Biomedical subjects

Robert S Tepper

Publications and source records attributed to Robert S Tepper.

13 recordsLinked to original sources

PubMed2006

Cyclic stretch induces PlGF expression in bronchial airway epithelial cells via nitric oxide release.

Mechanical strain of lung tissue is an important stimulus for the production of growth factors that are critical for lung growth and development. However, excessive mechanical strain, as may occur during mechanical ventilation, may produce an increase in growth factors that may contribute to lung injury. We hypothesized that mechanical strain of primary bronchial airway epithelial cells (BAEpCs) induced the production of placental growth factor (PlGF), a member of the VEGF family. BAEpCs were cultured on a deformable silicoelastic membrane and exposed to different magnitudes of stretch. Stretch induced PlGF and nitric oxide (NO) production that increased with increasing magnitude of stretch. Stretch also induced PlGF and inducible NO synthase (iNOS) gene expression. The stretch-induced PlGF production and NO synthesis were attenuated by PD98059, a specific mitogen-activated protein kinase kinase-1 and -2 inhibitor. Inhibition of NO generation by l-NAME or l-NMMA or scavenging NO by carboxy-PTIO prevented stretch-mediated erk1/2 activation. In addition, in unstretched BAEpCs, exogenous NO enhanced erk1/erk2 activation. Our data suggest that mechanical stretch of BAEpCs induces iNOS expression and induces PlGF release in an erk1/2 activation-dependent manner.

Bronchi↗

PubMed2006

Measurement of single breath-hold carbon monoxide diffusing capacity in healthy infants and toddlers.

We describe a method for measuring carbon monoxide diffusing capacity (DL(CO)) and alveolar volume (V(A)) in sleeping infants, using a single 4-sec breath-hold technique. The breath-hold maneuver is obtained by inducing a respiratory pause of the respiratory system. Several inflations of the respiratory system with room air to a lung volume with an airway pressure of 30 cmH2O (V30) inhibit inspiratory effort. The respiratory system is then inflated with a test gas containing helium and a stable isotope of carbon monoxide (C18O), and a respiratory pause is maintained for 4 sec and followed by passive expiration to functional residual capacity. Concentrations of helium and C18O are continuously measured with a mass spectrometer. Twelve healthy infants between 6-22 months of age were evaluated. For 9 of 12 subjects, duplicate measurements of alveolar volume at 30 cmH2O (V(A30)) and DL(CO) were within 10%, which are the recommendations for older children and adults. Among these 9 subjects, values of V(A30) and DL(CO) increased with increasing body length (r2 = 0.82 and 0.79, respectively). The remaining 3 subjects had two values within 10-15%. Measurement of V(A) and DL(CO) with the single breath-hold technique at an elevated lung volume offers the potential to assess growth and development of the lung parenchyma early in life.

Body Height↗

PubMed2005

High-resolution computed tomography imaging of airway disease in infants with cystic fibrosis.

RATIONALE: The development of early lung disease in patients with cystic fibrosis (CF) remains poorly defined. OBJECTIVE: Determine whether asymptomatic infants with CF have evidence for changes in airway structure when assessed by high-resolution computed tomography, and whether airway structure correlates with airway function in this age group. METHODS: Thirteen infants with CF (8-33 mo) and 13 control infants (7-25 mo) were evaluated. Airway wall and lumen areas were measured from three 1-mm-thick cross-sectional images obtained from upper, middle, and lower lobes during a respiratory pause with the lungs inflated to an airway pressure of 20 cm H2O. Lung tissue density was measured from images obtained during a respiratory pause at FRC. Forced expiratory flows were measured by the rapid thoracic compression technique in 11 infants with CF. RESULTS: Airway wall area increased more per unit increase in airway size, whereas airway lumen area increased less per unit increase in airway size in the CF than in the control group. Among infants with CF, a greater ratio of wall to lumen area correlated with lower airway function. In addition, lung density at relaxed (passive) FRC was lower for infants with CF than for control infants (0.38 vs. 0.43 g/ml; p < 0.02). CONCLUSIONS: Our results indicate that infants with CF have thickened airway walls, narrowed airway lumens, and air trapping, when assessed by high-resolution computed tomography, and measurements of airway structure correlated with airway function.

Case-Control Studies↗

PubMed2004

Parental smoking and airway reactivity in healthy infants.

