Charles V Smith

Altered Expressions of Fibroblast Growth Factor Receptors and Alveolarization in Neonatal Mice Exposed to 85% Oxygen

In the present study, we tested the hypothesis that exposure of newborn mice to sublethal hyperoxia would alter lung development and expressions of fibroblast growth factor receptors (FGFRs)-3 and FGFR-4. Newborn FVB mice were exposed to 85% O2 or maintained in room air for up to 14 d. No animal mortality was observed, and body weight gains were not affected by hyperoxia. At postnatal d 7 and 14 (P7, P14), lungs of mice exposed to 85% O2 showed fewer alveolar secondary crests and larger alveoli or terminal air spaces than did mice in room air. In pups kept in room air, lung levels of FGFR-3 and FGFR-4 mRNA were greater at P3 than at P1, but similar increases were not observed in hyperoxic mice. Immunoreactivity of FGFR-3 and FGFR-4 was lower in lungs of hyperoxic mice than in controls at P14. In pups kept in room air, lung fibroblast growth factor (FGF)-7 mRNA levels were greater at P14 than at P1, but similar changes were not observed in hyperoxic mice. The temporally and spatially specific alterations in the expressions of FGFR-3, FGFR-4, and FGF-7 in the mice exposed to hyperoxia may contribute to aberrant lung development.

Toward more transparent and reproducible omics studies through a common metadata checklist and data publications.

Biological processes are fundamentally driven by complex interactions between biomolecules. Integrated high-throughput omics studies enable multifaceted views of cells, organisms, or their communities. With the advent of new post-genomics technologies, omics studies are becoming increasingly prevalent; yet the full impact of these studies can only be realized through data harmonization, sharing, meta-analysis, and integrated research. These essential steps require consistent generation, capture, and distribution of metadata. To ensure transparency, facilitate data harmonization, and maximize reproducibility and usability of life sciences studies, we propose a simple common omics metadata checklist. The proposed checklist is built on the rich ontologies and standards already in use by the life sciences community. The checklist will serve as a common denominator to guide experimental design, capture important parameters, and be used as a standard format for stand-alone data publications. The omics metadata checklist and data publications will create efficient linkages between omics data and knowledge-based life sciences innovation and, importantly, allow for appropriate attribution to data generators and infrastructure science builders in the post-genomics era. We ask that the life sciences community test the proposed omics metadata checklist and data publications and provide feedback for their use and improvement.

Dexamethasone Enhancement of Hyperoxic Lung Inflammation in Rats Independent of Adhesion Molecule Expression

Infants and adults on oxygen often are treated with glucocorticoids in an attempt to reduce lung inflammatory injury. However, glucocorticoids hasten the development of hyperoxic lung injury in some animal models. The purpose of this study was to test the hypothesis that dexamethasone alters the lung inflammatory responses to hyperoxia exposure. We studied male Sprague-Dawley rats, placing them in >95% oxygen immediately after administration of 0, 0.1, 1, or 10 mg/kg of dexamethasone. At 0, 24, or 48 hr of exposure to hyperoxia, extravascular lung water contents were measured, and lung inflammatory responses were assessed by lung myeloperoxidase activities, lung neutrophil counts, and lung expression of E-Selectin and intercellular adhesions molecule-1 (ICAM-1). Dexamethasone, independent of exposure to hyperoxia, led to marked increases in lung neutrophil counts, without increases in lung myeloperoxidase activities or increases in the expression of the adhesion molecules. Hyperoxia exposure also enhanced lung neutrophil accumulation, and extravascular lung water increased earlier in animals exposed to hyperoxia and dexamethasone than in those exposed to hyperoxia alone. In conclusion, the increase in lung neutrophils in dexamethasone-treated rats without enhanced expression of E-Selectin or intracellular adhesions molecule-1 suggests that dexamethasone leads to lung neutrophil accumulation by its effect on neutrophils. The more rapid development of hyperoxic lung injury associated with earlier lung neutrophil accumulation suggests that dexamethasone-induced lung neutrophil sequestration primes the lung for the development of hyperoxic lung injury and supports further the conclusion that lung inflammation contributes significantly to the development of hyperoxic lung injury.

