MIF-Based Therapies in Cigarette Smoke-Related COPD and Pneumonia
Abstract
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and is especially common in military members and Veterans. COPD is a progressive, destructive process of airflow obstruction, leading to respiratory failure. A major cause of mortality in people with COPD is bacterial pneumonia, such as those caused by Streptococcus pneumonia (S. pneumoniae). In addition to aging, a history of primary cigarette smoke exposure (CSE), or significant second-hand CSE, is the most common environmental risk factor for developing COPD -- even years after smoking exposure ceases. We identified an innate immune protein, Macrophage migration inhibitory factor (MIF), and its receptor, CD74, as endogenous, protective molecules that determine susceptibility to COPD. We found that MIF becomes depleted with age, but this depletion may be significantly accelerated after chronic CSE, which then predisposes to both COPD and S. pneumoniae infection. We also identified that inherited variations the MIF gene may explain the different susceptibilities people have to COPD and to its complications, such as bacterial pneumonia. Therefore, augmenting MIF levels in susceptible individuals may be effective therapy against COPD as well as S. pneumoniae. We have already developed orally active MIF agonists (MIF20) with excellent safety and efficacy profiles that are ready to be tested in COPD and bacterial pneumonia models. We have evidence in models of acute lung and cardiac injury that MIF20 has therapeutic effects. However, MIF20 has not been tested in chronic CSE-related lung diseases, such as COPD. Our overall objective of this proposal is to test MIF augmentation strategies for the prevention and treatment of CSE-related COPD and S. pneumoniae infection. In order to achieve this objective, we propose to complete the following two aims: (1) Test the therapeutic efficacy of MIF augmentation in CSE-related COPD. We will first perform a dose-response, using three different routes of delivery (by mouth, intraperitoneal, nebulized) and then select an optimal dose as well as two routes of delivery to compare/contrast in chronic CSE, looking at COPD as one of the outcomes. In addition, we will identify CSE- and MIF-responsive proteins and immunologic profiles. Lung-targeted genetic MIF overexpressing mice will be used as a comparison group. In addition, we will use the extensive COPD clinical and biospecimen repository we currently have to identify low, medium, and high MIF-expressing genotypes among smokers and determine whether there is any association with plasma MIF as well as clinical and radiographic COPD parameters. These studies will form the basis of future MIF-based clinical studies in which MIF serves as a diagnostic or prognostic biomarker as well as a tool to identify subgroups of people who are most likely to benefit from MIF augmentation. (2) Test the therapeutic efficacy of MIF augmentation in CSE-related S. pneumoniae infection. Using the optimal dose and routes identified in Aim 1, we will determine whether MIF20 prevents or improves lung injury or mortality due to S. pneumoniae in the context of CSE. These studies will provide proof-of-concept for newly developed pharmacologic MIF agonists as a strategy to prevent or treat CSE-induced COPD and bacterial pneumonia.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610680
Entities
People
- Patty J Lee
Organizations
- United States Army
- Yale University