Parental tobacco smoking is associated with lower airway function and an increased incidence of wheezy respiratory illnesses in infants. We evaluated in 76 healthy infants whether exposure to parental tobacco smoking was associated with airway hyperreactivity, which could contribute to lower airway function and the increased wheezy illnesses. Airway function was measured using the raised-volume rapid thoracic compression technique, and airway reactivity was assessed by methacholine challenge (0.015-10 mg/ml), which was stopped for a more than 30% decrease in forced expiratory flow (FEF)(75) or the final dose with a less than 30% decrease. Parental tobacco smoking was associated with lower baseline airway function (FEF(50), 600 vs. 676 ml/second, p < 0.04; FEF(25-75), 531 vs. 597 ml/second, p < 0.05). Infants exposed to tobacco smoking were approximately half as likely to develop a more than 30% decline in FEF(75) at any given methacholine dose (hazard ratio = 0.4, p = 0.001). In addition, a history of asthma in an extended family member increased the likelihood that an infant would develop a more than 30% decline in FEF(75) (hazard ratio = 1.7, p = 0.04). We conclude that exposure to parental smoking is associated with lower airway function but not increased airway reactivity; however, family history of asthma is associated with heightened airway reactivity.

Bronchial Hyperreactivity↗

PubMed2004

Elastic properties of the respiratory system in infants with cystic fibrosis.

Respiratory system compliance (Crs) in infants with cystic fibrosis (CF) has been reported as decreased or not different compared with healthy control subjects; however, the reported measurements of Crs were "quasi-static" or by the single-breath occlusion technique, with all measurements limited to tidal lung volume, as well as using inspiratory rather than expiratory pressures. We compared the passive elastic properties of the respiratory system of sleeping infants with CF (n = 10) and healthy control subjects (n = 34) by measuring static deflation pressure--volume (PV) curves from a lung volume at 30 cm H(2)O (V(30)) to FRC. There was no significant difference between the groups for Crs, which was measured as the slope between airway relaxation pressures of 5 and 15 cm H(2)O, the linear portion of the deflation PV curve. In addition, when PV curves were normalized to V(30), there were no differences between the infants with CF and healthy control subjects in the fractional volumes at any airway pressure. The infants with CF had significantly lower forced expiratory flows; however, lower flows did not correlate with fractional volumes measured from the PV curve. Our findings indicate that infants with CF have normal elastic properties of the respiratory system.

Case-Control Studies↗

PubMed2004

Pulmonary function in bronchopulmonary dysplasia.

The purpose of this study was to examine lung function and bronchodilator responsiveness in infants with a history of prematurity and bronchopulmonary dysplasia (BPD), using the raised volume rapid thoracoabdominal compression technique as well as with whole-body plethysmography. Spirometric measurements were obtained in 28 infants with a history of BPD, defined as preterm birth with O2 requirement at 36 weeks postmenstrual age (gestational age at birth, 26.4 +/- 2.1 weeks, mean +/- SD; birthweight, 898 +/- 353 g; age at study, 68.0 +/- 35.6 weeks). Fractional lung volumes were measured in 27 subjects. Values were expressed as percentage of predicted normal values. Compared to normal infants, those with a history of BPD exhibited decreases in forced expiratory flows including forced expiratory volume in 0.5 sec (76.3 +/- 19.6%), forced expiratory flow at 75% of expired forced vital capacity (FEF75; 59.5 +/- 30.7%), and FEF(25-75) (74.0 +/- 26.8%; P<0.01 for all). Functional residual capacity (107.9 +/- 25.3%), residual volume (RV, 124.5 +/- 42.7%), and RV/total lung capacity (RV/TLC, 128.2 +/- 35.3%) were increased in infants with a history of BPD (P<0.05 for each). There was no difference in TLC between groups. Seventeen infants were studied both pre- and postalbuterol, and 6 (35%) demonstrated significant bronchodilator responsiveness. Infants with recurrent wheezing showed greater expiratory flow limitation, hyperinflation, and airways responsiveness, whereas those without wheezing showed only modest airway dysfunction. We conclude that infants with a history of BPD have pulmonary function abnormalities characterized by mild to moderate airflow obstruction and air trapping.

Airway Obstruction↗

PubMed2004

RSV causes HIF-1alpha stabilization via NO release in primary bronchial epithelial cells.

