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Biomedical subjects

Virender K Rehan

Publications and source records attributed to Virender K Rehan.

8 recordsLinked to original sources
PubMed2026

Inhaled vitamin A mitigates hyperoxia-induced acute and chronic lung damage in a neonatal rat model of bronchopulmonary dysplasia.

RATIONALE: Prevention of bronchopulmonary dysplasia (BPD) remains a critical unmet need. OBJECTIVES: We continued evaluating aerosolized vitamin A in a neonatal rat hyperoxia-injury model of BPD, testing whether lung-targeted inhalation yields superior outcomes compared to enteral or intramuscular (IM) delivery. METHODS: Rat pups were exposed to continuous 95% hyperoxia for seven days to induce lung damage. Vitamin A was administered from post-natal day (PD) 1-7 by inhalation, enteral or IM dosing. Persisting effectiveness of inhaled vitamin A was examined at PD 21, dwelling in normoxia after all interventions were discontinued at PD 7. MEASUREMENTS AND MAIN RESULTS: Comprehensive analyses include alveolar morphometrics, in vivo pulmonary function testing, assessment of hepatic vitamin A level, and quantitating gene and protein expression of relevant biomarkers of lung maturation, inflammation and damage/repair, employing singlex and multiplexed assays and whole-genome gene expression. CONCLUSIONS: Inhaled vitamin A suppressed hyperoxia-induced lung damage, with key hallmarks of BPD, including lung morphometrics and biomarkers associated with lung damage and inflammation, being effectively indistinguishable from healthy controls at both PD 7 and 21, Natural reparative processes were enhanced, with normal alveolarization and pulmonary function at PD 21. Despite raising hepatic vitamin A levels, enteral dosing was ineffective in restoring alveolar morphology at PD 7. Consistent with previous reporting, IM dosing yielded modest effect at PD 7 but with little evidence of benefit to pulmonary function at PD 21. Observation of dose-dependent effects with aerosolized vitamin A strengthens the evidence of the benefits of lung-targeted delivery, supporting further development of inhaled vitamin A as a BPD preventive strategy.

Journal Article↗
PubMed2005

Mechanism of nicotine-induced pulmonary fibroblast transdifferentiation.

We tested the hypothesis that in vitro nicotine exposure disrupts specific epithelial-mesenchymal paracrine signaling pathways and results in pulmonary interstitial lipofibroblast (LIF)-to-myofibroblast (MYF) transdifferentiation, resulting in altered pulmonary development and function. Studies were done to determine whether nicotine induces LIF-to-MYF transdifferentiation and to elucidate underlying molecular mechanism(s) involved and to determine whether nicotine-induced LIF-to-MYF transdifferentiation could be prevented by stimulating specific alveolar interstitial fibroblast lipogenic pathway. WI38 cells, a human embryonic pulmonary fibroblast cell line, were treated with nicotine with or without specific agonists of alveolar fibroblast lipogenic pathway, PTHrP, DBcAMP, or the potent PPARgamma stimulant rosiglitazone (RGZ) for 7 days. Expression of key lipogenic and myogenic markers was examined by RT-PCR, Western hybridization, and immunohistochemistry. The effect of nicotine on triglyceride uptake by WI38 cells and PTHrP binding to its receptor was also determined. Finally, the effect of transfecting WI38 cells with a PPARgamma expression vector on nicotine-induced LIF-to-MYF transdifferentiation was determined. Nicotine treatment resulted in significantly decreased expression of lipogenic and increased expression of myogenic markers in a dose-dependent manner, indicating nicotine-induced LIF-to-MYF transdifferentiation. This was accompanied by decreased PTHrP receptor binding to its receptor. The nicotine-induced LIF-to-MYF transdifferentiation was completely prevented by concomitant treatment with PTHrP, DBcAMP, RGZ, and by transiently overexpressing PPARgamma. Our data suggest nicotine induces alveolar LIF-to-MYF transdifferentiation through a mechanism involving downregulation of lipogenic PTHrP-mediated, cAMP-dependent PKA signaling pathway, which can be prevented using specific molecular targets. Potential therapeutic implications of these observations against in utero nicotine-induced lung injury remain to be tested.

Biomarkers↗
PubMed2004

Epinephrine delivery during neonatal resuscitation: comparison of direct endotracheal tube vs catheter inserted into endotracheal tube administration.

