Cyp19a1 is essential for macrophage function and pulmonary tissue repair following airway epithelial injury

Abstract

CYP19A1 (the aromatase) is a key enzyme in the biosynthesis of estrogens, which have important regulatory functions, including roles as a major mitogenic stimulus for cellular proliferation. Using a new myeloid cell-specific Cyp19a1-null (Cyp19a1-null) mouse model, we tested the role of macrophage CYP19A1 in pulmonary regenerative response to naphthalene-induced bronchiolar epithelial cell injury. Wild-type and Cyp19a1-null mice were treated with naphthalene (200 mg/kg, IP) to induce acute lung injury, or with corn oil as a vehicle control. Mouse lung was examined at 24 hour, 72 hours, or 14 days after the treatment, for extent of acute airway injury, post-injury cellular proliferation, and tissue repair, respectively. At 24 hours, a genotype difference in the extent of naphthalene-induced airway injury was not detected. At 72 hours, the fraction of airway epithelial cells that are positive for the cell proliferation marker Ki67 was higher in naphthalene-treated wild-type mice (40%-70%) than in naphthalene-treated Cyp19a1-null mice (20-30%); whereas the fraction was much lower in corn oil treated control mice (3-5%). At 14 days, the bronchiolar epithelium was recovered to a greater extent in wild-type (~80%) than in the Cyp19a1-null mice (<30%), as indicated by the abundance of Club cells (positive for Club cell secretary protein) in the airway epithelium. Further studies of isolated macrophages indicated that Cyp19a1-null macrophages had reduced phagocytosis (by ~70%) and migration (by ~50%) activities, compared to wild-type controls. Thus, the loss of macrophage CYP19A1negativelyimpacted macrophage function and impeded the post-injury cellular proliferation and tissue repair in the lung airways.