Inflammation is an essential effector process for responses to parasitism, infection and tissue injury. On the other hand, it also contributes to the pathogenesis of most human diseases. This paradox results in part from the fact that inflammation itself can, and often does;itself induce injury to the tissues in the process of resolving the infection or healing the wound. Optimally, therefore, an acute inflammatory response completes its protective (and pro-immunogenic) functions and then rapidly resolves, allowing the tissue to return to normal structure and function. A key element in this resolution is removal of the inflammatory cells themselves as well as the cell and tissue debris that is produced as an inevitable accompaniment to the process. This clearance function is primarily carried out by uptake of debris and cells into macrophages that accumulate at the site as part of the inflammatory process. Studies of macrophages in inflammation have tended in the past to focus on their contribution to recognizing the injurious stimulus in the first place, and in controlling the inflammation by virtue of their sequential production of pro- and then anti- inflammatory mediators. More recently, however, their participation in the resolution phase is becoming better understood, and, we hypothesize, results from a change in macrophage function that we identify as a change in "programing state". In particular, the reparative macrophages are hypothesized to gain a substantial capacity for macropinocytosis, the ingestion process suggested to remove both dying inflammatory cells and the particulate, and even soluble, debris that accompanies inflammation. Questions that are to be addressed in the proposal include: 1) demonstrating that macrophages with specifically high capability for macropinocytosis develop in the resolving inflamed lung and are effective scavengers of both debris and dying inflammatory cells, 2) distinguishing between incoming monocytes or previously macropinocytosis-poor macrophages as the source for such scavenger cells, 3) exploring the mechanism driving the macrophage programing by testing a proposed phosphatidylserine/IL- 4/PPARgamma signaling pathway (i.e. suggesting that it develops as a response to the presence of the activated and dying inflammatory cells themselves), 4) demonstrating that the pro-macropinocytic programing state and thus, clearance of inflammatory debris, can be enhanced in vivo by stimulating these pathways to improve the resolution.

Public Health Relevance

Inflammation is a significant contributor to most respiratory diseases. The studies in this proposal address the critical need to understand the mechanisms by which lung inflammation resolves and the tissue returns to normal structure and function. Accumulation of inflammatory leukocytes is the hall mark of the inflammatory process and is a necessary component of its protective roles against injury and infection. However, inflammation, though generally protective, also inevitably results in some collateral tissue damage over and above that created by the initial inducing agent. Accordingly, during resolution, the tissue debris and inflammatory cells need to be removed. We have shown that this removal involves macrophages (big eaters) and a unique form of uptake mechanism (macropinocytosis). In this proposal we will address novel hypotheses as to the sources and mechanisms for generating macrophages with enhanced macropinocytic (clearance) capability during the resolution phase of lung inflammation. A number of chronic inflammatory lung diseases appear to be associated with defects in such clearance and we suggest, and will begin to explore, ways to deliberately enhance the clearance processes as potential therapeutic approaches to overcoming the defects, enhance the resolution and return the lung to normal.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114381-01A1
Application #
8454234
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (03))
Program Officer
Eu, Jerry Pc
Project Start
2013-08-01
Project End
2017-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$637,072
Indirect Cost
$235,134
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A et al. (2014) Muc5b is required for airway defence. Nature 505:412-6