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Annals of Hematology

, Volume 98, Issue 4, pp 841–849 | Cite as

Inhaled steroids associated with decreased macrophage markers in nonasthmatic individuals with sickle cell disease in a randomized trial

  • Arielle L. Langer
  • Andrew Leader
  • Seunghee Kim-Schulze
  • Yelena Ginzburg
  • Miriam Merad
  • Jeffrey GlassbergEmail author
Original Article

Abstract

Inhaled mometasone was shown to improve pain scores and decrease soluble vascular cell adhesion molecule (sVCAM) concentration in a randomized controlled trial of nonasthmatic patients with sickle cell disease. We sought to explore potential changes in systemic inflammation as a mechanism underlying this effect. Serum samples from 41 trial participants (15 placebo- and 26 mometasone-treated) were analyzed using a 92 inflammatory marker panel at baseline and after 8 weeks of mometasone therapy. Individual marker analysis and correlation analysis were conducted. Adjusted for age, the mometasone-treated group decreased the concentration of CXCL9, CXCL11, CD40, IL-10, and IL-18 relative to placebo-treated participants. Hierarchical clustering and correlation analysis identified additional evidence for a decrease in cytokines linking to macrophage signaling and migration. There was no statistically significant change in markers of asthma and allergy, indicating that the improvement was unlikely mediated by modulation of occult reactive airway disease. This analysis of inflammatory markers suggests that decrease in macrophage activity may be involved in the mediation of the clinical benefit seen with use of inhaled mometasone in nonasthmatic patients with sickle cell disease.

Trial registration: clinicaltrials.gov identifier: NCT02061202.

Keywords

Sickle cell disease Macrophage activation Hemoglobinopathies Inhaled corticosteroids 

Notes

Acknowledgments

The authors would like to thank Jason Connor and Wil Meurer for Bayesian statistical support and Alexa Punzalan for trial oversight and execution.

Funding

This study was funded by the National Heart, Lung and Blood Institute (IND #117997).

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflicts of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individuals included in the study.

Supplementary material

277_2019_3635_MOESM1_ESM.docx (88 kb)
ESM 1 (DOCX 88 kb)

