Atopic asthma is a chronic inflammatory disorder in which Th2 inflammation plays an important role. Asthma is also a growing health problem whose prevalence has doubled in the last 20 years. The development of asthma is influenced and/or dictated by intrauterine as well as environmental factors that express themselves in early life. However, the environmental factors that are responsible for the increase in asthma prevalence are poorly understood. Recent studies have noted inverse relationships between Tb skin tests and asthma, a lower prevalence of asthma in polluted East as versus clean West Germany and a lower prevalence of asthma in populations with specific early life infections. These studies have led to the following hypothesis. Hypothesis: (1) There are crucial periods of time in utero and/or in early life during which Th1/Th2 polarization alters later life airway responses to asthma-relevant stimuli. (2) During these crucial periods, early life Th1 polarization prevents or diminishes the intensity of later life Th2 responses. We propose to test this hypothesis using a novel, lung-specific, externally regulatable overexpression transgenic system developed in our laboratory which allows genes to be activated in utero, in neonatal or in adult animals. We will: (1) Generate and characterize overexpression transgenic mice in which the airway cytokine milieu can be modified to generate/augment local Th1 responses at different points in time during development. Mice that overexpress IFN-gamma, IL-12 and/or IL-18 will be generated and evaluated. (2) Generate and characterize overexpression transgenic mice in which the airway cytokine milieu can be modified to generate/augment Th2 responses at different points in time during development. Mice that overexpress IL-4 will be generated and evaluated. (3) Characterize the effects of Th1 or Th2 polarization on host response to aeroallergen.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061904-02
Application #
6056582
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Project Start
1998-09-30
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Bhandari, Vineet; Choo-Wing, Rayman; Harijith, Anantha et al. (2012) Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. Am J Respir Cell Mol Biol 46:668-76
Bhandari, Vineet; Choo-Wing, Rayman; Lee, Chun G et al. (2008) Developmental regulation of NO-mediated VEGF-induced effects in the lung. Am J Respir Cell Mol Biol 39:420-30
Bhandari, Vineet; Elias, Jack A (2007) The role of angiopoietin 2 in hyperoxia-induced acute lung injury. Cell Cycle 6:1049-52
Choo-Wing, Rayman; Nedrelow, Jonathan H; Homer, Robert J et al. (2007) Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol 293:L142-50
Bhandari, Vineet; Elias, Jack A (2006) Cytokines in tolerance to hyperoxia-induced injury in the developing and adult lung. Free Radic Biol Med 41:4-18
Bhandari, Vineet; Choo-Wing, Rayman; Lee, Chun G et al. (2006) Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med 12:1286-93
Bhandari, Vineet; Choo-Wing, Rayman; Chapoval, Svetlana P et al. (2006) Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci U S A 103:11021-6
Baluk, Peter; Lee, Chun Geun; Link, Holger et al. (2004) Regulated angiogenesis and vascular regression in mice overexpressing vascular endothelial growth factor in airways. Am J Pathol 165:1071-85
Vicencio, Alfin G; Lee, Chun Geun; Cho, Soo Jung et al. (2004) Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia? Am J Respir Cell Mol Biol 31:650-6
Lee, Chun Geun; Link, Holger; Baluk, Peter et al. (2004) Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 10:1095-103

Showing the most recent 10 out of 28 publications