Lipoxins (LXs) and their analogues are known to display potent anti-inflammatory actions. Previously, we reported that lipoxin A4 (LXA4) possessed powerful anti-inflammatory properties in acute pancreatitis in rats and that it may ameliorate the concomitant acute lung injury by reducing cytokine generation and inhibiting neutrophil activation. Considering that the vascular endothelium plays an important role during adherence, migration and activation of leukocytes, the present study was designed to investigate the effects of LXA4 on the inflammatory response induced by tumor necrosis factor α (TNF-α) in human pulmonary microvascular endothelial cells (HPMECs) and explore the potential mechanisms involved in these processes. We found that LXA4 markedly down-regulated the expression of monocyte chemotactic protein-1 (MCP-1), E-selectin, and interleukin-6 (IL-6) mRNA, as well as intercellular adhesion molecule-1 (ICAM-1) in TNF-α-exposed HPMECs. Moreover, LXA4 inhibited the phosphorylation and nuclear translocation of nuclear factor-κB/p65 (NF-κB/p65) and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) in HPMECs following TNF-α stimulation. Heme oxygenase-1 (HO-1), a cytoprotective enzyme, was up-regulated by LXA4 in both non- and TNF-α-stimulated HPMECs. In conclusion, the protective effects of LXA4 to ALI may be executed through inhibition inflammation pathways of NF-κB and p38 MAPK and up-regulation of cytoprotective HO-1.
ShieldsCJWinterDCRedmondHP. Lung injury in acute pancreatitis: mechanisms, prevention, and therapy. Curr Opin Crit Care2002; 8: 158–63.
2.
De CamposTDereeJCoimbraR. From acute pancreatitis to end-organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt)2007; 8: 107–20.
3.
ZhouMTChenCSChenBCZhangQYAnderssonR. Acute lung injury and ARDS in acute pancreatitis: mechanisms and potential intervention. World J Gastroentero2010; 16: 2094–99.
4.
LundbergAHGrangerNRussellJCallicuttSGaberLWKotbMSabekOGaberAO. Temporal correlation of tumor necrosis factor-alpha release, upregulation of pulmonary ICAM-1 and VCAM-1, neutrophil sequestration, and lung injury in diet-induced pancreatitis. J Gastrointest Surg2000; 4: 248–57.
5.
CallicuttCSSabekOFukatsuKLundbergAHGaberLWilcoxHKotbMGaberAO. Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis. Surgery2003; 133: 186–96.
6.
LundbergAHGrangerDNRussellJSabekOHenryJGaberLKotbMGaberAO. Quantitative measurement of P- and E-selectin adhesion molecules in acute pancreatitis: correlation with distant organ injury. Ann Surg2000; 231: 213–22.
7.
PanesJGrangerDN. Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease. Gastroenterology1998; 114: 1066–90.
8.
De BeauxACFearonKC. Circulating endotoxin, tumour necrosis factor-alpha, and their natural antagonists in the pathophysiology of acute pancreatitis. Scand J Gastroenterol Suppl1996; 219: 43–6.
9.
SerhanCN. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids2005; 73: 141–62.
10.
HachichaMPouliotMPetasisNASerhanCN. Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1alpha-initiated neutrophil responses and trafficking: regulators of a cytokine-chemokine axis. J Exp Med1999; 189: 1923–30.
11.
ScaliaRGefenJPetasisNASerhanCNLeferAM. Lipoxin A4 stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: role of P-selectin. Proc Natl Acad Sci USA1997; 94: 9967–72.
12.
BakerNO'MearaSJScannellMMadernaPGodsonC. Lipoxin A4: anti-inflammatory and anti-angiogenic impact on endothelial cells. J Immunol2009; 182: 3819–26.
13.
SerhanCN. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution. Prostaglandins Other Lipid Mediat2002; 68-69: 433–55.
14.
ZhouMTChenBCSunHWDengZXAnderssonRZhangQY. The protective effects of Lipoxin A4 during the early phase of severe acute pancreatitis in rats. Scand J Gastroenterol2011; 46: 211–19.
15.
Cook-MillsJMDeemTL. Active participation of endothelial cells in inflammation. J Leukoc Biol2005; 77: 487–95.
16.
TakahashiTHatoFYamaneTFukumasuHSuzukiKOgitaSNishizawaYKitagawaS. Activation of human neutrophil by cytokine-activated endothelial cells. Circ Res2001; 88: 422–29.
17.
