PubMed Health⌕ Search

Biomedical subjects

Jonathan M Davis

Publications and source records attributed to Jonathan M Davis.

10 recordsLinked to original sources
PubMed2003

Prognostic value of myocardial perfusion imaging in predicting outcome after renal transplantation.

Cardiovascular disease is a significant cause of morbidity and mortality after renal transplantation. Pretransplant screening in a subset of these patients for occult coronary artery disease (CAD) may improve outcome. The objective of this study was to examine the outcome of 600 patients after renal transplantation for end-stage renal disease. Prospective outcome data were collected on 600 consecutive patients who had renal transplantation between 1996 and 1998 at our institution at 42 +/- 12 months after surgery. Stress single-photon emission computed tomographic (SPECT) myocardial perfusion imaging was performed in 174 patients before surgery, 136 (78%) of whom had diabetes mellitus. There were a total of 59 events: 17 cardiac deaths, 14 nonfatal myocardial infarctions, and 28 noncardiac deaths. There were 12 cardiac events and 11 noncardiac deaths among those who had SPECT myocardial perfusion imaging. In a multivariate analysis that included important risk factors, age (p = 0.03 and 0.003, respectively) and diabetes (p = 0.02 and 0.005, respectively) were the predictors of total events and cardiac events in patients who did not undergo stress SPECT perfusion imaging. In the subgroup who had stress perfusion imaging, an abnormal perfusion SPECT study was the only predictor of cardiac events (p = 0.006). The 42-month cardiac event-free survival rate was 97% in patients with normal SPECT images and 85% in patients with abnormal SPECT images (RR 5.04, 95% confidence interval 1.4 to 17.6, p = 0.006). Thus, there is a 2.8% event rate per year after renal transplantation, and approximately 50% of these events are noncardiac. In high-risk patients (most of whom had diabetes) with preoperative stress perfusion imaging, those with normal images had significantly lower cardiac events than those with abnormal images. These results have important implications in patient screening and postoperative management.

Adult↗
PubMed2003

Inhibition of c-Jun N-terminal kinase pathway improves cell viability in response to oxidant injury.

Oxidant insults can lead to apoptotic and nonapoptotic cell death. Lung epithelial cells exposed to high levels of oxygen do not die via apoptosis, but through a much slower, morphologically distinct process involving cell and nuclear swelling. In contrast, H2O2 induces a rapid apoptotic cell death. We first assessed the effect of oxidant exposure on activator protein-1 (c-Jun and Fos) and c-Jun N-terminal kinase (JNK) regulation in MLE12 cells. Both oxidants induced c-Jun and Fos expression, albeit with a different pattern of regulation-hyperoxia (95% O2) induced a biphasic response, whereas H2O2 (500 microM) induced a sustained response. We then examined the role of JNK by Western blot, JNK activity assay, and a pull-down assay and observed an identical pattern of regulation. To assess whether JNK functions in a pro-death or pro-survival capacity, we generated stable cell lines that constitutively express a dominant-negative mutation of JNK resulting in significant inhibition of JNK activity. Inhibition of the JNK pathway in this manner prevented hyperoxic and H2O2-induced cell death. These results demonstrate that hyperoxic cell death is pathway-driven and that both modes of death involve the JNK signaling pathway.

Animals↗
PubMed2003

Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury.

Despite the widespread use of exogenous surfactant, acute and chronic lung injury continues to be a major cause of morbidity in preterm infants. CC10 is a protein produced by Clara cells that inhibits phospholipase A2 and has anti-inflammatory and antifibrotic properties. We studied whether intratracheal (IT) recombinant human Clara cell protein (rhCC10) could safely minimize lung injury in a newborn piglet model of acute lung injury. Twenty-nine newborn piglets were given Survanta and then ventilated for 48 h receiving the following: room air (group 1); 100% O2 (group 2); or 100% O2 and 25, 5, or 1 mg/kg (groups 3, 4, and 5, respectively) of IT rhCC10 (diluted to 2 mL/kg with saline) at time 0. Laboratory studies, oxygen ratios, static pressure-volume curves, bronchoalveolar lavage (for inflammatory markers), and histologic analyses were performed over the 48-h study period. Pulmonary compliance and oxygenation were significantly improved in animals receiving 5 mg/kg IT rhCC10 compared with room air and 100% O2 controls (p < 0.004 and p < 0.05, respectively, ANOVA). Reductions in inflammatory markers were seen in animals receiving rhCC10, although changes did not reach statistical significance. No significant toxicity was noted. rhCC10 appeared safe and improved pulmonary function in this newborn piglet model of hyperoxic lung injury. We speculate that rhCC10 may represent a promising therapy for the prevention of lung injury in preterm infants.

