Impaired pulmonary defense against Pseudomonas aeruginosa in VEGF gene inactivated mouse lung.
Repeated bacterial and viral infections are known to contribute to worsening lung function in several respiratory diseases, including asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). Previous studies have reported alveolar wall cell apoptosis and parenchymal damage in adult pulmonary VEGF gene ablated mice. We hypothesized that VEGF expressed by type II cells is also necessary to provide an effective host defense against bacteria in part by maintaining surfactant homeostasis. Therefore, Pseudomonas aeruginosa (PAO1) levels were evaluated in mice following lung-targeted VEGF gene inactivation, and alterations in VEGF-dependent type II cell function were evaluated by measuring surfactant homeostasis in mouse lungs and isolated type II cells. In VEGF-deficient lungs increased PAO1 levels and pro-inflammatory cytokines, TNFα and IL-6, were detected 24 h after bacterial instillation compared to control lungs. In vivo lung-targeted VEGF gene deletion (57% decrease in total pulmonary VEGF) did not alter alveolar surfactant or tissue disaturated phosphatidylcholine (DSPC) levels. However, sphingomyelin content, choline phosphate cytidylyltransferase (CCT) mRNA, and SP-D expression were decreased. In isolated type II cells an 80% reduction of VEGF protein resulted in decreases in total phospholipids (PL), DSPC, DSPC synthesis, surfactant associated proteins (SP)-B and -D, and the lipid transporters, ABCA1 and Rab3D. TPA-induced DSPC secretion and apoptosis were elevated in VEGF-deficient type II cells. These results suggest a potential protective role for type II cell-expressed VEGF against bacterial initiated infection.
Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623, USA. ebreen@ucsd.edu
Ellen C
EC
Breen
Jaret L
JL
Malloy
Kechun
K
Tang
Feng
F
Xia
Zhenxing
Z
Fu
Robert E W
RE
Hancock
Joerg
J
Overhage
Peter D
PD
Wagner
Roger G
RG
Spragg
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000818:Animals; D019916:Choline-Phosphate Cytidylyltransferase / Q000032:analysis; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D005260:Female; D020868:Gene Silencing; D008168:Lung / Q000737:chemistry; D008171:Lung Diseases / Q000235:genetics* / Q000382:microbiology*; D008297:Male; D051379:Mice; D010713:Phosphatidylcholines / Q000032:analysis; D010743:Phospholipids / Q000032:analysis; D011552:Pseudomonas Infections / Q000235:genetics*; D011550:Pseudomonas aeruginosa; D011663:Pulmonary Surfactants / Q000032:analysis; D013109:Sphingomyelins / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D020692:rab3 GTP-Binding Proteins / Q000032:analysis
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D010713:Phosphatidylcholines; D010743:Phospholipids; D011663:Pulmonary Surfactants; D013109:Sphingomyelins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019916:Choline-Phosphate Cytidylyltransferase; C116711:Rab3d protein, mouse; D020692:rab3 GTP-Binding Proteins