Placenta growth factor induces 5-lipoxygenase–activating protein to increase leukotriene formation in sickle cell disease

Abstract

IntroductionInflammation is increasingly recognized as central to the pathophysiology of sickle cell disease (SCD) and is manifest as leukocytosis, elevated levels of inflammatory cytokines, and activation of neutrophils, monocytes, and endothelial cells. [1][2][3][4] It is present at steady state and is strongly associated with acute painful events, acute chest, and early mortality. 5,6 Current evidence strongly suggests that inflammation contributes to the endothelial cell dysfunction, potentiates vasoocclusion, and may also give rise to the airway hyperreactivity (AH) that often accompanies SCD. [7][8][9][10] Also intriguing is the spectrum of lung disease seen in this patient population, which spans from an increased incidence of AH and obstructive lung disease in children, [11][12][13] to restrictive lung disease and pulmonary vascular remodeling, which is associated with pulmonary hypertension in adults. [14][15][16][17][18] Leukotrienes (LT) mediate both inflammation and AH. 19-22 5-Lipoxygenase (5-LO) and its activating partner, 5-lipoxygenase activating protein (FLAP), catalyze the production of LT from arachidonic acid (AA) by generating 5-hydroperoxyeicostatraenoic acid (5-HPETE) and leukotriene A 4 (LTA 4 ). LTA 4 is the pivotal intermediate from which other LTs (ie, LTB 4 and cysteinyl LT [CysLT], LTC 4 , LTD 4 , and LTE 4 ) are formed. 20 LTB 4 is one of the most potent chemoattractant for neutrophils, eosinophils, and mediator of inflammation. CysLT, on the other hand, are potent bronchoconstrictors that play an important role in edema, inflammation, and mucus secretion in asthma and were previously termed "slow releasing substances." 23 LT play an important role in the pathogenesis of inflammatory disorders, specifically asthma, rheumatoid arthritis, and inflammatory bowel disease. [19][20][21] Studies by Bigby and coworkers 24,25 have shown that both tumor necrosis factor-␣ (TNF-␣) and lipopolysaccharide (LPS) induce the expression of FLAP in THP-1 cells. These studies showed the importance of nuclear factor-B (NF-B) and CCAAT/enhancer binding protein (C/EBP) transcription factors in the LPS-mediated FLAP expression. 24 LTB 4 levels are higher in SCD patients at steady state, which are further increased in vasoocclusive pain crises (VOC) and acute chest syndrome (ACS). 26 Very recently, increased LTE 4 has been observed in patients with SCD, which is associated with a higher incidence of pain. 27 However, less is understood about how LTs are increased in SCD at the molecular level.Placenta growth factor (PlGF) is an angiogenic growth factor with similar effects on endothelium as vascular endothelial growth factor (VEGF) and is primarily expressed by placental trophoblasts. [28][29][30] More recently, we and others show that erythroid cells, but not other hematopoietic cells, produce PlGF, and its expression is high in SCD and thalassemia. 31,32 VEGFR1 is its cognate receptor and is expressed on endothelial cells, alveolar epithelial cells, mast cells, and monocytes. We have previously shown that...

Placenta Growth Factor-induced Early Growth Response 1 (Egr-1) Regulates Hypoxia-inducible Factor-1α (HIF-1α) in Endothelial Cells

“…S1B) were significantly reduced by pharmacological inhibitors of HIF-1␣, phosphoinositide 3-kinase (PI3K), and NADPH oxidase (description of inhibitors provided in supplemental Table S1). Taken together, our results showed that PlGF-mediated FLAP expression required activation of PI3K, NADPH oxidase, and HIF-1␣ in HPMVEC as observed previously in monocytes (13).…”

“…Previously, we showed that plasma levels of placenta growth factor (PlGF) are higher in SCD subjects compared with healthy individuals and correlate with increased incidence of vaso-occlusive events (12). In our recent studies, we show that PlGF increases mRNA expression of both hypoxia-inducible factor-1 (HIF-1␣) and FLAP in monocytic cells (13).…”

“…However, the degradation of HIF-1␣ is prevented under hypoxic conditions, resulting in its accumulation and translocation to the nucleus where it forms active heterodimers with HIF-1␤ leading to transcription of hypoxia-related genes (16). Recently, we showed that up-regulation of HIF-1␣ mRNA levels in response to PlGF was independent of hypoxia both in endothelial cells and monocytes (13,17). However, the molecular mechanisms of PlGF-mediated elevation in HIF-1␣ expression are not yet studied.…”

“…Because transcriptional activation can be cell-and tissue-sensitive, we examined whether PlGF-mediated FLAP expression in HPMVEC involved the same set of transcription factors as was observed in THP-1 monocytic cells and peripheral blood monocytes (13). We used WT Ϫ371FLAP-Luc and different mutant constructs as described previously (13).…”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…Further data also indicate that erythroid PlGF aggravates inflammation and airway hyperreactivity in SCD via production of proinflammatory leukotriene (Patel et al 2009;.…”