The functional role of macrophages in the progression and resolution of lung fibrosis.
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Centre for Inflammation Research
Abstract
Tissue scarring (fibrosis) is the common endpoint in many inflammatory disorders of the lung. In progressive lung fibrosis there is an inexorable decline in exercise tolerance followed by respiratory failure and death. There is no effective treatment. The macrophage is an inflammatory cell that is associated with lung fibrosis. Recent studies in the liver and kidney indicate that macrophages are critical to the regulation of scarring. I propose to conduct a series of experiments to determine the role that macrophages (both those already in the lung and those derived from the circulation and bone marrow) play in the progression and resolution of fibrosis using well established mouse models of lung fibrosis. I will then determine whether the manipulation of macrophages of bone marrow origin can be used to alter, and ultimately reverse, fibrosis in the lung. I believe this work will be important to inform the rational design of targeted therapies for lung fibrosis based on macrophage cell therapy and potentially for other life threatening lung conditions, characterised by inflammation and scarring such as the acute respiratory distress syndrome (ARDS) that occurs in patients in intensive care.
Technical Summary
I wish to investigate the functional role of the macrophage in murine models of lung fibrosis.
Studies in murine models have identified a reversible component to lung fibrosis. Macrophages are key cells in both the genesis and resolution of fibrosis in many tissues; recently it was shown that a proportion of alveolar macrophages are of bone marrow (BM) origin.
My first goal is to define functionally the role of the macrophage at key stages in the progression and resolution of lung fibrosis by applying a transgenic mouse model of toxin mediated macrophage depletion (DTR mouse) to murine models of lung fibrosis (1 reversible, 1 progressive).
Next I will determine the relative importance of indigenous versus BM-derived alveolar macrophages in the regulation of lung fibrosis. Mice (wild type or DTR) will receive crossover BM transplants prior to the induction of lung fibrosis. Selective depletion of either the resident alveolar macrophage or the circulating BM-derived macrophage will enable us to demonstrate the relative importance of these macrophage populations in the control of fibrosis.
Lastly I will determine whether manipulation of macrophages can influence the fibrotic lung response. In the first instance we will study MMP-2 which regulates matrix turnover and myofibroblast proliferation in lung fibrosis. By performing BM transplants from MMP-2 knockout mice prior to lung fibrosis induction, we will determine whether manipulation of macrophages can be used to modify pulmonary fibrosis
At the end of this fellowship I believe that I will have established a series of data that will add significantly to the body of work that already exists on lung injury and repair. It is hoped that this research project will inform the design of targeted treatments for pulmonary fibrosis (and potentially other life threatening pulmonary disorders characterised by inflammation and repair such as ARDS).
Studies in murine models have identified a reversible component to lung fibrosis. Macrophages are key cells in both the genesis and resolution of fibrosis in many tissues; recently it was shown that a proportion of alveolar macrophages are of bone marrow (BM) origin.
My first goal is to define functionally the role of the macrophage at key stages in the progression and resolution of lung fibrosis by applying a transgenic mouse model of toxin mediated macrophage depletion (DTR mouse) to murine models of lung fibrosis (1 reversible, 1 progressive).
Next I will determine the relative importance of indigenous versus BM-derived alveolar macrophages in the regulation of lung fibrosis. Mice (wild type or DTR) will receive crossover BM transplants prior to the induction of lung fibrosis. Selective depletion of either the resident alveolar macrophage or the circulating BM-derived macrophage will enable us to demonstrate the relative importance of these macrophage populations in the control of fibrosis.
Lastly I will determine whether manipulation of macrophages can influence the fibrotic lung response. In the first instance we will study MMP-2 which regulates matrix turnover and myofibroblast proliferation in lung fibrosis. By performing BM transplants from MMP-2 knockout mice prior to lung fibrosis induction, we will determine whether manipulation of macrophages can be used to modify pulmonary fibrosis
At the end of this fellowship I believe that I will have established a series of data that will add significantly to the body of work that already exists on lung injury and repair. It is hoped that this research project will inform the design of targeted treatments for pulmonary fibrosis (and potentially other life threatening pulmonary disorders characterised by inflammation and repair such as ARDS).
