Acute inflammatory lung diseases affect over 450 million people worldwide each year. Pathologic hallmarks include neutrophil accumulation, alveolar epithelial and endothelial cell injury, and loss of epithelial-capillary integrity. For alveolar repair to occur, inflammation must be halted, debris and inflammatory cells removed, injured tissue cells replaced, and capillary barrier function re-established. Macrophages are key players in all of these. The primary objective of this proposal is to create a Program in Lung Macrophage Biology that will determine how lung macrophages are programmed to halt inflammation and promote alveolar repair. A concept at the heart of the proposal is that of macrophage subsets. During health, the airspaces are occupied by a stable population of resident alveolar macrophages (RAM) that arise during embryogenesis and self-renew throughout life. RAMs remain during inflammation but are joined by recruited macrophages (RecM) that mature from circulating monocytes. These RecM remain in the lungs until alveolar function is restored, and then in most cases undergo apoptosis. However, in certain situations RecM escape apoptosis. We have shown that this is associated with the development of fibrosis. The precise roles played by RAMs vs RecM in the resolution of inflammation and promotion of tissue repair remain largely unknown. However, our data suggest that their respective roles are very different. In this context, the Program in Lung Macrophage Biology will explore 3 complementary themes. Theme 1 tests the hypothesis that RecM apoptosis is essential for the resolution of inflammation and that delayed apoptosis leads to fibrosis. The mechanisms that regulate the extrinsic apoptosis pathway and the intracellular proteins that block it will be studied. Theme 2 tests the hypothesis that binding of airway-derived mucins to Siglecs (a class of sialic acid-binding receptors with immunoinhibitory function) expressed on macrophages calibrates macrophage inflammatory responses. Theme 3 provides a tight link with the other themes and explores how cellular metabolism regulates macrophage inflammatory and pro-reparative functions and how it regulates survival of macrophage subsets. In this context, we propose that RecM preferentially use glycolysis as an energy source, whereas RAMs have increased utilization of the TCA cycle. HIF-1a is stabilized in RecM and is viewed as a central metabolic regulator. The 3 themes are further linked by their focus on differential functions of RAM vs RecM, the utilization of fresh human macrophages and shared use of cutting edge technologies. The Program leverages a multidisciplinary team of highly accomplished investigators, novel transgenic animal systems that we have developed, and a strong clinical research component. The latter includes whole human lungs obtained from donors that died with ARDS, bronchoscopy specimens from patients with ARDS, and LPS exposure studies with healthy human volunteers.

Public Health Relevance

Pneumonia and other acute inflammatory diseases of the lungs, such as the acute respiratory distress syndrome (ARDS), result in damage to the alveolar epithelium and endothelium. Alveolar macrophages are critical orchestrators of alveolar repair, however the mechanisms that underpin their function remain largely unknown. The objective of this proposal is to create a Program that will determine the factors that regulate macrophage function and determine how macrophage subsets contribute to lung repair. Achieving the goals of this proposal will enhance our understanding of lung repair and pave the way for new strategies to hasten recovery from lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
1R35HL140039-01
Application #
9434798
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Postow, Lisa
Project Start
2018-02-15
Project End
2025-01-31
Budget Start
2018-02-15
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206