Date Published: August 22, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Irina Gavrilovskaya, Elena Gorbunova, Frederick Koster, Erich Mackow.
Hantavirus pulmonary syndrome is characterized by vascular permeability, hypoxia, and acute pulmonary edema. Vascular endothelial growth factor (VEGF) is induced by hypoxia, potently induces vascular permeability, and is associated with high-altitude-induced pulmonary edema. Hantaviruses alter the normal regulation of β3 integrins that restrict VEGF-directed permeability and hantavirus infected endothelial cells are hyperresponsive to the permeabilizing effects of VEGF. However, the role of VEGF in acute pulmonary edema observed in HPS patients remains unclear. Here we retrospectively evaluate VEGF levels in pulmonary edema fluid (PEF), plasma, sera, and PBMCs from 31 HPS patients. VEGF was elevated in HPS patients PEF compared to controls with the highest levels observed in PEF samples from a fatal HPS case. VEGF levels were highest in PBMC samples during the first five days of hospitalization and diminished during recovery. Significantly increased PEF and PBMC VEGF levels are consistent with acute pulmonary edema observed in HPS patients and HPS disease severity. We observed substantially lower VEGF levels in a severe HPS disease survivor after extracorporeal membrane oxygenation. These findings suggest the importance of patients’ VEGF levels during HPS, support the involvement of VEGF responses in HPS pathogenesis, and suggest targeting VEGF responses as a potential therapeutic approach.
Hantavirus Pulmonary Syndrome (HPS) is a hallmark capillary leak syndrome with a ~40% mortality rate, and Sin Nombre (SNV) is a prototypical HPS causing hantavirus associated with outbreaks of HPS disease in the Southwestern United States [1–5]. HPS is characterized by an acute febrile prodrome with thrombocytopenia rapidly progressing to acute pulmonary edema, hypoxia respiratory insufficiency, hypotension, and cardiogenic shock [1, 2, 5–7]. Hantaviruses predominantly infect the endothelial cell lining of vessels that form the primary fluid barrier of the vasculature. The pathogenesis of HPS is likely to result from the direct infection of pulmonary endothelial cells as well as hantavirus-induced responses of endothelial and immune cells. Immune cells are hypothesized to contribute to hantavirus disease through elevated levels of CD8+ T cells and cytokines such as TNF, yet the vascular endothelium is not disrupted in patients [5, 8–15]. In vitro SNV-infected endothelial cells are not permeabilized by infection alone or following the addition of TNF [14, 16], however pathogenic hantaviruses bind and inactivate β3 integrins which normally restrict VEGF-directed capillary permeability [17–21]. This nonlytic induction of vascular permeability suggests that hantaviruses alter normal responses of the endothelium to factors that elicit an edematous disease process [5–7, 10, 14, 16–18, 22–26].
Pulmonary symptoms of HPS patients are characterized by hypoxia and extensive capillary leakage resulting in acute bilateral pulmonary edema [2, 5–7, 22, 42, 45]. Hypoxia induces pulmonary epithelial and endothelial cells to secrete VEGF [32, 34–37, 39, 40, 46, 47], and VEGF acts on the endothelium to stimulate growth and dissociate adherence junctions between endothelial cells [32, 36, 46, 48–51]. This permits vascular remodeling, vessel repair, and angiogenesis, but can also locally increase capillary permeability [32, 36, 39, 44, 46, 48, 49, 52]. A VEGF-HIF-1α amplification loop is responsible for high-altitude-induced pulmonary edema, and over expressing VEGF in the lung causes pulmonary edema [33–35, 37–40, 52, 53]. Conversely, genetic delivery of antiVEGF antibody or antagonizing VEGF responses suppresses pulmonary edema in experimental animals [37, 54–57].