title: Transgenic expression of FoxM1 promotes endothelial repair following lung injury induced by polymicrobial sepsis in mice.
abstract: Enhancing endothelial barrier integrity for the treatment of acute lung injury (ALI) is an emerging novel therapeutic strategy. Our previous studies have demonstrated the essential role of FoxM1 in mediating endothelial regeneration and barrier repair following lipopolysaccharide-induced lung injury. However, it remains unclear whether FoxM1 expression is sufficient to promote endothelial repair in experimental models of sepsis. Here, employing the FoxM1 transgenic (FoxM1 Tg) mice, we showed that transgenic expression of FoxM1 promoted rapid recovery of endothelial barrier function and survival in a clinically relevant model of sepsis induced by cecal ligation and puncture (CLP). We observed lung vascular permeability was rapidly recovered and returned to levels similar to baseline at 48 h post-CLP challenge in FoxM1 Tg mice whereas it remained markedly elevated in WT mice. Lung edema and inflammation were resolved only in FoxM1 Tg mice at 24 h post-CLP. 5-bromo-2-deoxyuridine incorporation assay revealed a drastic induction of endothelial proliferation in FoxM1 Tg lungs at 24h post-CLP, correlating with early induction of expression of FoxM1 target genes essential for cell cycle progression. Additionally, deletion of FoxM1 in endothelial cells, employing the mouse model with endothelial cell-restricted disruption of FoxM1 (FoxM1 CKO) resulted in impaired endothelial repair following CLP challenge. Together, these data suggest FoxM1 expression in endothelial cells is necessary and sufficient to mediate endothelial repair and thereby promote survival following sepsis challenge.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, United States of America.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Huang
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine; D002199:Capillary Permeability; D002432:Cecum / Q000293:injuries; D002453:Cell Cycle / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D008026:Ligation; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011654:Pulmonary Edema / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D008070:Lipopolysaccharides; D001973:Bromodeoxyuridine