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A novel approach to prevent in utero nicotine lung injury

Institution: LA Biomedical Research Institute at Harbor-UCLA Medical Center
Investigator(s): Virender Rehan, M.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14RT-0073H Award: $597,916
Subject Area: General Biomedical Science
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Smoking during pregnancy not only poses significant immediate risks for the unborn fetus but also may have life long implications. It has broad adverse effects on fetal outcome, including increased risk of spontaneous abortion, stillbirth, low birth weight, early neonatal mortality, sudden infant death syndrome, and poor long-term pulmonary outcome. Although not widely appreciated, there is strong evidence for the deleterious effects on both prenatal and postnatal lung development following exposure to maternal smoke during pregnancy. The mechanisms underlying the general effects of exposure to maternal smoking on fetal growth and viability are generally thought to be due to impaired oxygen supply to the fetus, however, the mechanisms underlying the harmful effects of smoking on lung are more much more complex and incompletely understood. We are very much interested in unraveling the mechanisms of the chronic lung diseases in general, and due to nicotine, in particular. Understanding how this disease process is caused is the key to its effective prevention and treatment.

Our initial studies point towards a new and more fundamental mechanism in the understanding of the lung damage due to a variety of insults including nicotine. These studies suggest that infant’s lung has crucial fat containing cells that under the influence of factors such as nicotine transform into a muscle like cell, which is the hallmark of the damaged lung. Once this change occurs, a normal functioning cell, which is essential for good lung function, is converted into a cell that has the potential to result in serious lung damage, problems with the oxygenation, and it makes infants more prone to asthma. Using both cell culture systems and whole animal models, we have very strong evidence for the fundamental molecular mechanism that leads to chronic lung diseases. Based on this evidence, now we are proposing a novel approach to prevent nicotine-associated lung damage that is acquired from prenatal nicotine exposure. In addition to providing new insights into nicotine-induced lung injury and how to treat it, our proposal will open new avenues of investigation into the nature of normal and abnormal lung development in general. This has an enormous potential of opening up novel interventional strategies to tackle a wide spectrum of chronic lung diseases.
Publications

Evidence for the presence and functional role of Iipofibroblasts in human lung
Periodical: Experimental Lung Research Index Medicus:
Authors: Rehan ART
Yr: 0 Vol: Nbr: Abs: Pg:

In Utero Nicotine Exposure alters fetal rat lung alveolar Type II cell proliferation Differentiation and metabolism
Periodical: American Journal of Physiology Index Medicus:
Authors: Rehan ART
Yr: 0 Vol: Nbr: Abs: Pg:

lipo-to myofibroblast transdifferentiation by agonists of parathyroid Homone related Protein signaling pathway
Periodical: Review Nature medicine Index Medicus:
Authors: Virender Rehan ART
Yr: 0 Vol: Nbr: Abs: Pg:

Evidence for the presence and functional role of lipofibroblasts in human lung
Periodical: Experimental Lung Research Index Medicus:
Authors: Rehan V, Sugano S, Wang Y, Santos J, Romero S, Keane M, Dasgupta C, Stahlman M ART
Yr: 0 Vol: Nbr: Abs: Pg:

Reversal of nicotine-induced lipo-to-myofibroblast transdifferentiation by agonists parathyroid hormone protein signaling pathway
Periodical: Nature Medicine Index Medicus:
Authors: Sakurai R, Wang Y, Rehan V ART
Yr: 0 Vol: Nbr: Abs: Pg:

Reversal of alveolar interstitial fibroblast to myofibroblast transdifferentiation by stimulants of PTHrp-medicated cAMP- dependent PKA signaling pathway
Periodical: Journal of Investigative Medicine Index Medicus:
Authors: Sakurai R, Wang Y, Santos J, Huynh K ABS
Yr: 2006 Vol: Nbr: 54 Abs: S189 Pg: 1

A paracrine model for lung development, disease, an treatment-perspective.
Periodical: Pediatric Research Index Medicus:
Authors: Torday, JS; Rehan, VK ART
Yr: 2007 Vol: Nbr: Abs: Pg:

The mechanism fo rthe paradoxical decrease in respiratory distress syndromem and increase in bronchopulmonary dysplasia associated with choriomnionitis.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Rehan,; Dargan--Batra,; Wang,; cerny; Sakurai,; Santos; Beloosesky; Gayle; Torday ART
Yr: 2007 Vol: Nbr: Abs: Pg:

Prevention of bronchopulmonary dysplasia: Finally, something that works.
Periodical: Journal of Pediatrics Index Medicus:
Authors: Rehan, VK ART
Yr: 2006 Vol: 73 Nbr: 11 Abs: Pg: 1027-1032

Exploiting the PTHrP signaling pathway to treat chronic lung disease.
Periodical: Drugs of Today Index Medicus:
Authors: Rehan, VK; Torday, JS ART
Yr: 2007 Vol: 43 Nbr: 5 Abs: Pg: 317-331

Prevention and treatment of bronchopulmonary dysplasia: Contemporary status and future outlook.
Periodical: Lung Index Medicus:
Authors: Cerny, L; Torday, JS; Rehan, VK ART
Yr: 2008 Vol: 186 Nbr: 2 Abs: Pg: 75-89

Hyperoxia-induced neonatal lung inujury involves activation of TGF-B and Wnt signaling: Protection by rosiglitazone.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Dasgupta, C; Wang. Y; sakurai, R; Torday, JS; Rehan, VK ART
Yr: 2009 Vol: 296 Nbr: 6 Abs: Pg: L1031-1041

Peroxisome proliferator-activted receptor (PPAR) y Agonist enhance lung maturation in a neonatao rat model.
Periodical: Pediatric Research Index Medicus:
Authors: Wang, Y; Sakurai, R; Cerny, L; Torday, JS; Rehan, VK ART
Yr: 2009 Vol: 65 Nbr: 2 Abs: Pg: 150-155

Mechanism os nicotine-induced up-regulation of wingless/int Wnt) signaling in human alveolar interstitial fibroblasts.
Periodical: Experimental Lung Research Index Medicus:
Authors: Sakurai, R; Wang, Y; Cerny, LM, Guo, P; Torday, JS, Rehan, VK ART
Yr: 2009 Vol: Nbr: Abs: Pg: Under review

Intrauterine growth restriction altars fetal lung programming by affecting essential epithelial-mesenchymal signaling paathways.
Periodical: Pediatric Pulmonology Index Medicus:
Authors: Karadag, A; Sakurai, R; Wang, Y; Desai, M; Ross, MG; Torday, JS; Rehan,VK ART
Yr: 2009 Vol: 44 Nbr: 7 Abs: Pg: 635-644

1a,25(OH)2D3, and its 3 epimer promote pulmonary alveolar epithelia-mesnchymal interactions and inhibit interstitial fibroblast apoptosis.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Reiko, R; Shin, E; Fonseca, S; Scott, W; torday, J; Rehan, VK ART
Yr: 2009 Vol: Nbr: Abs: Pg: