Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1beta [MIP-1beta]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.
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PMID:Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. 1268 30

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. PlGF is released from marrow erythroid cells, and serum PlGF concentrations have been reported to distinguish sickle cell patients from healthy controls. We observed that erythroid colony forming units (CFU-Es) from homozygous sickle cell (SS) patients are less sensitive to inhibition by rhgammaIFN than those from healthy controls, and the contribution of PlGF to this process was evaluated. At 10-1000-pg/mL concentrations, PlGF neither inhibits nor enhances CFU-E colony formation, and no differences were observed between the responses of SS patients or healthy controls. rhPlGF 100 pg/mL reversed the inhibitory effects of rhgammaIFN on CFU-E colony formation. rhPlGF significantly attenuated rhgammaIFN induction of the Fas ligand in an erythroid cell line (HCD57). Both HCD57 cells and CD36+ human marrow cells express Flt-1, which is a receptor for PlGF. A neutralizing antibody against Flt-1 partially attenuated the IFN-protective effect of rhPlGF, although this effect was not statistically significant. In conclusion, increased PlGF concentrations in the marrow of SS patients may protect erythroid progenitors from cytokine-induced inhibition of colony formation, and it may be a mechanism by which erythropoiesis in sickle cell disease is preserved despite concurrent inflammation.
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PMID:Placental growth factor attenuates suppression of erythroid colony formation by interferon. 1901 Feb 94

The pathophysiology of pulmonary hypertension (PHT) in sickle cell disease (SCD) is probably multifactorial. Soluble fms-like tyrosine kinase-1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. By adhering to and inhibiting VEGF and placenta growth factor, it induces endothelial dysfunction. We sought to evaluate the association of sFLT-1 with clinical complications of SCD. We confirmed that sFLT-1 was significantly elevated in SCD patients compared to healthy, race-matched control subjects. The level of sFLT-1 was significantly higher in patients with PHT, but no association was observed between sFLT-1 and the frequency of acute pain episodes or history of acute chest syndrome. sFLT-1 was correlated with various measures of haemolysis, erythropoietin and soluble vascular cell adhesion molecule-1. By inducing endothelial dysfunction, sFLT-1 may contribute to the pathogenesis of SCD-associated PHT, although this effect does not appear to be independent of haemolysis.
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PMID:Association of soluble fms-like tyrosine kinase-1 with pulmonary hypertension and haemolysis in sickle cell disease. 2122 48