Noninvasive Respiratory Support of Juvenile Rabbits by High-Amplitude Bubble Continuous Positive Airway Pressure

Bubble continuous positive airway pressure (B-CPAP) applies small-amplitude, high-frequency oscillations in airway pressure (ΔPaw) that may improve gas exchange in infants with respiratory disease. We developed a device, high-amplitude B-CPAP (HAB-CPAP), which provides greater ΔPaw than B-CPAP provides. We studied the effects of different operational parameters on ΔPaw and volumes of gas delivered to a mechanical infant lung model. In vivo studies tested the hypothesis that HAB-CPAP provides noninvasive respiratory support greater than that provided by B-CPAP. Lavaged juvenile rabbits were stabilized on ventilator nasal CPAP. The animals were then supported at the same mean airway pressure, bias flow, and fraction of inspired oxygen (FiO2) required for stabilization, whereas the bubbler angle was varied in a randomized crossover design at exit angles, relative to vertical, of 0 (HAB-CPAP0; equivalent to conventional B-CPAP), 90 (HAB-CPAP90), and 135° (HAB-CPAP135). Arterial blood gases and pressure-rate product (PRP) were measured after 15 min at each bubbler angle. Pao2 levels were higher (p < 0.007) with HAB-CPAP135 than with conventional B-CPAP. PaCO2 levels did not differ (p = 0.073) among the three bubbler configurations. PRP with HAB-CPAP135 were half of the PRP with HAB-CPAP0 or HAB-CPAP90 (p = 0.001). These results indicate that HAB-CPAP135 provides greater respiratory support than conventional B-CPAP does.

Effective Gas Exchange in Paralyzed Juvenile Rabbits Using Simple, Inexpensive Respiratory Support Devices

We have developed two devices: a high-amplitude bubble continuous positive airway pressure (HAB-CPAP) and an inexpensive bubble intermittent mandatory ventilator (B-IMV) to test the hypotheses that simple, inexpensive devices can provide gas exchange similar to that of bubble CPAP (B-CPAP) and conventional mechanical ventilation (CMV). Twelve paralyzed juvenile rabbits were intubated, stabilized on CMV, and then switched to CPAP. On identical mean airway pressures (MAPs), animals were unable to maintain pulse oximeter oxygen saturation (SpO2) >80% on conventional B-CPAP, but all animals oxygenated well (97.3 ± 2.1%) on HAB-CPAP. In fact, arterial partial pressures of O2 (Pao2) were higher during HAB-CPAP than during CMV (p = 0.01). After repeated lung lavages, arterial partial pressures of CO2 (Paco2) were lower with B-IMV than with CMV (p < 0.0001), despite identical ventilator settings. In lavaged animals, when HAB-CPAP was compared with CMV at the same MAP and 100% O2, no differences were observed in Pao2, but Paco2 levels were higher with HAB-CPAP (70 ± 7 versus 50 ± 5 mm Hg; p < 0.05). Arterial blood pressures were not impaired by HAB-CPAP or B-IMV. The results confirm that simple inexpensive devices can provide respiratory support in the face of severe lung disease and could extend the use of respiratory support for preterm infants into severely resource-limited settings.

