Chorioamnionitis stimulates angiogenesis in saccular stage fetal lungs via CC chemokines

Abstract

The fetal lung vasculature forms in tandem with developing airways. Whereas saccular airway morphogenesis is arrested in bronchopulmonary dysplasia (BPD), the potential vascular phenotype in BPD at this stage of development is less well-understood. As inflammation increases the risk of BPD and induces arrest of saccular airway morphogenesis, we tested the effects of Escherichia coli LPS on fetal mouse lung vascular development. Injecting LPS into the amniotic fluid of Tie2-lacZ endothelial reporter mice at embryonic day 15 stimulated angiogenesis in the saccular stage fetal lung mesenchyme. LPS also increased the number of endothelial cells in saccular stage fetal mouse lung explants. Inflammation appeared to directly promote vascular development, as LPS stimulated pulmonary microvascular endothelial cell angiogenesis, cell migration, and proliferation in vitro. Whereas LPS did not increase expression of VEGF, angiopoietin-1 (Ang-1), Tie2, fetal liver kinase-1 (Flk-1), fms-like tyrosine kinase-1 (Flt-1), PDGFA, PDGFB, heparin-binding EGF-like growth factor (HB-EGF), or connective tissue growth factor (CTGF), LPS did stimulate the production of the angiogenic CC chemokines macrophage inflammatory protein-1α (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1). Both MIP-1α and MCP-1 increased angiogenesis in fetal mouse lung explants. In addition, inhibitory antibodies against MIP-1α and MCP-1 blocked the effects of LPS on fetal lung vascular development, suggesting these chemokines are downstream mediators of LPS-induced angiogenesis. We speculate that an inflammation-mediated surge in angiogenesis could lead to formation of aberrant alveolar capillaries in the lungs of patients developing BPD.

Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

“…Besides other mononuclear cells, MIP-1α acts on monocytes and DC (27) and may therefore be involved in recruiting these cells into the lungs of the newborn mice. Consistently, antibodies to MIP-1α inhibited the harmful angiogenesis induced by intraamniotic injection of LPS in mice (28). Blockade of MIP-2, a neutrophil chemoattractant, reduces hyperoxia-induced alveolar septal thickening in a rat model of BPD (29).…”

Animal models of bronchopulmonary dysplasia. The term mouse models

“…By staining for ␣-smooth muscle actin (␣-SMA), investigators also showed that positioning of myofibroblasts in the airways of treated animals is altered, which may affect terminal airway branching and future alveolarization. By exposing fetal mice at embryonic day 15 to Escherichia coli LPS, investigators showed increased levels of proangiogenic chemokines MIP-1␣ and monocyte chemoattractant protein-1 (MCP-1) in explanted fetal lung tissue, which corresponded to increased levels in tracheal aspirates of infants exposed to in utero chorioamnionitis (55). Velten et al's model (84), as described above, works toward the goal of better mimicking the confluence of factors that contribute to BPD by combining prenatal inflammation with PN hyperoxia.…”

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

“…Samples were collected and processed as previously described. 15,26 Briefly, endotracheal suctioning was sterilely performed and the aspirate was collected in a specimen trap. After centrifugation at 1000 Â g at 4 C for 5 minutes, the supernatant was separated, and samples were coded, aliquoted, and stored in a de-identified manner at À80 C until later use.…”