Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome

Michael Opene, Joseph Kurantsin-Mills, Sumair Husain and Basil O. Ibe
Pulmonary Circulation
Vol. 4, No. 3 (September 2014), pp. 482-495
DOI: 10.1086/677363
Stable URL: http://www.jstor.org/stable/10.1086/677363
Page Count: 14
  • Download PDF
  • Add to My Lists
  • Cite this Item
Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome
We're having trouble loading this content. Download PDF instead.

Abstract

AbstractInitiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E2 (PGE2) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC4 and PGE2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC4 and PGE2 than HbAA-perfused lungs: 10.40 ± 0.62 versus 0.92 ± 0.2 ng/g dry lung weight (mean ± SEM; P = 0.0001) for LTC4. Inclusion of autologous platelets (platelet-rich plasma) elevated LTC4 production to 12.6 ± 0.96 and 7 ± 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient’s pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC4 and PGE2, both of which may contribute to onset of the acute chest syndrome in SCD.

Notes and References

This item contains 47 references.

References
  • 1.
    ['1. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structure, biosynthesis, and biological effects. Science 1987;237(4819):1171–1176.']
  • 2.
    ['2. Voelkel NF. Species variation in the pulmonary responses to arachidonic acid metabolites. Protaglandins 1985;29(5):867–889.']
  • 3.
    ['3. Morganroth ML, Stenmark KR, Zirrolli JA, Mauldin R, Mathias M, Reeves JT, Murphy RC, Voelkel NF. Leukotriene C4 production during hypoxic vasoconstriction in the isolated rat lung. Protaglandins 1984;28(6):867–875.']
  • 4.
    ['4. Hallstrand TS, Lai Y, Henderson WR Jr., Altemeier WA, Gelb MH. Epithelial regulation of eicosanoid production in asthma. Pulm Pharmacol Ther 2012;25(6):432–437.']
  • 5.
    ['5. Knight-Perry J, DeBaun MR, Strunk RC, Field JJ. Leukotriene pathway in sickle cell disease: a potential target for directed therapy. Expert Rev Hematol 2009;2(1):57–68.']
  • 6.
    ['6. Foster HR, Fuerst E, Lee TK, Cousins DJ, Woszczek G. Characterization of P2Y12 receptor responsiveness to cysteinyl leukotrienes. PLoS ONE 2013;8(3):e58305. doi:10.1371/journal.pone.0058305.']
  • 7.
    ['7. Barrrett NA, Fernandez JM, Maekawa A, Xing W, Li L, Parsons MW, Austen KF, Kanaoka Y. Cysteinyl leukotriene 2 receptor on dendritic cells negatively regulates ligand-dependent allergic pulmonary inflammation. J Immunol 2012;189(9):4556–4565.']
  • 8.
    ['8. Scoggan KA, Jakobsson PJ, Ford-Hutchinson AW. Production of leukotriene C4 in different human tissues is attributable to distinct membrane bound biosynthetic enzymes. J Biol Chem 1997;272(15):10182–10187.']
  • 9.
    ['9. Nicholson DW, Ali A, Vaillancourt JP, Calaycay JR, Mumford RA, Zamboni RJ, Ford-Hutchinson AW. Purification to homogeneity and the N-terminal sequence of human leukotriene C4 synthase: a homodimeric glutathione S-transferase composed of 18-kDa subunits. Proc Natl Acad Sci USA 1993;90(5):2015–2019.']
  • 10.
    ['10. Bhalla M, Abboud MR, McLoud TC, Shepard JO, Munden MM, Jackson SM, Beaty JR, Laver JH. Acute chest syndrome in sickle cell disease: CT evidence of microvascular occlusion. Radiology 1993;187(1):45–49.']
  • 11.
    ['11. Gray A, Anionwu EN, Davies SC, Brozovic M. Patterns of mortality in sickle cell disease in the United Kingdom. J Clin Pathol 1991;44(6):459–463.']
  • 12.