RSV infection is characterized by airway edema. Stabilization of hypoxia inducible factor-1alpha (HIF-1alpha) is important in both inflammation and edema formation. In this study we evaluated whether RSV induced release of nitric oxide (NO) by bronchial airway epithelial cells leading to the stabilization of HIF-1alpha and subsequent transcription of VEGF(165). Primary human bronchial epithelial cells (HBEpC) were used; cell supernatants were analyzed. Western blot analysis was used for the detection of HIF-1alpha. Bronchial airway epithelial monolayer permeability was assessed using electric cell-substrate impedance sensing (ECIS) in real time. There was increased stabilization of HIF-1alpha in RSV infected cells. Addition of an NO inhibitor blocked RSV mediated HIF-1alpha expression. Antagonism of NO also inhibited VEGF production and HBEpC monolayer permeability. Our results demonstrate that in HBEpC, RSV induced NO causes stabilization of HIF-1alpha in vitro.

Benzoates↗

PubMed2004

Model of forced expiratory flows and airway geometry in infants.

Early measurements of autopsied lungs from infants, children, and adults suggested that the ratio of peripheral to central airway resistance was higher in infants than older children and adults. Recent measurements of forced expiration suggest that infants have high flows relative to lung volume. We employed a computational model of forced expiratory flow along with physiological and anatomic data to evaluate whether the infant lung is a uniformly scaled-down version of the adult lung. First, we uniformly scaled an existing computational model of adult forced expiration to estimate forced expiratory flows (FEF) and density dependence for an 18-mo-old infant. The values obtained for FEF and density dependence were significantly lower than those reported for healthy 18-mo-old infants. Next, we modified the model for the infant lung to reproduce standard indexes of expiratory flow [forced expiratory volume in 0.5 s (FEV(0.5)), FEFs after exhalation of 50 and 75% forced vital capacity, FEF between 25 and 75% expired volume] for this age group. The airway sizes obtained for the infant lung model that produced accurate physiological measurements were similar to anatomic data available for this age and larger than those in the scaled model. Our findings indicate that the airways in the infant lung model differ from those in the scaled model, i.e., middle and peripheral airway sizes are larger than result from uniform downscaling of the adult lung model. We show that the infant lung model can be made to reproduce individual flow-volume curves by adjusting lumen area generation by generation.

Adult↗

PubMed2004

Respiratory syncytial virus causes increased bronchial epithelial permeability.

BACKGROUND: Respiratory syncytial virus (RSV)-induced diseases are mediated through active cytokines released during infection. We hypothesized that RSV infection causes bronchial epithelial monolayer permeability in vitro via induction of vascular endothelial growth factor (VEGF). METHODS: Human bronchial epithelial cells were infected with RSV. In some cultures, VEGF antibody was included to block VEGF response; in other cultures, palivizumab was added to block RSV infection. Permeability was assessed in real-time using electric cell-substrate impedance sensing. VEGF release was assessed using enzyme-linked immunosorbent assay. Gap formation was assessed using live cell imaging. RESULTS: RSV-infected cells demonstrated a decrease in the resistance of the monolayer indicating an increase in permeability; this increase was blocked with VEGF-specific antibody, and palivizumab. Intercellular gap formation developed in RSV-infected epithelial monolayers. CONCLUSION: RSV increases permeability of the bronchial airway epithelial monolayer via VEGF induction.

Bronchi↗

PubMed2003

Sensitivity of spirometric measurements to detect airway obstruction in infants.

We evaluated the ability of forced expiratory flow volume curves from raised lung volumes to assess airway function among infants with differing severities of respiratory symptoms. Group 1 (n = 33) had previous respiratory symptoms but were currently asymptomatic; group 2 (n = 36) was symptomatic at the time of evaluation. As a control group, we used our previously published sample of 155 healthy infants. Flow volume curves were quantified by FVC, FEF50, FEF75, FEF25-75, FEV0.5, and FEV0.5/FVC, which were expressed as Z scores. All variables except FVC had Z scores that were significantly less than zero and distinguished groups 1 and 2 with progressively lower Z scores. The mean Z scores of the flow variables (FEF50%, FEF75%, and FEF25-75%) were more negative than the Z scores for the timed expired volumes (FEV0.5 or FEV0.5/FVC) for both groups. In general, measures of flow identified a greater number of infants with abnormal lung function than measures of timed volume; FEF50 had the highest performance in detecting abnormal lung function. In summary, forced expiratory maneuvers obtained by the raised volume rapid compression technique can discriminate among groups of infants with differing severity of respiratory symptoms, and measures of forced expiratory flows were better than timed expiratory volume in detecting abnormal airway function.

