Rare Pulmonary Connective Tissue Type Mast Cells Regulate Lung Endothelial Cell Angiogenesis.

Abstract Within the human lung, mast cells typically reside adjacent to the conducting airway, and assume a “mucosal” phenotype (MCT). In rare pathological conditions, “connective tissue” phenotype mast cells (MCTC) can be found in the lung parenchyma. MCTC accumulate in the lungs of infants with severe bronchopulmonary dysplasia (BPD), a chronic lung disease associated with preterm birth, which is characterized by pulmonary vascular dysmorphia. The human LUVA mast cell line was used to model MCTC or MCT. The ability of MCTC to affect vascular organization during fetal lung development was tested in mouse lung explant cultures. The effect of MCTC on in vitro tube formation and barrier function was studied using primary fetal human pulmonary microvascular endothelial cells (feHPMVCs). The mechanistic role of MCTC proteases was tested using inhibitors. MCTCLUVA, but not MCTLUVA, were associated with vascular dysmorphia in lung explants. In vitro, the addition of MCTCLUVA potentiated feHPMVC interactions, inhibited tube stability, and disrupted endothelial cell junctions. Protease inhibitors ameliorated the ability of MCTCLUVA to alter endothelial cell angiogenic activities in vitro and ex vivo. These data indicate that MCTC may directly contribute to disrupted angiogenesis in BPD. A better understanding of factors regulating mast cell subtype, and their different effector functions, is essential.