    ['12. Powars D, Weidman JA, Odom-Maryon T, Niland JC, Johnson C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine 1988;67(1):66–76.']
  • 13.
    ['13. Zennadi R, Chien A, Xu K, Batchvarova M, Telen MJ. Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium. Blood 2008;112(8):3474–3483.']
  • 14.
    ['14. Kaul DK, Finnegan E, Barabino GA. Sickle red cell–endothelium interactions. Microcirculation 2009;16(1):97–111.']
  • 15.
    ['15. Ibe BO, Kurantsin-Mills J, Raj JU, Lessin LS. Plasma and urinary leukotrienes in sickle cell disease: possible role in the inflammatory process. Eur J Clin Invest 1994;24(1):57–64.']
  • 16.
    ['16. Kurantsin-Mills J, Ibe BO, Natta CL, Raj JU, Siegel RS, Lessin LS. Elevated urinary levels of thromboxane and prostacyclin metabolites in sickle cell disease reflects activated platelets in the circulation. Br J Haematol 1994;87(3):580–585.']
  • 17.
    ['17. Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest 2000;106(3):411–420.']
  • 18.
    ['18. Haynes J. Jr., Obiako B. Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids. Am J Physiol Heart Circ Physiol 2002;282(1):H122–H130.']
  • 19.
    ['19. Ibe BO, Morris J, Kurantsin-Mills J, Raj JU. Sickle erythrocytes induce prostacyclin and thromboxane synthesis by isolated perfused lung. Am J Physiol Lung Cell Mol Physiol 1997;272(4):L597–L602.']
  • 20.
    ['20. Ibe BO, Portugal AM, Raj JU. Metabolism of platelet activating factor by intrapulmonary vascular smooth muscle cells: effect of oxygen on phospholipase A2 protein expression and activities of acetyl–CoA acetyltransferase and cholinephosphotransferase. Mol Genet Metab 2002;77(3):237–248.']
  • 21.
    ['21. Ibe BO, Abdallah MF, Portugal AM, Raj JU. Platelet-activating factor stimulates ovine foetal pulmonary vascular smooth muscle cell proliferation: role of nuclear factor-kappa B and cyclin-dependent kinases. Cell Prolif 2008;41(2):208–229.']
  • 22.
    ['22. Aquino SL, Gamsu G, Fahy JV, Claster S, Embury SH, Mentzer WC, Vichinsky EP. Chronic pulmonary disorders in sickle cell disease: findings at thin-section CT. Radiology 1994;193(3):807–811.']
  • 23.
    ['23. Kaul DK, Fabry ME, Costantini F, Rubin EM, Nagel RL. In vivo demonstration of red cell–endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse. J Clin Invest 1995;96(6):2845–2853.']
  • 24.
    ['24. Oh SO, Ibe BO, Johnson C, Kurantsin-Mills J, Raj JU. Platelet-activating factor in plasma of patients with sickle cell disease in steady state. J Lab Clin Med 1997;130(2):191–196.']
  • 25.
    ['25. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312(3):159–163.']
  • 26.
    ['26. Matsui NM, Borsig L, Rosen SD, Yaghmai M, Varki A, Embury SH. P-selectin mediates the adhesion of sickle erythrocytes to endothelium. Blood 2001;98(6):1955–1962.']
  • 27.
    ['27. Haynes J Jr., Taylor AE, Dixon D, Voelkel N. Microvascular hemodynamics in the sickle red blood cell perfused isolated rat lung. Am J Physiol Heart Circ Physiol 1993;264(2):H484–H489.']
  • 28.
    ['28. Raj JU, Toga H, Ibe BO, Anderson J. Effects of endothelin, platelet activating factor and thromboxane A2 in ferret lungs. Respir Physiol 1992;88(1–2):129–140.']
  • 29.
    ['29. Pritchard KA Jr., Ou J, Ou Z, Shi Y, Franciosi JP, Signorino, P, Kaul S, et al. Hypoxia-induced acute lung injury in murine models of sickle cell disease. Am J Physiol Lung Cell Mol Physiol 2004;286(3):L705–L714.']
  • 30.
