This proposal describes a 5 year training program for the development of an academic career in pulmonary medicine. Cigarette smoke-induced emphysema (EM) is a chronic process which demonstrates features of persistent inflammation, loss of elasticity and compliance, and subsequent collapse of small airways leading to permanent airflow limitations. This pathogenic process seems highly dependent on individual inherent and acquired compositions as only 25% of cigarette smokers develop EM. In this proposal, we hypothesize that the dysfunctional biosynthesis of leukotriene B4 (LTB4) and subsequent abnormal trafficking of leukocyte subpopulations and insufficient tissue healing are pivotal events that promote cigarette smoke-induced pulmonary EM. Mechanisms of the findings from our recently published studies suggest that 1) LTB4 is an important downstream leukotriene metabolite protective against EM, 2) LTB4 deficiency creates a dysfunctional tissue healing environment by suppressing necessary fibrotic healing and induction/activation of TGF-b1. Understading the interactions between LTB4 and these tissue reponses in the pathogenesis of emphysema will lead to novel therapies in the treatment and prevention of EM. In this proposal, we will test this hypothesis by performing the following experiments: (l)(a) determine time-course, magnitude, and cellular responses in the IL-13-induced murine pulmonary emphysema with and without LTB4 deficiency, (l)(b) investigate the effects of LTB4 deficiency in the IL-13-induced trafficking of leukocyte subpopulations, fibrosis, and TGF-b1 responses;(ll)(a) determine time-course, magnitude, and cellular responses in the NON-IL-13-induced murine pulmonary emphysema with and without LTB4 deficiency, (ll)(b) investigate the effects of LTB4 deficiency in the NON-IL-13-induced trafficking of leukocyte subpopulation, fibrosis, and TGF-b1 responses;(lll)(a) investigate the patterns of LTB4 biosynthesis by comparing human subjects who developed emphysema from cigarette smoking and those who did not, (lll)(b) investigate patterns of the LTB4 biosynthetic enzymes and receptors at the levels of transcription and translation in the same subjects. By successfully completing these objectives, we will have gained significant insights into the biology of LTB4 that impacts on the development of cigarette smoke induced pulmonary emphsyema, and we hope that the understanding of this pathobiology will lead to novel thrapies in the treatment and prevention of emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL091127-05
Application #
8296624
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Tigno, Xenia
Project Start
2008-07-08
Project End
2014-02-28
Budget Start
2012-07-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$128,697
Indirect Cost
$9,422
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Paige, Mikell; Wang, Kan; Burdick, Marie et al. (2014) Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema. J Immunol 192:5059-68
Shim, Yun M; Burnette, Autumn; Lucas, Sean et al. (2013) Physical deconditioning as a cause of breathlessness among obese adolescents with a diagnosis of asthma. PLoS One 8:e61022
Paige, Mikell; Burdick, Marie D; Kim, Suhyon et al. (2011) Pilot analysis of the plasma metabolite profiles associated with emphysematous Chronic Obstructive Pulmonary Disease phenotype. Biochem Biophys Res Commun 413:588-93
De Oliveira, Eliseu O; Wang, Kan; Kong, Hye-Sik et al. (2011) Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema. Bioorg Med Chem Lett 21:6746-50
Snelgrove, Robert J; Jackson, Patricia L; Hardison, Matthew T et al. (2010) A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330:90-4
Shim, Y Michael; Paige, Mikell; Hanna, Halim et al. (2010) Role of LTB? in the pathogenesis of elastase-induced murine pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol 299:L749-59