Nicotine Disrupts PTHrP-Driven Paracrine Signaling Globally

Institution:	LA Biomedical Research Institute at Harbor-UCLA Medical Center
Investigator(s):	Virender Rehan,
Award Cycle:	2006 (Cycle 15)	Grant #: 15IT-0250	Award: $133,126
Subject Area:	General Biomedical Science
Award Type:	Inno Dev & Exp Awards (IDEAS)

Abstracts

Initial Award Abstract

Cigarette smoking is the single major cause of chronic fibrosis affecting lungs, heart, kidney, and gums in the United States. Chronic fibrosis is associated with long-term ill health and it contributes to hundreds of thousands of premature deaths each year. Further, although the prevalence of smoking during pregnancy is decreasing, an unacceptably large percentage of women still smoke while pregnant. The mechanism(s) underlying predisposition to fibrosis in different organs in response to smoke/nicotine exposure either before or after birth is (are) poorly understood. However, there is now strong evidence to support that a break-down in cell-cell cross talk, i.e., how cells talk to each other molecularly, in different organs may be playing a crucial role in fibrosis in various organs. We have identified a specific protein that is essential in maintaining this cell-cell communication in the lung under normal conditions of good health. If, however, the levels of this protein go down, it sets the stage for lung fibrosis. Indeed we have seen that nicotine exposure does decrease the levels of this protein in the lung significantly. Further, maintaining normal levels of this protein in the lung during exposure to conditions that would otherwise cause lung fibrosis, e.g., exposure to nicotine, a normal lung health was maintained, and fibrosis could be prevented. This is a huge step in designing treatment strategies against lung fibrosis. However, we feel that the mechanism, which helps in maintaining normal lung health, is not restricted only to the lung, but is likely to a fundamental mechanism in many other organs systems as well. Therefore, now we propose to look at whether nicotine exposure also adversely affects the levels of the relevant protein essential for cell-cell communication in other organs, such as the kidney, liver, brain, and long bones, as well. Incidentally, all of these organs are already known to express this protein, but how exposure to nicotine affects the levels of this protein it is not known. The proposed studies are likely to provide us a novel understanding that for the first time might open up the possibility of preventing nicotine-induced organ damage in almost all organ systems simultaneously. In fact, we will look at not only the prevention but also the possibility of reversibility of nicotine-induced injury in various organs. Our hypothesis and proposed studies will unravel the molecular mechanisms of fibrosis in general, enabling us to better understand, prevent, treat, or even reverse this process through more rationale and focussed interventions. In line with Tobacco-Related Disease Research Program goals, this has an enormous potential of opening up novel interventional strategies to tackle not only the nicotine-induced fibrosis, but also all chronic diseases characterized by fibrosis in general.

Publications

In Utero Nicotine Exposure Alters Fetal Rat Lung Alveolar Type II Cell Proliferation Differentiation and Metabolism
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology.			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol:	Nbr: 292	Abs:	Pg: 323-33

Reversal of nicotine-induced lipo-to-myofibroblast transdifferentiation by agonists Parathyroid Hormone-related Protein signaling pathway.
Periodical: Lung			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol:	Nbr:	Abs:	Pg:

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

The mechanism foe the paradoxical decrease in respiratory distress syndrome and increase in bronchopulmonary dysplasia associated with chorioamnionitis.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology.			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol:	Nbr:	Abs:	Pg:

Prevention of Bronchopulmonary dysplasia: Finally, something that works
Periodical: Indian J Pediatr.			Index Medicus:
Authors: Rehan Vk				ART
Yr: 2066	Vol:	Nbr: 73	Abs:	Pg: 1027-32

Exploiting the PTHrP Signaling Pathway to Treat Chronic Lung Disease.
Periodical: Drugs of Today			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol: 5	Nbr: 43	Abs:	Pg: 317-331

