Functions of Type II Pneumocyte-Derived Vascular Endothelial Growth Factor in Alveolar Structure, Acute Inflammation, and Vascular Permeability

Abstract

Vascular endothelial growth factor-A (VEGF) is a potent regulator of vascular permeability, inflammatory response, and cell survival in the lung. To explore the functions of VEGF produced locally in type II pneumocytes, we generated mice with a conditional deletion of VEGF-A using Cre recombinase driven by the human surfactant protein C (SPC) promoter. In 7-to 10-week-old VEGF-knockout (SPC-VEGF-KO) mice, lung histology and physiology were essentially normal, except for higher dynamic lung compliance and lower pulmonary vascular permeability. Emphysema was seen in 28-to 32-week-old animals. To investigate the role of type II pneumocyte-derived VEGF in acute lung injury, we challenged 7-to 10-week-old SPC-VEGF-KO mice and their wild-type littermates with intestinal ischemia-reperfusion. Bronchoalveolar lavage fluid total cell count, pulmonary permeability, and lung injury score were significantly attenuated, and total lung VEGF levels were significantly lower in SPC-VEGF-KO mice compared with wild-type controls. In SPC-VEGF-KO mice, activated caspase 3-positive type II epithelial cells were increased after intestinal ischemia-reperfusion, even though there was no significant difference in the total number of cells positive for terminal deoxynucleotidyl transferase dUTP nick-end labeling. We conclude that VEGF in type II cells helps protect alveolar epithelial cells from caspase-dependent apoptosis. However, VEGF produced from type II cells may contribute to increased vascular permeability during acute lung injury. (Am J

CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema

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Impaired Lung 123I-MIBG Uptake on SPECT in Pulmonary Emphysema

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Unsuspected effects of a lung‐specific cre deleter mouse line

“…A second transgenic mouse line carrying a similar Sftpc-cre transgene has also been generated in order to be breed with a Vegf conditional mutant mouse line (Mura et al, 2010). According to the data reported, the lungs of 7-to 10-week-old Vegf fl/fl ; Sftpc-cre 1 mutant mice showed normal appearance and histology, indicating no detectable deleterious effect of this Cre transgene.…”

“…This second Sftpc-cre mouse strain was established in the ICR genetic background. The difference in behavior of the two transgenic lines can either be due to variation in the genetic background, or more likely, to distinct random integration event of the transgene in the genome that can affect transgene expression levels (Matthaei, 2007;Mura et al, 2010;Okudo et al, 2005).…”