Early Career Development in Academic Pediatrics of Participants in the APS-SPR Medical Student Research Program

To recruit and train the next generations of pediatric clinician-scientists, the American Pediatric Society and Society for Pediatric Research initiated a program in 1991 to support medical students with interests in research and pediatrics to conduct research at institutions other than their respective medical schools. Since 1991, the American Pediatric Society-Society for Pediatric Research Medical Student Research Program (MSRP) has funded 732 of 2209 applicants from 132 US or Canadian medical schools for 8–12 wk of research under the direction of experienced investigators. PubMed-attributable publications tabulated in 2001 for MSRP applicants through 2000 indicated that participants had published more actively than had nonparticipant applicants. Male nonparticipants exhibited greater publication activities than did female nonparticipants, but female and male participants published equally. Of all MSRP participants between 1991 and 1996, as of 2008, 36% were in pediatrics, and a remarkable 29% were in academic pediatrics.

OVEREXPRESSION OF HUMAN GLUTATHIONE REDUCTASE IN CHINESE HAMSTER OVARY CELLS PROTECTS CELLS FROM OXIDANT INJURY. ▴ 1474

OVEREXPRESSION OF HUMAN GLUTATHIONE REDUCTASE IN CHINESE HAMSTER OVARY CELLS PROTECTS CELLS FROM OXIDANT INJURY. ▴ 1474

Iron-catalyzed oxidation of Trp residues in low-density lipoprotein

Abstract The mechanisms of oxidation of low-density lipoproteins (LDLs) are not well defined, but epidemiological and experimental studies suggest that iron-catalyzed processes may contribute to atherogenesis. The aim of this study was to test the hypothesis that iron-catalyzed oxidations of LDLs in vitro produce diagnostic biomarkers of oxidation of the apolipoprotein that could be applied to studies in vivo. LDLs were oxidized in the presence of Fe2+, EDTA, and ascorbic acid for up to 40 h. Following delipidation and trypsin digestion, the peptides were separated by HPLC, with four peaks detected at 365 nm, whereas none were observed in peptides from unoxidized LDLs. The peptides were identified by MALDI-QTOF mass spectrometry as IVQILP(W+4) EQNEQVK, IYSL(W+4)EHSTK, FEGLQE(W+4)EGK, and YH(W+4)EHTGLTLR, with (W+4) rather than the W residues of the unoxidized protein. The mass gains (+4 increase in m/z in tryptophan, W) and absorbance at 365 nm indicate kynurenines, which were trypsin-releasable peptides that are on the surface of LDL particles. All four peptides thus characterized share the sequence of WE. The preferential oxidation of W residues in WE sequences suggest contributions from the C-proximate glutamate residues in chelation of the iron species, thereby influencing site selectivities of oxidation. These kynurenine-containing peptides might serve as biomarkers of iron-mediated oxidations in vivo.

Respiratory failure due to retained esophagus: A complication of esophageal replacement

Recurrent fistulas occur in about 10% of infants treated for esophageal atresia with distal tracheoesophageal fistula. Failed repair of a recurrent fistula rarely requires esophageal replacement and removal or diversion of the native esophagus. We present a patient who underwent multiple operations for recurrent tracheosophageal fistula whose native esophagus was eventually replaced with a colonic interposition graft. Over the subsequent 9 years he experienced failure to thrive, respiratory distress, and repeated pulmonary infections attributed to chronic aspiration. Eventually, he developed respiratory failure and required endotracheal intubation and mechanical ventilation. He became increasingly difficult to ventilate and, in spite of aggressive efforts, suffered a cardiac arrest from which he could not be resuscitated. At postmortem, a dilated blind segment of native esophagus, which was compressing and obstructing the malacic trachea, was found in the posterior mediastinum. Death was caused by massive air embolus, which was in turn attributed to the high airway pressures needed to ventilate the patient. Tracheal compression by a remnant of native esophagus should be considered in the differential diagnosis of respiratory failure after esophageal replacement.

Mice Expressing a Heme Oxygenase-1 (HO-1) Transgene Driven by a Surfactant Protein C (SPC) Promoter Are More Susceptible to Hyperoxic Lung Injury

Mice Expressing a Heme Oxygenase-1 (HO-1) Transgene Driven by a Surfactant Protein C (SPC) Promoter Are More Susceptible to Hyperoxic Lung Injury