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Protective function of VEGF on the development of emphysema

Institution: University of California, San Diego
Investigator(s): Kechun Tang, M.D., Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12RT-0062 Award: $420,000
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
SPECIFIC AIMS: Emphysema is the major component of the morbidity and mortality in chronic obstructive pulmonary disease (COPD) that occurs predominately in cigarette smoker. Millions of patients suffer from emphysema in America. Even though protease-antiprotease hypothesis, which suggest that inflammation causes an imbalance or increase in level of proteases leading to lung damage, is widely supported, It can not explain why many patients with lung inflammation do not develop to emphysema. Vascular endothelium growth factor (VEGF) appears to be the most biologically active angiogenic factor and is critical for growth and development of endothelium, epithelium and their matrix. Even though VEGF is very abundant in the lungs, its role to maintain the lung structures has not yet been fully established. In this project, we propose VEGF is crucial to the remodeling function of lungs and can effectively prevent and reverse the development of emphysema.

RESEARCH DESIGN AND METHODS: In our preliminary experiments, we have established the method of injection of recombinant adeno-associate virus (AAV) into the lungs from trachea. After AAV-Cre injection, VEGF site-specific knockout in the lungs occurs in VEGF-LoxP transgenic mice. In these VEGF knockout lungs, We found that the VEGF content decrease, alveolar size increase, and the slop of P/V curve increase with the compliance decrease. The specific aims of this project are: (1) VEGF is crucial in maintaining the normal structural architecture of the lungs. Furthermore, decreasing the normal level of lung VEGF, via site-specific lung inactivation of the VEGF gene leads to changes in lung structure and function that resemble an emphysematous type lung; (2) Lung specific VEGF over-expression has the potential to reverse that changes in lung structure, function and extracellular matrix and cellular composition observed in VEGF knockout lungs; (3) Cigarette smoking decreases VEGF expression and leads to an emphysematous phenotype in mice; and (4) Overexpression of VEGF in the lungs prevents or reverses the development of emphysema caused cigarette smoking in mice.

END POINTS: The above studies will address issues fundamental to the understanding of the mechanisms of VEGF to maintain the normal structure and remodeling function of lungs and the effects of VEGF to delay the development of emphysema caused by cigarette smoking. . The unique technique of using AAV to delivery VEGF or Cre gene into the lungs provides a wonderful way for VEGF over-expression or inducing VEGF gene knockout in the lungs. The results of this research may provide the hypothesis that the remodeling of lungs is another important factor for emphysema development, and the evaluation for VEGF as a practical medicine to prevent or even reversible treat the development of emphysema.
Publications

Extracellular matrix remodeling following lung targeted VEGF inactivation in VEGFloxP mice.
Periodical: ATS/Respiratory and Critial Care Medicine Index Medicus:
Authors: Breen E, Wagner P, Tang K ABS
Yr: 2004 Vol: Nbr: Abs: Pg:

Three-Dimensional Magnetic Imaging of Mouse lungs.
Periodical: Proceedings of American Thoracic Society Index Medicus:
Authors: Rossiter HB, Scadeng M, And Breen EG ABS
Yr: 2005 Vol: A Nbr: 2 Abs: Pg: 334

Lung-targeted VEGF inactivation leads to altered surfactant metabolism
Periodical: Proceedings of American Thoracic Society Index Medicus:
Authors: Malloy JL, Tang K Breen EC ABS
Yr: 2006 Vol: A Nbr: 3 Abs: Pg: 191

Proteasedependent remodelling in VEGF deficient mouse lungs
Periodical: Proceedings of American Thoracic Society Index Medicus:
Authors: Rossiter HB, Scadeng M, Tang K, and Breen EC ABS
Yr: 2006 Vol: A Nbr: 3 Abs: Pg: 411