    ['30. Setty BNY, Stuart MJ. Eicosanoids in sickle cell disease: potential relevance of neutrophil leukotriene B4 to disease pathophysiology. J Lab Clin Med 2002;139(2):80–89.']
  • 31.
    ['31. Davidson D, Drafta D. Prolonged pulmonary hypertension caused by platelet-activating factor and leukotriene C4 in the rat lung. J Appl Physiol 1992;73(3):955–961.']
  • 32.
    ['32. Daak AA, Ghebremeskel K, Elbashir MI, Bakhita A, Hassan Z, Crawford MA. Hydroxyurea therapy mobilises arachidonic acid from inner cell membrane aminophospholipids in patients with homozygous sickle cell disease. J Lipids 2011;2011:718014. doi:10.1155/2011/718014.']
  • 33.
    ['33. Lehr HA, Guhlmann A, Nolte D, Keppler D, Messmer K. Leukotrienes as mediators in ischemia-reperfusion injury in a microcirculation model in the hamster. J Clin Invest 1991;87(6):2036–2041.']
  • 34.
    ['34. Steiner DRS, Gonzalez NC, Wood JG. Leukotriene B4 promotes reactive oxidant generation and leukocyte adherence during acute hypoxia. J Appl Physiol 2001;91(3):1160–1167.']
  • 35.
    ['35. Kilfeather S. 5-lipoxygenase inhibitors for the treatment of COPD. Chest 2002;121(5 suppl.):197S–200S.']
  • 36.
    ['36. Brittain HA, Eckman JR, Swerlick RA, Howard RJ, Wick TM. Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiological flow: a potential role for platelet activation in sickle cell disease. Blood 1993;81(8):2137–2143.']
  • 37.
    ['37. Silvain J, Pena A, Cayla G, Brieger D, Bellemain-Appaix A, Chastre T, Vignalou J-B, et al. Impact of red blood cell transfusion on platelet aggregation in healthy volunteers: results of the TRANSFUSION study. Eur Heart J 2010;31(22):2816–2821.']
  • 38.
    ['38. Vallés J, Santos MT, Aznar J, Martínez M, Moscardó A, Piñón M, Broekman MJ, Marcus AJ. Platelet-erythrocyte interactions enhance αIIbβ3 integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood 2002;99(11):3978–3984.']
  • 39.
    ['39. Nobili E, Salvado MD, Folkersen L, Castiglione L, Kastrup J, Watterholm A, Tremoli E, et al. Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease. PLoS ONE 2012;7(7):e41786. doi:10.1371/journal.pone.0041786.']
  • 40.
    ['40. Dassé Séry R, N’guessan K, Akré Dagra P, Yao R, Sombo Mambo F. Pulmonary events induced by non-steroidal anti-inflammatory drugs in patients with sickle cell disease [in French]. Sante 2011;21(4):187–191.']
  • 41.
    ['41. Ong HT, Ong LM, Tan TE, Chean KY. Cardiovascular effects of common analgesics. Med J Malays 2013;68(2):189–194.']
  • 42.
    ['42. Lang PA, Kasinathan RS, Brand VB, Duranton C, Lang C, Koka S, Shumilina E, et al. Accelerated clearance of Plasmodium-infected erythrocytes in sickle cell trait and annexin-A7 deficiency. Cell Physiol Biochem 2009;24(5–6):415–428.']
  • 43.
    ['43. Kaul DK, Zhang X, Dasgupta T, Fabry ME. Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress. Am J Physiol Heart Circ Physiol 2008;295(1):H39–H47.']
  • 44.
    ['44. Kaul DK, Liu X-d, Chang H-Y, Nagel RL, Fabry ME. Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. J Clin Invest 2004;114(8):1136–1143.']
  • 45.
    ['45. Field JJ, DeBaun MR. Asthma and sickle cell disease: two distinct diseases or part of the same process? Hematology 2009;2009:45–53.']
  • 46.
    ['46. Newaskar M, Hardy KA, Morris CR. Asthma in sickle cell disease. Sci World J 2011;11:1138–1152.']
  • 47.
    ['47. Machado RF, Gladwin MT. Chronic sickle cell lung disease: new insights into the diagnosis pathogenesis and treatment of pulmonary hypertension. Brit J Haematol 2005;129(4):449–464.']