Macrophage-Mediated Lung Repair Programs Following Injury

Project Summary
Over the past several years, we have experienced the social and physical consequences of a viral pandemic;
however, the cellular and molecular mechanisms of repair following such infections are not fully understood. The
lung serves as the site of gas exchange. Due to this function, it is constantly exposed to noxious environmental
stimuli—including bacteria and viruses. Following viral respiratory infection, many of the epithelial cells lining the
airways are lost and must be reconstituted. The epithelial-intrinsic mechanisms underlying such recovery are
well understood, but the role of the immune system in this process is not well defined. In close contact with
epithelial cells in the distal lung are alveolar macrophages, innate immune cells capable of sensing diverse
stimuli and integrating these signals into effector responses. Our previous work has shown that macrophages
engage in reciprocal growth factor exchange with fibroblasts, a communication circuit we predict to be active in
other cell types and contexts. In the lung, macrophages have been observed to help mediate inflammation and
repair via communication with epithelial cells following injury, however, the role of these interactions in the context
of viral infection remains unknown. Using a mouse-adapted influenza A virus, we observe a marked loss of
epithelial cells followed by rapid recovery, all under a constant presence of macrophages. This study aims to
determine the role of macrophages in this repair process. We hypothesize that optimal epithelial repair
requires macrophages at specific time points and anatomical locations following viral-induced damage.
We also propose that bidirectional crosstalk between macrophages and epithelial cells promotes tissue
repair. The proposed work will serve to 1) define when and where macrophages are required for optimal repair
following viral injury and 2) provide mechanistic understanding of macrophage-epithelial communication
networks in the injured and regenerating lung. Completion of this project will allow us to identify molecular targets
whose modulation may improve patient outcomes following viral infection. The Franklin lab is the ideal research
environment to perform these studies. Dr. Franklin (sponsor) is an expert in macrophage biology and has
previously unraveled interactions between macrophages and non-immune cells. Our location at Harvard Medical
School also grants access to world-class experts and resources to complete our aims. For example, Dr. Carla
Kim (co-sponsor) is an expert on lung damage and repair and will provide guidance on lung biology and epithelial
progenitor cell function following damage. Together, my mentoring team and institutional resources will help me
achieve the goals outlined in this proposal and allow me to grow both as a scientist and an individual.

Grant Number: 5F31HL172650-02
NIH Institute/Center: NIH
Principal Investigator: Alan Baez Vazquez