Administration, Inhalation↗
PubMed2003

Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase.

OBJECTIVE: To examine whether treatment of premature infants with intratracheal recombinant human CuZn superoxide dismutase (r-h CuZnSOD) reduces bronchopulmonary dysplasia and improves pulmonary outcome at 1 year corrected age. DESIGN: Three hundred two premature infants (600-1200 g birth weight) treated with exogenous surfactant at birth for respiratory distress syndrome were randomized to receive either intratracheal r-h CuZnSOD (5 mg/kg in 2 mL/kg saline) or placebo every 48 hours (as long as intubation was required) for up to 1 month of age. Short-term, as well as longer-term pulmonary outcome was assessed. RESULTS: There were no differences between groups in the incidence of death or the development of bronchopulmonary dysplasia (oxygen requirement with an Edwards chest radiograph score of >or=3) at 28 days of life or 36 weeks' postmenstrual age. r-h CuZnSOD was well-tolerated and not associated with significant increases in any adverse event. At a median of 1 year corrected age, health assessments and physical examinations were performed on 209 (80%) surviving infants, with complete data available on 189 infants. Thirty-seven percent of placebo-treated infants had repeated episodes of wheezing or other respiratory illness severe enough to require treatment with asthma medications such as bronchodilators and/or corticosteroids compared with 24% of r-h CuZnSOD-treated infants, a 36% reduction. In infants <27 weeks' gestation, 42% treated with placebo received asthma medications compared with 19% of r-h CuZnSOD-treated infants, a 55% decrease. Infants <27 weeks' gestation who received r-h CuZnSOD also had a 55% decrease in emergency department visits and a 44% decrease in subsequent hospitalizations. Growth measurements and the results of physical examinations were comparable between groups. CONCLUSIONS: These data indicate that treatment at birth with r-h CuZnSOD may reduce early pulmonary injury, resulting in improved clinical status when measured at 1 year corrected age. r-h CuZnSOD appears to be a safe and effective therapy that improves pulmonary outcome in high-risk premature infants.

Age Factors↗
PubMed2002

Suppression of nuclear factor-kappa B activity by nitric oxide and hyperoxia in oxygen-resistant cells.

Inhaled nitric oxide (iNO) is used clinically to treat pulmonary hypertension in newborns, often in conjunction with hyperoxia (NO/O2). Prolonged exposure to NO/O2 causes synergistic lung injury and death of lung epithelial cells. To explore the mechanisms involved, oxygen-resistant HeLa-80 cells were exposed to NO +/- O2. Exposure to NO and O2 induced a synergistic cytotoxicity, accompanied with apoptotic characteristics, including elevated caspase-3-like activity, Annexin V incorporation, and nuclear condensation. This apoptosis was associated with a synergistic suppression of NF-kappaB activity. Cells lacking functional NF-kappaB p65 subunit were more sensitive to NO/O2 than their wild type counterparts. This injury was partially rescued by transfection with a p65 expression construct, suggesting an inverse relationship between NF-kappaB and susceptibility to the cytotoxicity of NO/O2. Despite the reduced NF-kappaB activity in cells exposed to NO +/- O2, IkappaBalpha was degraded, suggesting that pathways regulating the steady-state levels of IkappaB were not involved. However, exposure to NO/O2 caused a marked reduction in nuclear localization and an increase in protein carbonyl formation of NF-kappaB p65 subunit. These results suggest that NO/O2-induced apoptosis occurs by suppressing NF-kappaB activity.

3T3 Cells↗
PubMed2002

Effects of variable concentrations of inhaled nitric oxide and oxygen on the lungs of newborn piglets.