Age Factors↗

PubMed2002

Spirometry in 3- to 6-year-old children with cystic fibrosis.

Spirometry is routinely used to assess pulmonary function of older children and adults with cystic fibrosis (CF); however, few data exist concerning the preschool age group. We have reported normative spirometric data for 3- to 6-year-old children. The current study was designed to assess a similarly aged group of clinically stable patients with CF. Thirty-three of 38 children with CF were able to perform 2 or 3 technically acceptable maneuvers. These patients had significantly decreased FVC, FEV(1), FEV(1)/FVC, and FEF(25-75) when expressed as z scores (number of SD from predicted): -0.75 +/- 1.63, -1.23 +/- 1.97, -0.87 +/- 1.33, and -0.74 +/- 1.63, respectively. There were significant positive correlations of the Brasfield radiological score with FVC and FEV(1) z scores (r(2) = 0.26, p < 0.01 and r(2) = 0.24, p < 0.01). In addition, homozygous patients for the DeltaF508 mutation had lower z scores for FVC (-1.21 versus 0.47, p < 0.01) and FEV(1) (-1.38 versus 0.21, p < 0.05) than heterozygous patients. Of the 14 patients who had full flow-volume spirometric measurements during infancy, 10 had FEF(25-75) z scores greater than -2 at both evaluations. Our findings suggest that spirometry can successfully be used to assess lung function in preschool children with CF and has the potential for longitudinal assessment from infancy through adulthood.

Age Factors↗

PubMed2002

Sex-specific prediction equations for Vmax(FRC) in infancy: a multicenter collaborative study.

Measurements of maximal flow at functional residual capacity (Vmax(FRC)) from partial forced expiratory maneuvers remain the most popular method for assessing small airway function in infants and young children. However, the lack of appropriate reference data that are both applicable outside the centers that developed them and reflect the normal variability between healthy subjects has limited interpretation of Vmax(FRC) results in both clinical practice and research. To address this problem, we collated Vmax(FRC) data from 459 healthy infants (226 boys) tested on 654 occasions during the first 20 months of life from three collaborating centers. Multiple linear regression analysis indicated that sex, age, and length were important predictors of Vmax (FRC), which was, on average, 20% higher in girls than in boys during the first 9 months of life. (Vmax(FRC))0.5 (ml x second(-1)) = 4.22 + 0.00210 x length2 (cm) for boys (RSD = 3.01; R2 = 0.48), and -1.23 + 0.242 x length for girls (RSD = 2.72; R2 = 0.49). Alternative models incorporating both age and length z scores are also described. Failure to use sex-specific prediction equations for Vmax(FRC) may preclude detection of clinically significant changes in girls and lead to false reports of diminished airway function in boys. Appropriate use of z scores, which indicate a "normal" range (z scores of 0 +/- 2) for Vmax(FRC), during infancy should also improve interpretation of both clinical and research studies.

Body Constitution↗

PubMed2002

Cockroach extract antigen increases bronchial airway epithelial permeability.

BACKGROUND: The bronchial epithelial cells of airways are subject to recurrent environmental injury throughout the life of an individual. Recently, a high incidence of asthma has been reported in inner-city children. The increased incidence of asthma in inner-city children is thought to be caused, in part, by frequent exposure to allergens of the common household pest the cockroach. OBJECTIVE: We sought to investigate whether cockroach extract antigen (CrAg) induces vascular permeability factor, also known as vascular endothelial growth factor (VEGF), and whether it increases permeability in bronchial airway epithelial cells (BAECs). METHODS: We estimated CrAg-induced VEGF release in BAECs by using an ELISA and VEGF mRNA expression by using an RT-PCR reaction. The influence of CrAg on BAEC barrier function was estimated by measuring electrical resistance with an electric cell substrate impedance-sensing system. RESULTS: Our results demonstrate that CrAg induces VEGF release in BAECs in a time-dependent manner. The VEGF induction was also confirmed by means of VEGF mRNA expression in CrAg-stimulated BAECs. CrAg decreased electrical resistance across BAEC monolayers. The maximum decrease in electrical resistance was noticed 6 hours after activation and reached a plateau thereafter. Neutralizing antibodies to VEGF significantly inhibited the decrease in BAEC electrical resistance caused by CrAg. CONCLUSIONS: These data suggest that CrAg induces VEGF release in BAECs and alters bronchial airway permeability.

Animals↗