Physiologic vitamin D hormone 1a,25(OH)2D3 has spatial and temporal-specific actions during perinatal pulmonary matutation.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Fonseca, S; Sakurai, R; Shin, E; Torday, JS; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A19, A112

Mechanism of reduced lung injury by high frequency nasal ventilation in a pretern lam model of bronchopulmonary dysplasia.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Fong, J; Lee, R Sakurai, R; Lane, R; Albertine, K; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A10

Antenatal administration of peroxisome proliferator-actived recptor PPAR)y agonist reosiglitazone (RHZ) prevents hyperoxia-induced lung injury postnatally.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Sakurai, R; Shin, E; Corral J, Torday,J Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A428

Protection of hyperoxia-induced neonatal lung injury by parenterally administered bone marrow-derived mesenchymal stem cells.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Guo, P; Cruz, E; Chap, K; Mittal ,S; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A430

Prevnetion of in utero nicotine-induced bone marrow mesenchymal stem cell (BMMSC) myofibroblast differentiation by augmenting lipofibroblast phenotype.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Guo, P; Cruz, E; Chap, K; Mittal ,S; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A434

A novel mechanism for bleomycin-induced pulmonary fibrosis: Selective apoptosis of bone marrow mesenchymal stem cell-devired llipobroblasts.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Cruz, E; Chap, K Guo, P; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A435

In Utero Nicotine Exposure Alters Fetal Rat Lung Alveolar Type II Cell Proliferation Differentiation and Metabolism
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology.			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol:	Nbr: 292	Abs:	Pg: 323-33

Reversal of nicotine-induced lipo-to-myofibroblast transdifferentiation by agonists Parathyroid Hormone-related Protein signaling pathway.
Periodical: Lung			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol:	Nbr:	Abs:	Pg:

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

The mechanism foe the paradoxical decrease in respiratory distress syndrome and increase in bronchopulmonary dysplasia associated with chorioamnionitis.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology.			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol:	Nbr:	Abs:	Pg:

Prevention of Bronchopulmonary dysplasia: Finally, something that works
Periodical: Indian J Pediatr.			Index Medicus:
Authors: Rehan Vk				ART
Yr: 2066	Vol:	Nbr: 73	Abs:	Pg: 1027-32

Exploiting the PTHrP Signaling Pathway to Treat Chronic Lung Disease.
Periodical: Drugs of Today			Index Medicus:
Authors: Rehan VK				ART
Yr: 2007	Vol: 5	Nbr: 43	Abs:	Pg: 317-331

Physiologic vitamin D hormone 1a,25(OH)2D3 has spatial and temporal-specific actions during perinatal pulmonary matutation.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Fonseca, S; Sakurai, R; Shin, E; Torday, JS; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A19, A112

Mechanism of reduced lung injury by high frequency nasal ventilation in a pretern lam model of bronchopulmonary dysplasia.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Fong, J; Lee, R Sakurai, R; Lane, R; Albertine, K; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A10

Antenatal administration of peroxisome proliferator-actived recptor PPAR)y agonist reosiglitazone (RHZ) prevents hyperoxia-induced lung injury postnatally.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Sakurai, R; Shin, E; Corral J, Torday,J Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A428

Protection of hyperoxia-induced neonatal lung injury by parenterally administered bone marrow-derived mesenchymal stem cells.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Guo, P; Cruz, E; Chap, K; Mittal ,S; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A430

Prevnetion of in utero nicotine-induced bone marrow mesenchymal stem cell (BMMSC) myofibroblast differentiation by augmenting lipofibroblast phenotype.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Guo, P; Cruz, E; Chap, K; Mittal ,S; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A434

A novel mechanism for bleomycin-induced pulmonary fibrosis: Selective apoptosis of bone marrow mesenchymal stem cell-devired llipobroblasts.
Periodical: Journal of Investigative Medicine			Index Medicus:
Authors: Cruz, E; Chap, K Guo, P; Torday, J; Rehan, VK				ABS
Yr: 2009	Vol: 57	Nbr: 01	Abs:	Pg: A435