OBJECTIVES: The optimal method for epinephrine administration during neonatal resuscitation is not known. We hypothesized that epinephrine will be delivered more efficiently when administered via a feeding catheter inserted into the endotracheal tube (C-ETT) vs when administered directly into the ETT (D-ETT). Our objectives were to (1) compare the delivery of epinephrine to the distal end of the ETT when administered via D-ETT vs C-ETT; (2) measure the retention of epinephrine within the ETT vs the feeding catheter used for the drug delivery; and (3) compare the delivery of the drug with and without an air flush after administration via C-ETT. METHODS: All experiments were performed in vitro, simulating epinephrine administration during neonatal resuscitation, according to the standard guidelines. Radiolabeled epinephrine, diluted to 1 microCi/ml, was used and experiments were repeated at least 4 times. Epinephrine administration via D-ETT was followed by one manual breath via a self-inflating bag attached to the ETT. Epinephrine delivery via C-ETT was followed by 1 ml saline flush, and in some experiments, this was also followed by a 1 cm(3) air flush. Epinephrine delivery and retention were assessed by measuring the radioactive content of the effluent fluid and that of the ETT or of the feeding catheter used for drug delivery. RESULTS: Significantly higher dosage of the drug was delivered when administered via D-ETT vs C-ETT, if air flush following C-ETT method was not used. However, with an air flush following the saline flush after the drug instillation, there was no difference in the amount of epinephrine delivered between the two methods. Retention in the ETT wall or the catheter was <7.5% of the administered dose with either method. CONCLUSIONS: Without an air flush following C-ETT method of epinephrine delivery, higher dosage of the drug is delivered via D-ETT vs C-ETT method. An air flush following the saline flush during C-ETT method improves drug delivery. Given that the C-ETT method is more cumbersome and time consuming, and does not improve drug delivery, D-ETT administration should be the method of choice for epinephrine delivery during neonatal resuscitation.

Catheterization↗
PubMed2004

Deconvoluting lung evolution using functional/comparative genomics.

Parathyroid Hormone-related Protein (PTHrP) is a highly evolutionarily conserved, stretch-regulated gene that is necessary for the embryonic transition from branching morphogenesis to alveolization of the lung. It is expressed throughout vertebrate phylogeny, beginning with its expression in the fish swim bladder as an adaptation to gravity; microgravity downregulates the expression of PTHrP by alveolar type II cells, and by bones from rats exposed to 0 x g, suggesting that PTHrP signaling has been exploited for adaptation to 1 x g. PTHrP/PTHrP receptor signaling is upregulated by stretching alveolar type II cells and intersitial lung fibroblasts, whereas overdistension downregulates PTHrP and PTHrP receptor mRNA, further suggesting an evolutionary adaptation. Both surfactant homeostasis and alveolar capillary perfusion are under PTHrP control, indicating that alveolization and ventilation/perfusion matching may have evolved under the influence of PTHrP signaling. Phylogenetic analysis of lung evolution reflects the concomitant increases in alveolar surface area and surfactant production by "amplifying" the PTHrP pathway signal. This mechanism is discussed as a function of increased evolutionary respiratory demand to keep up with the increased metabolic demand for oxygen, and the role of the PTHrP signaling mechanism in leveraging this process.

Animals↗
PubMed2002

1Alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25-dihydroxy vitamin D3: production and biological activity studies in pulmonary alveolar type II cells.

Pulmonary alveolar type II cells have been shown to be a possible target for the secosteroid hormone, 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], during perinatal transition. At present, there is great interest to isolate and identify the metabolites of 1alpha,25(OH)2D3 produced in its target tissues and to determine the contribution of each individual metabolite of 1alpha,25(OH)2D3 to the final expression of the pleiotropic actions attributed to 1alpha,25(OH)2D3. Of all the known metabolites of 1alpha,25(OH)2D3, 1alpha,25(OH)2-3-epi-D3 has gained most attention as it is produced only in specific tissues and possesses significant activity in tissues in which it is produced. Furthermore, in vivo studies indicate that this metabolite when compared to 1alpha,25(OH)2D3 is less calcemic. Therefore, we performed the present study to identify production of 1alpha,25(OH)2-3-epi-D3 in alveolar type II cells, and to evaluate its effect on surfactant synthesis. We incubated NCI-H441 cells, an alveolar type II cell line, with 1alpha,25(OH)2D3 and demonstrated that these cells metabolize 1alpha,25(OH)2D3 to various previously well-characterized polar metabolites, and to a less polar metabolite which was unequivocally identified as 1alpha,25(OH)2-3-epi-D3 by GC/MS and HPLC analysis. Further, biological activity studies in H441 cells indicated that 1alpha,25(OH)2-3-epi-D3 possesses significant activity in terms of its ability: (i) to increase surfactant phospholipid synthesis, (ii) to induce surfactant SP-B mRNA gene expression, and (iii) to increase surfactant SP-B protein synthesis. However, the activity of 1alpha,25(OH)2-3-epi-D3 when compared to 1alpha,25(OH)2D3 in generating VDR-mediated transcriptional activity in ROS 17/2.8 cells transfected with human osteocalcin VDRE/growth hormone gene construct, was significantly reduced. The high metabolic stability of 1alpha,25(OH)2-3-epi-D3, as previously proposed by us, may be a possible explanation for the high in vitro activity in spite of the reduced VDR-mediated transcriptional activity. In summary, we report for the first time the pathways of 1alpha,25(OH)2D3 metabolism in pulmonary alveolar type II cells and indicate that 1alpha,25(OH)2-3-epi-D3, a natural intermediary metabolite of 1alpha,25(OH)2D3 possesses significant activity in stimulating surfactant synthesis in alveolar type II cells.

