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Elevated levels of placental growth factor represent an adaptive host response in sepsis.

Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, Aird WC - J. Exp. Med. (2008)

Bottom Line: Belikoff, J.The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF.In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation.

View Article: PubMed Central - PubMed

Affiliation: The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

ABSTRACT
Recently, we demonstrated that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are increased in sepsis (Yano, K., P.C. Liaw, J.M. Mullington, S.C. Shih, H. Okada, N. Bodyak, P.M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. 2006. J. Exp. Med. 203:1447-1458). Moreover, enhanced VEGF/Flk-1 signaling was shown to contribute to sepsis morbidity and mortality. We tested the hypothesis that PlGF also contributes to sepsis outcome. In mouse models of endotoxemia and cecal ligation puncture, the genetic absence of PlGF or the systemic administration of neutralizing anti-PlGF antibodies resulted in higher mortality compared with wild-type or immunoglobulin G-injected controls, respectively. The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF. In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation. Mortality of endotoxemic PlGF-deficient mice was increased by Ad-mediated overexpression of VEGF and was blocked by expression of soluble Flt-1. Collectively, these data suggest that up-regulation of PlGF in sepsis is an adaptive host response that exerts its benefit, at least in part, by attenuating VEGF signaling.

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Effect of PlGF deficiency on liver phenotype in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Blood samples were taken at 24 h and assayed for plasma levels of alanine aminotransferase (ALT). (B) The liver was removed at 24 h and assayed for MPO activity. (C) The liver was removed at 24 h and stained for CD45. Data in A and B are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice. Bar, 50 μm.
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fig5: Effect of PlGF deficiency on liver phenotype in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Blood samples were taken at 24 h and assayed for plasma levels of alanine aminotransferase (ALT). (B) The liver was removed at 24 h and assayed for MPO activity. (C) The liver was removed at 24 h and stained for CD45. Data in A and B are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice. Bar, 50 μm.

Mentions: The results described in the previous three sections suggest that PlGF deficiency is associated with disproportionate endotoxemia-mediated changes in the liver, including sustained elevation of VEGF, increased permeability, and higher expression of activation markers. Based on these findings, we wished to further explore the effect of PlGF deficiency on the liver phenotype. Alanine aminotransferase, a measure of liver damage, was increased in PlGF−/− versus wild-type controls (wild-type, 63.3 ± 35.1 U/liter; PlGF−/−, 223.3 ± 92.9 U/liter; Fig. 5 A). Moreover, endotoxemia resulted in significantly greater myeloperoxidase (MPO) activity in the liver of PlGF−/− versus wild-type controls (Fig. 5 B). Consistent with these latter findings, CD45 staining demonstrated increased leukocyte infiltration in the liver of PlGF−/− compared with wild-type endotoxemic mice (Fig. 5 C). In contrast to the findings in the liver, MPO activity in the lung did not differ between endotoxemia wild-type and PlGF−/− mice (unpublished data).


Elevated levels of placental growth factor represent an adaptive host response in sepsis.

Yano K, Okada Y, Beldi G, Shih SC, Bodyak N, Okada H, Kang PM, Luscinskas W, Robson SC, Carmeliet P, Karumanchi SA, Aird WC - J. Exp. Med. (2008)

Effect of PlGF deficiency on liver phenotype in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Blood samples were taken at 24 h and assayed for plasma levels of alanine aminotransferase (ALT). (B) The liver was removed at 24 h and assayed for MPO activity. (C) The liver was removed at 24 h and stained for CD45. Data in A and B are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice. Bar, 50 μm.
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Related In: Results  -  Collection

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fig5: Effect of PlGF deficiency on liver phenotype in a mouse model of endotoxemia. PLGF+/+ (WT) or PLGF−/− (KO) male mice were injected i.p. with or without 16 mg/kg LPS. (A) Blood samples were taken at 24 h and assayed for plasma levels of alanine aminotransferase (ALT). (B) The liver was removed at 24 h and assayed for MPO activity. (C) The liver was removed at 24 h and stained for CD45. Data in A and B are expressed as means + SD of three independent experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.0001 compared with untreated controls (and where indicated between PlGF-deficient and wild-type mice. Bar, 50 μm.
Mentions: The results described in the previous three sections suggest that PlGF deficiency is associated with disproportionate endotoxemia-mediated changes in the liver, including sustained elevation of VEGF, increased permeability, and higher expression of activation markers. Based on these findings, we wished to further explore the effect of PlGF deficiency on the liver phenotype. Alanine aminotransferase, a measure of liver damage, was increased in PlGF−/− versus wild-type controls (wild-type, 63.3 ± 35.1 U/liter; PlGF−/−, 223.3 ± 92.9 U/liter; Fig. 5 A). Moreover, endotoxemia resulted in significantly greater myeloperoxidase (MPO) activity in the liver of PlGF−/− versus wild-type controls (Fig. 5 B). Consistent with these latter findings, CD45 staining demonstrated increased leukocyte infiltration in the liver of PlGF−/− compared with wild-type endotoxemic mice (Fig. 5 C). In contrast to the findings in the liver, MPO activity in the lung did not differ between endotoxemia wild-type and PlGF−/− mice (unpublished data).

Bottom Line: Belikoff, J.The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF.In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation.

View Article: PubMed Central - PubMed

Affiliation: The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

ABSTRACT
Recently, we demonstrated that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are increased in sepsis (Yano, K., P.C. Liaw, J.M. Mullington, S.C. Shih, H. Okada, N. Bodyak, P.M. Kang, L. Toltl, B. Belikoff, J. Buras, et al. 2006. J. Exp. Med. 203:1447-1458). Moreover, enhanced VEGF/Flk-1 signaling was shown to contribute to sepsis morbidity and mortality. We tested the hypothesis that PlGF also contributes to sepsis outcome. In mouse models of endotoxemia and cecal ligation puncture, the genetic absence of PlGF or the systemic administration of neutralizing anti-PlGF antibodies resulted in higher mortality compared with wild-type or immunoglobulin G-injected controls, respectively. The increased mortality associated with genetic deficiency of PlGF was reversed by adenovirus (Ad)-mediated overexpression of PlGF. In the endotoxemia model, PlGF deficiency was associated with elevated circulating levels of VEGF, induction of VEGF expression in the liver, impaired cardiac function, and organ-specific accentuation of barrier dysfunction and inflammation. Mortality of endotoxemic PlGF-deficient mice was increased by Ad-mediated overexpression of VEGF and was blocked by expression of soluble Flt-1. Collectively, these data suggest that up-regulation of PlGF in sepsis is an adaptive host response that exerts its benefit, at least in part, by attenuating VEGF signaling.

Show MeSH
Related in: MedlinePlus