Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.

Acute lung injury is one of the common lethal complications in sepsis. It is clinically characterized by refractory hypoxemia, diffuse pulmonary infiltrates, and high permeability pulmonary edema. Several molecules could contribute to increased vascular permeability during sepsis. In this study, we investigated whether VEGF, originally known as a vascular permeability factor, plays a possible role in sepsis-associated lung vascular hyperpermeability. Initially, we examined time-dependent expression of VEGF and its receptors, Flt1 and KDR, in human pulmonary endothelial cells (HPMEC-ST1.6R) when stimulated with LPS + INFγ. Following stimulation, VEGF expression was significantly increased, but Flt1 and KDR remained unchanged. VEGF release by HPMEC-ST1.6R after stimulation was significantly increased, and it was suppressed by JNK, MEK, and p38 MAPK inhibitors. Next, when experimental mouse models of sepsis were used, septic conditions resulted in enhanced lung vascular permeability, as assessed by IgM concentrations in bronchoalveolar lavage fluid, and led to a significant increase in blood VEGF concentrations. Bevacizumab, an anti-VEGF antibody, significantly suppressed pulmonary hyperpermeability in sepsis. These results suggest that VEGF is involved as one of the factors that increase lung vascular permeability in sepsis.

A man in his 40s presented with a 7-day history of fever and abdominal pain after polypectomy of the sigmoid colon. On physical examination, he had mild tenderness on deep palpation of the left lower abdominal quadrants without guarding, rigidity or rebound tenderness. Contrast-enhanced CT revealed the thrombosis of the inferior mesenteric vein and the portal vein. Blood cultures were positive forEscherichia coli. We diagnosed him with pylephlebitis after colonic polypectomy, as a rare complication. He was started on cefmetazole and heparin. Antibiotic and anticoagulation therapy were initiated. He had a complete recovery within 17 days. The patient had no evidence of underlying hypercoagulable condition, and no signs of recurrence at a 3-month follow-up. Pylephlebitis after colonic polypectomy is extremely rare. Although bacteraemia after colonoscopy was a rare complication, phlebitis should be considered in the differential diagnosis of patients who present with persisted fever and abdominal pain after polypectomy.