ZhangXWuDJiangX. Icam-1 and acute pancreatitis complicated by acute lung injury. JOP2009; 10: 8–14.
18.
SuXAoLZouNSongYYangXCaiGYFullertonDAMengX. Post-transcriptional regulation of TNF-induced expression of ICAM-1 and IL-8 in human lung microvascular endothelial cells: an obligatory role for the p38 MAPK-MK2 pathway dissociated with HSP27. Biochim Biophys Acta2008; 1783: 1623–31.
19.
PanLLLiuXHGongQHWuDZhuYZ. Hydrogen sulfide attenuated tumor necrosis factor-alpha-induced inflammatory signaling and dysfunction in vascular endothelial cells. PLoS One2011; 6: e19766–e19766.
20.
Nascimento-SilvaVArrudaMABarja-FidalgoCVillelaCGFierroIM. Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells. Am J Physiol Cell Physiol2005; 289: C557–63.
21.
FrossardJLLengletSMontecuccoFSteffensSGalanKPelliGSpahrLMachFHadengueA. Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. J Clin Pathol2011; 64: 387–93.
22.
MandiYNagyZOcsovskiIFarkasG. Effects of tumor necrosis factor and pentoxifylline on ICAM-1 expression on human polymorphonuclear granulocytes. Int Arch Allergy Immunol1997; 114: 329–35.
LeserHGGrossVScheibenbogenCHeinischASalmRLausenMRuckauerKAndreesenRFarthmannEHScholmerichJ. Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis. Gastroenterology1991; 101: 782–85.
25.
WangYPWuYLiLYZhengJLiuRGZhouJPYuanSYShangYYaoSL. Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-kappaB and MAPKs in BV-2 microglial cells. J Neuroinflamm2011; 8: 95–95.
26.
WuSHLiaoPYDongLChenZQ. Signal pathway involved in inhibition by lipoxin A(4) of production of interleukins induced in endothelial cells by lipopolysaccharide. Inflamm Res2008; 57: 430–37.
ViatourPMervilleMPBoursVChariotA. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci2005; 30: 43–52.
29.
ZhongHSuYangHErdjument-BromageHTempstPGhoshS. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell1997; 89: 413–24.
30.
JozsefLZoukiCPetasisNASerhanCNFilepJG. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-kappa B and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc Natl Acad Sci USA2002; 99: 13266–71.
31.
KureINishiumiSNishitaniYTanoueTIshidaTMizunoMFujitaTKutsumiHAritaMAzumaTYoshidaM. Lipoxin A(4) reduces lipopolysaccharide-induced inflammation in macrophages and intestinal epithelial cells through inhibition of nuclear factor-kappaB activation. J Pharmacol Exp Ther2010; 332: 541–48.
32.
OhiraTBannenbergGAritaMTakahashiMGeQVan DykeTEStahlGLSerhanCNBadweyJA. A stable aspirin-triggered lipoxin A4 analog blocks phosphorylation of leukocyte-specific protein 1 in human neutrophils. J Immunol2004; 173: 2091–98.
33.
GorskaMMLiangQStaffordSJGoplenNDharajiyaNGuoLSurSGaestelMAlamR. MK2 controls the level of negative feedback in the NF-kappaB pathway and is essential for vascular permeability and airway inflammation. J Exp Med2007; 204: 1637–52.
34.
AbrahamNGLinJHMitrioneSMSchwartzmanMLLevereRDShibaharaS. Expression of heme oxygenase gene in rat and human liver. Biochem Biophys Res Commun1988; 150: 717–22.
35.
WillisDMooreARFrederickRWilloughbyDA. Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med1996; 2: 87–90.
36.
WagenerFAda SilvaJLFarleyTde WitteTKappasAAbrahamNG. Differential effects of heme oxygenase isoforms on heme mediation of endothelial intracellular adhesion molecule 1 expression. J Pharmacol Exp Ther1999; 291: 416–23.
37.
HayashiSTakamiyaRYamaguchiTMatsumotoKTojoSJTamataniTKitajimaMMakinoNIshimuraYSuematsuM. Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ Res1999; 85: 663–71.
38.
FreitasAAlves-FilhoJCSeccoDDNetoAFFerreiraSHBarja-FidalgoCCunhaFQ. Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation. Br J Pharmacol2006; 149: 345–54.
39.
VachharajaniTJWorkJIssekutzACGrangerDN. Heme oxygenase modulates selectin expression in different regional vascular beds. Am J Physiol Heart Circ Physiol2000; 278: H1613–17.
