Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury.
Capillary leakage and alveolar edema are hallmarks of acute lung injury (ALI). Neutrophils and serum macromolecules enter alveoli, promoting inflammation. Vascular endothelial growth factor (VEGF) causes plasma leakage in extrapulmonary vessels. Angiopoietin (Ang)-1 and -4 stabilize vessels, attenuating capillary leakage. We hypothesized that VEGF and Ang-1 and -4 modulate vessel leakage in the lung, contributing to the pathogenesis of ALI. We examined a murine model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 and 129/J mice were studied at baseline and 24, 48, and 96 h after single or multiple doses of aerosolized LPS. Both strains exhibited time- and dose-dependent increases in inflammation and a deterioration of lung mechanics. Bronchoalveolar lavage (BAL) protein levels increased significantly, suggesting capillary leakage. Increased BAL neutrophil and total protein content correlated with time-dependent increased tissue VEGF and decreased Ang-1 and -4 levels, with peak VEGF and minimum Ang-1 and -4 expression after 96 h of LPS challenge. These data suggest that changes in the balance between VEGF and Ang-1 and -4 after LPS exposure may modulate neutrophil influx, protein leakage, and alveolar flooding during early ALI.
Karmpaliotis
Dimitrios
D
Division of Pulmonary and Critical Care Medicine, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02364, USA.
Kosmidou
Ioanna
I
Ingenito
Edward P
EP
Hong
Kailin
K
Malhotra
Atul
A
Sunday
Mary E
ME
Haley
Kathleen J
KJ
D000208:Acute Disease; D042683:Angiopoietin-1; D042682:Angiopoietins; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002452:Cell Count; D016207:Cytokines / Q000032:analysis; D016228:Endothelial Growth Factors / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008171:Lung Diseases / Q000503:physiopathology*; D008222:Lymphokines / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009330:Nebulizers and Vaporizers; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D042683:Angiopoietin-1; D042682:Angiopoietins; C467628:Angpt1 protein, mouse; D016207:Cytokines; D016228:Endothelial Growth Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008222:Lymphokines; D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C118117:angiopoietin 4