitment of PMNs in pulmonary air spaces, as assessed by bronchoalveolar lavage performed at 240 minutes, although the degree of pulmonary leukosequestration caused by lipopolysaccharide was not affected. CONCLUSIONS: In a dose-dependent fashion, LY255283 ameliorated lipopolysaccharide-induced ARDS in pigs, possibly by blocking the recruitment of activated PMNs into alveoli.

Acute Disease↗
PubMed1992

Nonbronchoscopic approach to bronchoalveolar lavage in children with artificial airways.

Bronchoalveolar lavage (BAL) performed with a fiberoptic bronchoscope (FOB) is a useful method for sampling alveolar contents. Since the smallest FOB with a channel has a diameter of 3.6 mm, BAL is difficult to accomplish through artificial airways (AA) less than 5.0 mm I.D. We used a 4F balloon wedge pressure catheter to perform BAL through small AA. Supplemental O2 or ventilatory support was delivered via an adaptor through which the catheter was introduced. After it was passed distal to the AA, the balloon was inflated with normal saline (NS) to a predetermined volume, and advanced until resistance was felt. The balloon was deflated, advanced slightly, and then reinflated to achieve airway occlusion. Five aliquots of 0.75 mL/kg of NS were used for BAL. The procedure was performed in 20 children from 1 month (950 g) to 6 1/2 years of age (median, 9 months). All specimens contained abundant alveolar macrophages, indicating good recovery of alveolar contents. Clinically significant information was obtained in 17 (85%) cases, and no patient required an open lung biopsy. In conclusion, nonbronchoscopic bronchoalveolar lavage is a valuable method for obtaining alveolar contents in children with small AA that preclude the use of an FOB, and it obviates the need for open lung biopsy in many patients. This technique could be used as a research tool for measuring constituents of alveolar contents in infants and small animals.

Catheterization, Peripheral↗
PubMed1992

Reduction of eicosanoid production by essential fatty acid depletion does not attenuate the inflammatory response induced by Pseudomonas aeruginosa pneumonia in rat lung.

Sipid mediators of inflammation have been implicated in the pathogenesis of Pseudomonas aeruginosa (PA) related pulmonary damage in patients with cystic fibrosis. We studied the role of these mediators in a rat model of PA endobronchitis using essential fatty acid deficient (EFAD) animals. Whole blood from EFAD animals produced significantly less leukotriene B4 (LTB4) and hydroxyheptadecatrienoic acid when stimulated ex vivo than did whole blood from control animals (p less than 0.005). Similarly, lung lavage fluid from EFAD animals infected with PA contained less LTB4 and thromboxane B2 (TXB2) than that from control animals. Despite these differences, cellular infiltration of airways in response to PA infection was virtually identical in animals from the regular diet and the EFAD groups. Both EFAD and control animals had a significant increase in white blood cells (WBC) in lung lavage fluid at 1, 3 and 6 days following infection with PA when compared to animals receiving sterile beads. Localized areas of consolidation and nodularity were grossly evident in the lungs of all PA infected animals irrespective of their ability to generate the lipid inflammatory mediators. Microscopic examination of lung sections demonstrated similar changes in all infected animals. We conclude that LTB4 and TXB2 production occurs early in the course of PA pulmonary infection in rats. This early rise in lipid mediators is temporally associated with an influx of WBC into the airways. However, attenuation of eicosanoid production by use of an EFAD diet does not lead to a reduction in the inflammatory response to PA infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Binding of radiolabeled high affinity antagonist to leukotriene D4 receptor in guinea pig lung membranes: interconversion of agonist-receptor binding affinity states.

The kinetic parameters and the pharmacological specificity of a high affinity leukotriene D4 (LTD4) receptor antagonist, ICI-198615, binding to guinea pig lung membranes were characterized. Binding of [3H]ICI-198615 to the membranes was rapid and displaceable with excess ICI-198615. The specific binding of [3H] ICI-198615 was dependent upon the concentration of membrane protein. Monovalent cations (Na+, Li+, and Cs+), divalent cations (Mg2+, Ca2+, and Mn2+), and guanine nucleotides did not significantly affect the specific binding of [3H]ICI-198615 to guinea pig lung LTD4 receptors. The specific binding of [3H]ICI-198615 to guinea pig lung membranes was saturable and the equilibrium saturation binding was best approximated by a single-site model. The dissociation constant (KD) and the density (Bmax) were 0.08 +/- 0.04 nM and 1030 +/- 180 fmol/mg, respectively. In competition studies, LTD4, stereoisomer (5R,6S)-LTD4, and leukotriene E4 (LTE4) competed with [3H]ICI-198615 binding to specific sites, with a stereoselectivity and a rank order of potency equivalent to those described in [3H]LTD4 binding studies and in functional studies. LTD4 and LTE4 displaced maximally 70 and 40%, respectively, of the [3H]ICI-198615 specific binding component defined by ICI-198615. Several LTD4 receptor antagonists (ICI-198615, WY-48252, WY-49511, FPL-55712, and LY-171883) displaced [3H]ICI-198615 specific binding, with a rank order of potency equivalent to that described in the guinea pig tracheal smooth muscle contraction system. The leukotriene structure-like receptor antagonists, e.g., SK&F 104353 and SK&F 104373, also competed with the [3H]ICI-198615 specific binding, with binding affinities comparable to those expected from the functional studies. However, SK&F 104353 and SK&F 104373 displaced maximally 70% of the specific binding component of [3H]ICI-198615, equivalent to that displaced by LTD4. Guanosine-5'-3-thiotriphosphate (GTP gamma S), EDTA, and Na+ shifted the LTD4 displacement curve to the right, indicating that these agents regulated the binding of LTD4 to the receptor. In the absence of GTP gamma S or cations, the LTD4 displacement curve was heterogeneous. The LTD4 displacement curve was resolved into a higher affinity component (KDH = 0.5 +/- 0.2 nM; percentage of receptor density at high affinity = 24 +/- 3%) and a low affinity component (KDL = 60 +/- 7 nM; percentage of receptor density at low affinity = 76 +/- 3%).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Bond strength of a luting composite to dentin with different bonding systems.

This study evaluated the tensile bond strength of Conclude luting composite to dentin under different environmental conditions with Scotchbond dental adhesive, the FNP system, and unfilled BIS-GMA resin used as bonding agents. Although the bonding systems reportedly yield high tensile bond values to enamel, large differences were observed in this study for bond values to dentin. Only the FNP bonding system produced consistently high tensile load values to dentin under the three environmental conditions tested.

Adhesives↗