Calcitriol↗
PubMed2002

Oxygen-induced metabolic changes and transdifferentiation in immature fetal rat lung lipofibroblasts.

Preterm infants lack adequate surfactant production and often require oxygen support for adequate oxygenation. Prolonged oxygen treatment leads to the development of bronchopulmonary dysplasia (BPD), a disease process characterized by the blunting of alveolarization and proliferation of myofibroblasts. In the present study, we investigated metabolic adaptive changes in cultured fibroblasts isolated from immature (d18) and near-term (d21), fetal rat lungs in response to normoxic (21%) and hyperoxic (95%) exposures. We used the [1,2-13C2]D-glucose tracer and gas chromatography/mass spectrometry to characterize glucose carbon redistribution between the nucleic acid ribose, lactate, and palmitate synthetic pathways, and reverse transcriptase-polymerase chain reaction to assess adipose differentiation related protein (ADRP) mRNA expression in response to hyperoxic exposure. Exposure to hyperoxia at each passage caused decrease (*, p<0.05 vs. 21% O2) in ADRP mRNA expression in the d18 fibroblasts. This passage-dependent transdifferentiation is accompanied by a moderate (9-20%) increase in the synthesis of nucleic acid ribose from glucose through the non-oxidative steps of the pentose cycle. In contrast, d18 fibroblasts showed over an 85% decrease in the de novo synthesis of palmitate from glucose, while d21 fibroblasts showed a less pronounced 32-38% decrease in de novo lipid synthesis in hyperoxia-exposed cultures. It can be concluded from these studies that: (1) there is a maturation dependent sensitivity to hyperoxia; (2) transdifferentiation of flbroblast as demonstrated by changes in ADRP expression is accompanied by metabolic enzymes changes affecting ribose acid synthesis from glucose, and (3) hyperoxia specifically inhibits lipogenesis from glucose. Hyperoxia-induced metabolic changes thus play a key role in the transdifferentiation of lung fibroblasts to myofibroblasts and the pathogenesis of BPD.

Animals↗
PubMed2002

Outcome of very-low-birth-weight (< 1,500 grams) infants born to mothers with diabetes.

Premature delivery is common in pregnancies complicated by maternal diabetes. However, the outcome of very-low-birth-weight infants (VLBWI) born to mothers with diabetes is not known. Employing a matched double-cohort design, we investigated the influence of maternal diabetes on the outcome of VLBWI born in Winnipeg from 1988 to 1994. We compared mortality rates and early and late morbidity rates in VLBWI born to mothers with diabetes mellitus (DM) (cases, n = 43, 23 with gestational DM and 20 with pregestational DM) and without DM (controls, n = 539). Controls were matched for gestational age (GA), sex, and the year of birth. All subjects were enrolled in the Newborn Follow-Up Program. Relative risks and 95% confidence limits were calculated for each variable and Chi 2 analysis, Student t-test, and Mann-Whitney test were used as appropriate for analysis. Diabetes mellitus control was assessed by conventional criteria. There were no differences between cases and controls in mode of delivery, birth weight (mean +/- SD, 1,160 +/- 25 g vs 1,110 +/- 26 g), GA (29 +/- 2.8 wk vs 29 +/- 2.4 wk), smallness for gestational age (35% vs 30%), head circumference (26.5 +/- 1.9 vs 26.2 +/- 2.2 cm), length (38.8 +/- 2.8 vs 37.5 +/- 3.7 cm), Apgar score < 4 at 1 min (42% vs 40%) and < 7 at 5 min (37% vs 42%). Incidence of hyaline membrane disease (60% vs 71%), bronchopulmonary dysplasia (33% vs 31%), patent ductus arteriosus (30% vs 43%), necrotizing enterocolitis (12% vs 12%), sepsis (23% vs 25%), acute renal failure (9% vs 10%), intraventricular hemorrhage--all grades (74% vs 64%), retinopathy of prematurity--all stages (30% vs 26%), median days on ventilator (4 vs 4 days), and median days on supplemental oxygen (46 vs 42 days) were similar in both groups (p = NS, 95% confidence limits included 1 for all of these variables). There was no significant difference in mortality (21% vs 15%) or the incidence of major congenital anomalies. Weight, head circumference, and length at 6, 12, and 18 months were similar in both groups. There were no group differences in developmental quotients, prevalence of neurodevelopmental impairments, respiratory morbidity, or number of hospitalizations up to the last follow-up (18 months). Our data suggest that with contemporary perinatal care there is no significant increase in mortality rates or early and late morbidity rates between VLBWI born to mothers with DM and VLBWI of nondiabetic mothers. It seems that with reasonable diabetic control, prematurity rather than the diabetic state determines the neonatal outcome, and this knowledge can be useful in parental counselling.

Adult↗