Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury.

Publication Type:

Journal Article

Source:

American journal of physiology. Lung cellular and molecular physiology, Volume 302, Issue 2, p.L185-92 (2012)

Keywords:

Acute Lung Injurydigestive disease, digestive deseases Animalsdigestive disease, digestive deseases Capillary Permeabilitydigestive disease, digestive deseases Dopaminedigestive disease, digestive deseases Dopamine Antagonistsdigestive disease, digestive deseases Lipopolysaccharidesdigestive disease, digestive deseases Maledigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred BALB Cdigestive disease, digestive deseases Mice, Inbred C57BLdigestive disease, digestive deseases Mice, Knockoutdigestive disease, digestive deseases Neovascularization, Physiologicdigestive disease, digestive deseases Neutrophil Infiltrationdigestive disease, digestive deseases Neutrophilsdigestive disease, digestive deseases Nitric Oxide Synthasedigestive disease, digestive deseases Nitric Oxide Synthase Type IIIdigestive disease, digestive deseases Peroxidasedigestive disease, digestive deseases Phosphorylationdigestive disease, digestive deseases Pulmonary Edemadigestive disease, digestive deseases Receptors, Dopamine D2digestive disease, digestive deseases Signal Transductiondigestive disease, digestive deseases Vascular Endothelial Growth Factor Adigestive disease, digestive deseases Vascular Endothelial Growth Factor Receptor-2

Abstract:

The neurotransmitter dopamine and its dopamine receptor D2 (D2DR) agonists are known to inhibit vascular permeability factor/vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability. Lung injury is a clinical syndrome associated with increased microvascular permeability. However, the effects of dopamine on pulmonary edema, a phenomenon critical to the pathophysiology of both acute and chronic lung injuries, have yet to be established. Therefore, we sought to determine the potential therapeutic effects of dopamine in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Compared with sham-treated controls, pretreatment with dopamine (50 mg/kg body wt) ameliorated LPS-mediated edema formation and lowered myeloperoxidase activity, a measure of neutrophil infiltration. Moreover, dopamine significantly increased survival rates of LPS-treated mice, from 0-75%. Mechanistically, we found that dopamine acts through the VEGF-VEGFR2 axis to reduce pulmonary edema, as dopamine pretreatment in LPS-treated mice resulted in decreased serum VEGF, VEGFR2 phosphorylation, and endothelial nitric oxide synthase phosphorylation. We used D2DR knockout mice to confirm that dopamine acts through D2DR to block vascular permeability in our lung injury model. As expected, a D2DR agonist failed to reduce pulmonary edema in D2DR(-/-) mice. Taken together, our results suggest that dopamine acts through D2DR to inhibit pulmonary edema-associated vascular permeability, which is mediated through VEGF-VEGFR2 signaling and conveys protective effects in an ALI model.