Genetic Delivery of Bevacizumab to Suppress Vascular Endothelial Growth Factor-Induced High-Permeability Pulmonary Edema

Background The current study was undertaken to investigate the effects of pretreatment with isoflurane and sevoflurane on the development of neurogenic pulmonary edema in an animal model. Methods Rats were exposed to room air (control), 1.5% isoflurane, or 2.5% sevoflurane for 4 h. They were then anesthetized with intraperitoneal injections of pentobarbital sodium, and fibrinogen and thrombin were injected into the cisterna magna to induce neurogenic pulmonary edema. Results Consecutive injections of fibrinogen and thrombin caused increases in blood pressure, with the peak values obtained in the isoflurane and sevoflurane groups being lower than the control values. The incidence of significant neurogenic pulmonary edema was 58%, 100%, and 8% in the control, isoflurane, and sevoflurane groups, respectively. The lung water ratio, an index of severity of edema, was 4.86 +/- 0.78, 6.15 +/- 0.64, and 4.40 +/- 0.32 in the control, isoflurane, and sevoflurane groups, respectively. Furthermore, immunohistochemical staining for vascular endothelial growth factor demonstrated an increase of expression in the rat lungs exposed to isoflurane. Treatment with an anti-vascular endothelial growth factor antibody during exposure to isoflurane completely inhibited the effect of isoflurane to promote neurogenic pulmonary edema in this model. Conclusion Exposure to 1.5% isoflurane enhances the development of neurogenic pulmonary edema development in this animal model, most likely via release of vascular endothelial growth factor from bronchial epithelial cells, an effect not observed with sevoflurane.

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Lung Overexpression of the Vascular Endothelial Growth Factor Gene Induces Pulmonary Edema

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.22.6.3779 ◽

2000 ◽

Vol 22 (6) ◽

pp. 657-664 ◽

Cited By ~ 187

Author(s):

Robert J. Kaner ◽

John V. Ladetto ◽

Ravi Singh ◽

Norimasa Fukuda ◽

Michael A. Matthay ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Pulmonary Edema ◽

Vascular Endothelial ◽

Factor Gene ◽

Growth Factor Gene ◽

Endothelial Growth Factor

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Pathogenesis of High Altitude Pulmonary Edema: Does Alveolar Epithelial Lining Fluid Vascular Endothelial Growth Factor Exacerbate Capillary Leak?

High Altitude Medicine & Biology ◽

10.1089/ham.2004.5.399 ◽

2004 ◽

Vol 5 (4) ◽

pp. 399-409 ◽

Cited By ~ 17

Author(s):

Robert J. Kaner ◽

Ronald G. Crystal

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Pulmonary Edema ◽

Vascular Endothelial ◽

Epithelial Lining ◽

Capillary Leak ◽

Epithelial Lining Fluid ◽

Alveolar Epithelial ◽

High Altitude Pulmonary Edema ◽

Endothelial Growth Factor

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Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

Journal of Virology ◽

10.1128/jvi.00817-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8765-8772 ◽

Cited By ~ 11

Author(s):

Irina N. Gavrilovskaya ◽

Elena E. Gorbunova ◽

Erich R. Mackow

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Pulmonary Edema ◽

Giant Cell ◽

Giant Cells ◽

Vascular Endothelial ◽

Andes Virus ◽

Factor C ◽

Endothelial Growth Factor

Hantaviruses primarily infect endothelial cells (ECs) and nonlytically cause vascular changes that result in hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Acute pulmonary edema during HPS may be caused by capillary leakage and failure of lymphatic vessels to clear fluids. Uniquely regulated lymphatic ECs (LECs) control fluid clearance, although roles for lymphatics in hantavirus disease remain undetermined. Here we report that hantaviruses productively infect LECs and that LEC infection by HPS causing Andes virus (ANDV) and HFRS causing Hantaan virus (HTNV) are inhibited by αvβ3integrin antibodies. Although αvβ3integrins regulate permeabilizing responses directed by vascular endothelial growth factor receptor 2 (VEGFR2), we found that only ANDV-infected LECs were hyperpermeabilized by the addition of VEGF-A. However, VEGF-C activation of LEC-specific VEGFR3 receptors blocked ANDV- and VEGF-A-induced LEC permeability. In addition, ∼75% of ANDV-infected LECs became viable mononuclear giant cells, >4 times larger than normal, in response to VEGF-A. Giant cells are associated with constitutive mammalian target of rapamycin (mTOR) activation, and we found that both giant LECs and LEC permeability were sensitive to rapamycin, an mTOR inhibitor, and VEGF-C addition. These findings indicate that ANDV uniquely alters VEGFR2-mTOR signaling responses of LECs, resulting in giant cell and LEC permeability responses. This suggests that ANDV infection alters normal LEC and lymphatic vessel functions which may contribute to edematous fluid accumulation during HPS. Moreover, the ability of VEGF-C and rapamycin to normalize LEC responses suggests a potential therapeutic approach for reducing pulmonary edema and the severity of HPS following ANDV infection.

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