We previously demonstrated that inhalation of high concentrations of nitric oxide (iNO) and oxygen for 48 hr causes significant lung injury in newborn piglets. To determine if these effects persist at lower concentrations, groups of newborn piglets were mechanically ventilated for 48 hr with (study 1) constant O(2) (90-100%) and decreasing iNO (100-2 ppm) or (study 2) constant iNO (50 ppm) and decreasing O(2) (95-30%). Bronchoalveolar lavage (BAL) fluid was assayed for surfactant function, and markers of lung inflammation and physiologic parameters were monitored. Neutrophil chemotactic activity (NCA), % neutrophils, and total protein (TP) concentrations decreased significantly in BAL fluid of study 1 piglets as iNO was reduced and inhaled oxygen fraction remained constant, indicating less pulmonary injury at low iNO levels. Low-dose iNO (2 ppm) did not have antiinflammatory effects. However, surfactant function was minimally affected by lowering iNO, and was abnormal in all groups. In contrast, in study 2, pulmonary inflammation and injury were lower when O(2) was decreased to 70% or less, with iNO constant at 50 ppm. Surfactant function normalized and oxygenation improved in study 2 piglets when the inhaled oxygen fraction was decreased and iNO remained constant. These data suggest that iNO- and O(2)-induced lung injury may be minimized by weaning O(2) or iNO, although better physiologic function may be obtained when iNO concentrations are constant and O(2) is reduced. This has important implications in the clinical management of critically ill newborns treated with O(2) and iNO for pulmonary disorders.

Animals↗
PubMed2002

Role of oxidant injury in the pathogenesis of neonatal lung disease.

UNLABELLED: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in newborn infants treated with oxygen and mechanical ventilation for a primary lung disorder. With significant improvements in survival of many critically ill infants, BPD has become an extremely important complication of newborn intensive care. The pathogenesis of BPD is complex and involves a variety of causative factors. However, increasing evidence has suggested that an oxidative insult could be an extremely important component of the injury process. Premature infants are especially sensitive to oxidant injury since they are exposed to supraphysiological concentrations of oxygen at birth while endogenous antioxidant enzyme activity may be relatively deficient. CONCLUSION: Superoxide dismutase is an antioxidant enzyme that has been shown in numerous basic and clinical studies to protect cells against oxidant injury.

Animals↗
PubMed2002

Distinct patterns of apoptosis in the lung during liquid ventilation compared with gas ventilation.

To determine whether liquid ventilation (LV) causes less cell injury and improves lung function compared with conventional gas ventilation (GV), we analyzed pulmonary physiological profiles, lung histology, and cell death in 110- and 120-day preterm lambs, which were randomized to receive either ventilation modality on FI(O(2)) = 1. LV lungs were well expanded with adequate pulmonary function, whereas GV animals exhibited marked atelectasis, poor pulmonary function, and increased mortality. Both ventilatory strategies induced marked lung cell apoptosis, but with distinct patterns of distribution. Although GV induced apoptosis of epithelium primarily in the lining and within the lumina of bronchioles, LV induced significant apoptosis much more homogeneously throughout lung parenchyma including alveoli and interstitial spaces. These studies suggest that although both forms of ventilation cause regional apoptosis, LV more effectively delivers oxygen and recruits the lung more homogeneously than GV.

Animals↗
PubMed2002

Effects of exogenous surfactant and recombinant human copper-zinc superoxide dismutase on oxygen-dependent antimicrobial defenses.

The use of human recombinant CuZn superoxide dismutase (rhSOD) in addition to exogenous surfactant has been studied as a therapeutic strategy to prevent acute and chronic lung injury in premature infants with blood monocytes (MO). However, scavenging of superoxide by rhSOD may compromise bacterial killing by phagocytes. In the present study, we investigated the interaction of exogenous surfactant and rhSOD with the antibacterial activity of human blood MO. MO were preincubated in the presence or absence of: (1) modified natural surfactant (Curosurf); 1 mg/ml); (2) rhSOD (2,500 U/ml) and (3) bovine catalase (25,000 U/ml). Bacteria (Legionella pneumophila or Escherichia coli) were then added and incubated for 6 h. Viable bacteria were determined by counting colony-forming units. The ability of the MO to generate superoxide anions (O2-) in response to bacterial infection was also investigated. The antibacterial capacity of MO was not impaired by the presence of rhSOD either alone or combined with Curosurf. In some instances, bactericidal activity was even potentiated by the addition of rhSOD. Exposure of MO to catalase interfered with the increased bacterial killing of MO and rhSOD, suggesting that hydrogen peroxide (H2O2) production was critically important in the process of bacterial killing. Both bacterial species were also found to induce the generation of intra- and extracellular O2- by MO. Data indicate that rhSOD potentiates the killing of bacteria by human MO. The mechanism of action appears to be related to the ability of bacteria to induce the generation of O2-, which in turn is converted to H2O2 in the presence of rhSOD. This has important implications in the development of therapeutic intervention strategies using antioxidant therapy in premature infants with respiratory distress syndrome.

Adult↗