Macrophage Colony-Stimulating Factor Aggravates Rather than Regenerates Emphysematous Lungs in Mice

Abstract

Background: Lung regeneration is an innovative strategy that may cure pulmonary emphysema. The bone marrow (BM) harbors pulmonary stem cells. Hematopoietic cytokine-driven mobilization of BM cells may thus support lung regeneration. Objectives: The aim of this study was to determine whether systemic administration of macrophage colony-stimulating factor (M-CSF) leads to the regeneration of lungs in a murine model of elastase-induced emphysema. Methods: C57BL/6J mice were administered elastase intratracheally. Four weeks later, in the absence or presence of elastase treatment, mice were intraperitoneally given either M-CSF or saline on days 1–5 each week for 3 weeks. Lung tissue was harvested 24 h after the last injection. Results: M-CSF administration without prior elastase did not affect the mean linear intercept, surface area, or surface area/lung volume. In contrast, M-CSF administration following elastase injury caused a greater increase in the mean linear intercept and greater decreases in surface area and surface area/lung volume than saline administration following elastase, indicating that M-CSF aggravated emphysema. This aggravation of emphysema was accompanied by accumulation of pulmonary alveolar macrophages (AMs) expressing metalloproteinase (MMP)-9 and MMP-12. M-CSF stimulated AMs to express MMPs in vitro. Conclusions: These results suggest that M-CSF administration does not support lung regeneration but rather aggravates the lung destruction associated with elastase injury.