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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (03))
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Atif, Shaikh M; Gibbings, Sophie L; Redente, Elizabeth F et al. (2018) Immune Surveillance by Natural IgM Is Required for Early Neoantigen Recognition and Initiation of Adaptive Immunity. Am J Respir Cell Mol Biol 59:580-591
McCubbrey, Alexandra L; Barthel, Lea; Mohning, Michael P et al. (2018) Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis. Am J Respir Cell Mol Biol 58:66-78
Jansing, Nicole L; McClendon, Jazalle; Henson, Peter M et al. (2017) Unbiased Quantitation of Alveolar Type II to Alveolar Type I Cell Transdifferentiation during Repair after Lung Injury in Mice. Am J Respir Cell Mol Biol 57:519-526
Neudecker, Viola; Brodsky, Kelley S; Clambey, Eric T et al. (2017) Neutrophil transfer of miR-223 to lung epithelial cells dampens acute lung injury in mice. Sci Transl Med 9:
Frasch, S Courtney; McNamee, Eóin N; Kominsky, Douglas et al. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-?. J Immunol 197:1425-34
Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:
Janssen, William J; Stefanski, Adrianne L; Bochner, Bruce S et al. (2016) Control of lung defence by mucins and macrophages: ancient defence mechanisms with modern functions. Eur Respir J 48:1201-1214
Fornetti, J; Flanders, K C; Henson, P M et al. (2016) Mammary epithelial cell phagocytosis downstream of TGF-?3 is characterized by adherens junction reorganization. Cell Death Differ 23:185-96
Fernandez-Boyanapalli, Ruby F; Falcone, Emilia Liana; Zerbe, Christa S et al. (2015) Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment. J Allergy Clin Immunol 136:1399-1401.e3
Gibbings, Sophie L; Goyal, Rajni; Desch, A Nicole et al. (2015) Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood 126:1357-66

Showing the most recent 10 out of 14 publications