The mechanisms underlying complex human diseases such as asthma and chronic obstructive pulmonary disease (COPD) are still not fully understood. While mouse models of pulmonary inflammation are a powerful approach to discover the pathophysiology of these diseases, validation of the findings in humans is an essential prerequisite to the development of potential therapeutic strategies. Group V secretory phospholipase A2 (sPLA2) is an enzyme that generates lipid mediators from membrane phospholipids and has critical functions in innate immune response against pathogens. We have recently found that group V sPLA2 has a key role in a mouse model of allergic pulmonary inflammation that has many features of human asthma and is induced by an extract of the house dust mite Dermatophagoides farinae (Df). Now our preliminary data indicate that mice genetically modified to lack group V sPLA2 (Pla2g5-null mice) do not develop alternative activated macrophages (AAMacs) in the lung following Df exposure and that group V sPLA2 is expressed preferentially in AAMacs compared to other types of macrophages both in mouse and human. Because AAMacs have been linked to allergic immune responses we hypothesize that group V sPLA2 is necessary for development of AAMacs and therefore for pulmonary inflammation. The goal of this application is to understand the function of group V sPLA2 per se and AAMacs in general in the pathogenesis of pulmonary inflammation. To reach this goal we will assess the mechanism by which endogenous group V sPLA2 controls the development of AAMacs;we will analyze the lipid profile of AAMAcs developed in the lung after Df exposure or AAMacs derived from bone marrow of normal mice and Pla2g5-null mice. To study the functions of AAMacs in Df induced pulmonary inflammation we will adoptively transfer normal or mutated AAMacs into the mice exposed to Df. We will verify the critical function of group V sPLA2 in the development of these cells and in pulmonary inflammation in a mouse model of chronic pulmonary inflammation induced by Sendai virus that resembles human COPD and in which the AAMacs have a validated critical role. We will use mice genetically modified to lack only AAMacs to ascertain the function of AAMacs in Df and viral induced pulmonary inflammation. Because group V sPLA2 has been found in the BAL of patients with severe asthma and because our preliminary data suggest that it is important in development of human AAMacs, it is likely that its function is conserved between species. Therefore we will validate our findings in specimens of severe asthmatic patients. In addition to discover a new pathway leading to pulmonary inflammation, these studies will identify group V sPLA2 as a unique conserved marker of mouse and human alternative activated macrophages and a potential therapeutic target in the pathogenesis of human allergic and inflammatory diseases.

Public Health Relevance

The basic mechanisms of asthma and pulmonary inflammation are still not fully understood and patients are still in need of better treatments. Th goal of this proposal is to discover a critical and missing step in the pathogenesis of asthma and pulmonary inflammation in which group V secretory phospholipase A2 plays an essential and previously unrecognized role and to validate these findings in human diseases, an essential prerequisite for discovery of new therapeutic treatments to improve the quality of life of the patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113071-02
Application #
8605549
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Eu, Jerry Pc
Project Start
2013-01-15
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$350,770
Indirect Cost
$148,270
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115