The objective of this proposal is to exploit a newly discovered anti-inflammatory function involving the aminopeptidase activity of the leukotriene A4 hydrolase for the treatment of pulmonary emphysema. The leukotriene A4 hydrolase is a dual-functioning enzyme with dichotomously opposing functions. As an epoxide hydrolase, it catalyzes the conversion of leukotriene A4 to leukotriene B4 in pro-inflammatory processes. As an aminopeptidase, it catalyzes the digestion of the tripeptide sequences like Pro-Gly-Pro in anti-inflammatory processes. For the first time, we have created a pharmacological agent (4-MDM) with which the aminopeptidase activity of the leukotriene A4 hydrolase can be selectively up-regulated. We hypothesized that the treatment with 4-MDM will protect lungs from developing pulmonary emphysema. Preliminary results demonstrated that the 4-MDM treatment effectively protected murine lungs from emphysema induced by intra- nasal elastase. Subsequently, we formulated 4-MDM to be stably water soluble as a potential oral agent (CDX- MDM). Enhanced water solubility of the CDX-MDM has enabled us to administer this agent in a chronic animal model of pulmonary emphysema. Building upon this preliminary work, we propose to conduct the efficacy study of the CDX-MDM in a murine model of pulmonary emphysema induced by cigarettes smoke which resembles human disease most closely. Emphysema develops over a long duration of trigger (cigarette smoke) exposure. Therefore, developing a biomarker assay which measures the pharmaceutical effects of the drug could also be a desirable tool to overcome the long duration of onset during the development of a pharmaceutical agent. We developed a biomarker assay which the aminopeptidase activity of the leukotriene A4 hydrolase can be measured in plasma ex vivo. In this grant application, we also propose to test this assay with the plasma samples from the animals treated with the CDX-MDM or placebo. In combination, this project will provide necessary evidence on which the CDX-MDM will be developed as a potential therapy for emphysema.
Pulmonary emphysema is an irreversible lung disease of increasing prevalence for which effective disease modifying therapy is not available. Based on these needs, we propose specific aims with a novel compound to develop a medical therapy for pulmonary emphysema. We believe that our project will lead to new therapeutic options for patients who suffer from pulmonary emphysema.
|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|