Genetic delivery of bevacizumab to suppress vascular endothelial growth factor-induced high-permeability pulmonary edema

Masaki Watanabe, Julie L. Boyer, Ronald Crystal

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

High-permeability pulmonary edema causing acute respiratory distress syndrome is associated with high mortality. Using a model of intratracheal adenovirus (Ad)-mediated overexpression of human vascular endothelial growth factor (VEGF)-A165 in mouse lung to induce alveolar permeability and consequent pulmonary edema, we hypothesized that systemic administration of a second adenoviral vector expressing an anti-VEGF antibody (AdαVEGFAb) would protect the lung from pulmonary edema. Pulmonary edema was induced in mice by intratracheal administration of AdVEGFA165. To evaluate anti-VEGF antibody therapy, the mice were treated intravenously with AdαVEGFAb, an adenoviral vector encoding the light and heavy chains of an anti-human VEGF antibody with the bevacizumab (Avastin) antigen-binding site. Lung VEGF-A165 and phosphorylated VEGF receptor (VEGFR)-2 levels, histology, lung wet-to-dry weight ratios, and bronchoalveolar lavage fluid (BALF) levels of total protein were assessed. Administration of AdαVEGFAb to mice decreased AdVEGFA165-induced levels of human VEGF-A165 and phosphorylated VEGFR-2 in the lung. Histological analysis of AdαVEGFAb-treated mice demonstrated a reduction of edema fluid in the lung tissue that correlated with a reduction of lung wet-to-dry ratios and BALF total protein levels. Importantly, administration of AdαVEGFAb 48hr after induction of pulmonary edema with AdVEGFA165 was effective in suppressing pulmonary edema. Administration of an adenoviral vector encoding an anti-VEGF antibody that is the equivalent of bevacizumab effectively suppresses VEGF-A165-induced high-permeability pulmonary edema, suggesting that anti-VEGF antibody therapy may represent a novel therapy for high-permeability pulmonary edema.

Original languageEnglish
Pages (from-to)598-610
Number of pages13
JournalHuman Gene Therapy
Volume20
Issue number6
DOIs
Publication statusPublished - 1 Jun 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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