Endothelial FoxM1 Mediates Bone Marrow Progenitor Cell-Induced Vascular Repair and Resolution of Inflammation following Inflammatory Lung Injury

Abstract

Adult stem cell treatment is a potential novel therapeutic approach for acute respiratory distress syndrome. Given the extremely low rate of cell engraftment, it is believed that these cells exert their beneficial effects via paracrine mechanisms. However, the endogenous mediator(s) in the pulmonary vasculature remains unclear. Employing the mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO), here we show that endothelial expression of the reparative transcriptional factor FoxM1 is required for the protective effects of bone marrow progenitor cells (BMPC) against LPS-induced inflammatory lung injury and mortality. BMPC treatment resulted in rapid induction of FoxM1 expression in WT but not FoxM1 CKO lungs. BMPC-induced inhibition of lung vascular injury, resolution of lung inflammation, and survival, as seen in WT mice, were abrogated in FoxM1 CKO mice following LPS challenge. Mechanistically, BMPC treatment failed to induce lung EC proliferation in FoxM1 CKO mice, which was associated with impaired expression of FoxM1 target genes essential for cell cycle progression. We also observed that BMPC treatment enhanced endothelial barrier function in WT, but not in FoxM1-deficient EC monolayers. Restoration of β-catenin expression in FoxM1-deficient ECs normalized endothelial barrier enhancement in response to BMPC treatment. These data demonstrate the requisite role of endothelial FoxM1 in the mechanism of BMPC-induced vascular repair to restore vascular integrity and accelerate resolution of inflammation, thereby promoting survival following inflammatory lung injury.

Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome

“…( Fig 1A ). To determine alterations in lung vascular permeability, we employed the EBA assay to assess pulmonary transvascular flux of Evans blue-conjugated albumin [14, 15]. As shown in Fig 1B in oil-free mice, we observed a marked increase in EBA flux that peaked at 24 hours post-LPS challenge (4mg/kg, i.p.)…”

“…The Evans blue-conjugated albumin (EBA) extravasation assay was performed as previously described [18]. Briefly, EBA (20mg/kg) was retro-orbitally injected into mice 30 minutes before tissue collection.…”

“…Myeloperoxidase (MPO) activity was measured as previously described [18]. Briefly, lung tissues free of blood were collected following perfusion with PBS and homogenized in 50mM phosphate buffer.…”

“…Cell Proliferation Assay was performed as previously described [18]. Briefly, 5-bromo-2-deoxyuridine (BrdU) was administered 6 hours prior to tissue collection (75mg/kg, i.p.).…”

SASH1, a new potential link between smoking and atherosclerosis

“…In the vasculature, FOXM1 was shown to promote endothelial repair in mice after inflammatory lung injury 232 . In this model, endothelial bone marrow progenitors promote healing of the wound, however in FOXM1 deficient mice, the protective effect of endothelial bone marrow progenitor cells after LPS induced vascular injury was abrogated.…”