References

  1. 1.
    van Tuijn CFJ, Schimmel M, van Beers EJ, Nur E, Biemond BJ (2017) Prospective evaluation of chronic organ damage in adult sickle cell patients: a seven-year follow-up study. Am J Hematol 92(10):E584–E590.  https://doi.org/10.1002/ajh.24855 CrossRefGoogle Scholar
  2. 2.
    Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W (1989) Mortality in children and adolescents with sickle cell disease. Cooperative study of sickle cell disease. Pediatrics 84(3):500–508Google Scholar
  3. 3.
    Nandedkar SD, Feroah TR, Hutchins W, Weihrauch D, Konduri KS, Wang J, Strunk RC, DeBaun MR, Hillery CA, Pritchard KA (2008) Histopathology of experimentally induced asthma in a murine model of sickle cell disease. Blood 112(6):2529–2538.  https://doi.org/10.1182/blood-2008-01-132506 CrossRefGoogle Scholar
  4. 4.
    Pritchard KA Jr, Feroah TR, Nandedkar SD, Holzhauer SL, Hutchins W, Schulte ML, Strunk RC, Debaun MR, Hillery CA (2012) Effects of experimental asthma on inflammation and lung mechanics in sickle cell mice. Am J Respir Cell Mol Biol 46(3):389–396.  https://doi.org/10.1165/rcmb.2011-0097OC CrossRefGoogle Scholar
  5. 5.
    Andemariam B, Adami AJ, Singh A, McNamara JT, Secor ER, Guernsey LA, Thrall RS (2015) The sickle cell mouse lung: proinflammatory and primed for allergic inflammation. Transl Res 166(3):254–268.  https://doi.org/10.1016/j.trsl.2015.03.001 CrossRefGoogle Scholar
  6. 6.
    Stuart J, Stone PC, Akinola NO, Gallimore JR, Pepys MB (1994) Monitoring the acute phase response to vaso-occlusive crisis in sickle cell disease. J Clin Pathol 47(2):166–169CrossRefGoogle Scholar
  7. 7.
    Holtzclaw JD, Jack D, Aguayo SM, Eckman JR, Roman J, Hsu LL (2004) Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice. Am J Respir Crit Care Med 169(6):687–695.  https://doi.org/10.1164/rccm.200302-224OC CrossRefGoogle Scholar
  8. 8.
    Torres LS, Okumura JV, Silva DG, Mimura KK, Belini-Junior E, Oliveira RG, Lobo CL, Oliani SM, Bonini-Domingos CR (2016) Inflammation in sickle cell disease: differential and down-expressed plasma levels of annexin A1 protein. PLoS One 11(11):e0165833.  https://doi.org/10.1371/journal.pone.0165833 CrossRefGoogle Scholar
  9. 9.
    Duits AJ, Pieters RC, Saleh AW, van Rosmalen E, Katerberg H, Berend K, Rojer RA (1996) Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific increment during vasoocclusive crisis. Clin Immunol Immunopathol 81(1):96–98CrossRefGoogle Scholar
  10. 10.
    Sakhalkar VS, Rao SP, Weedon J, Miller ST (2004) Elevated plasma sVCAM-1 levels in children with sickle cell disease: impact of chronic transfusion therapy. Am J Hematol 76(1):57–60.  https://doi.org/10.1002/ajh.20016 CrossRefGoogle Scholar
  11. 11.
    Shiu YT, Udden MM, McIntire LV (2000) Perfusion with sickle erythrocytes up-regulates ICAM-1 and VCAM-1 gene expression in cultured human endothelial cells. Blood 95(10):3232–3241Google Scholar
  12. 12.
    Setty BN, Stuart MJ (1996) Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 88(6):2311–2320Google Scholar
  13. 13.
    Keegan PM, Surapaneni S, Platt MO (2012) Sickle cell disease activates peripheral blood mononuclear cells to induce cathepsins k and v activity in endothelial cells. Anemia 2012:201781–201787.  https://doi.org/10.1155/2012/201781 CrossRefGoogle Scholar
  14. 14.
    Rodrigues L, Costa FF, Saad ST, Grotto HZ (2006) High levels of neopterin and interleukin-3 in sickle cell disease patients. J Clin Lab Anal 20(3):75–79.  https://doi.org/10.1002/jcla.20104 CrossRefGoogle Scholar
  15. 15.
    Qari MH, Dier U, Mousa SA (2012) Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease. Clin Appl Thromb Hemost 18(2):195–200.  https://doi.org/10.1177/1076029611420992 CrossRefGoogle Scholar
  16. 16.
    Vinchi F, Costa da Silva M, Ingoglia G, Petrillo S, Brinkman N, Zuercher A, Cerwenka A, Tolosano E, Muckenthaler MU (2016) Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127(4):473–486.  https://doi.org/10.1182/blood-2015-08-663245 CrossRefGoogle Scholar
  17. 17.
    Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, Zamboni DS, Bozza MT (2014) Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci U S A 111(39):E4110–E4118.  https://doi.org/10.1073/pnas.1405023111 CrossRefGoogle Scholar
  18. 18.
    Dasgupta SK, Thiagarajan P (2005) The role of lactadherin in the phagocytosis of phosphatidylserine-expressing sickle red blood cells by macrophages. Haematologica 90(9):1267–1268Google Scholar
  19. 19.
    Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM (2000) Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood 96(7):2451–2459Google Scholar
  20. 20.
    Balandya E, Reynolds T, Obaro S, Makani J (2016) Alteration of lymphocyte phenotype and function in sickle cell anemia: implications for vaccine responses. Am J Hematol 91(9):938–946.  https://doi.org/10.1002/ajh.24438 CrossRefGoogle Scholar
  21. 21.
    Vingert B, Tamagne M, Desmarets M, Pakdaman S, Elayeb R, Habibi A, Bernaudin F, Galacteros F, Bierling P, Noizat-Pirenne F, Cohen JL (2014) Partial dysfunction of Treg activation in sickle cell disease. Am J Hematol 89(3):261–266.  https://doi.org/10.1002/ajh.23629 CrossRefGoogle Scholar
  22. 22.
    Musa BO, Onyemelukwe GC, Hambolu JO, Mamman AI, Isa AH (2010) Pattern of serum cytokine expression and T-cell subsets in sickle cell disease patients in vaso-occlusive crisis. Clin Vaccine Immunol 17(4):602–608.  https://doi.org/10.1128/CVI.00145-09 CrossRefGoogle Scholar
  23. 23.
    Koffi KG, Sawadogo D, Meite M, Nanho DC, Tanoh ES, Attia AK, Sanogo I, Sangare A (2003) Reduced levels of T-cell subsets CD4+ and CD8+ in homozygous sickle cell anaemia patients with splenic defects. Hematol J 4(5):363–365.  https://doi.org/10.1038/sj.thj.6200310 CrossRefGoogle Scholar
  24. 24.
    Johnston LK, Rims CR, Gill SE, McGuire JK, Manicone AM (2012) Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. Am J Respir Cell Mol Biol 47(4):417–426.  https://doi.org/10.1165/rcmb.2012-0090OC CrossRefGoogle Scholar
  25. 25.
    Chana KK, Fenwick PS, Nicholson AG, Barnes PJ, Donnelly LE (2014) Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 133(1):207–216 e201–211.  https://doi.org/10.1016/j.jaci.2013.08.044 CrossRefGoogle Scholar
  26. 26.
    Murthy S, Larson-Casey JL, Ryan AJ, He C, Kobzik L, Carter AB (2015) Alternative activation of macrophages and pulmonary fibrosis are modulated by scavenger receptor, macrophage receptor with collagenous structure. FASEB J 29(8):3527–3536.  https://doi.org/10.1096/fj.15-271304 CrossRefGoogle Scholar
  27. 27.
    Cai Y, Sugimoto C, Arainga M, Alvarez X, Didier ES, Kuroda MJ (2014) In vivo characterization of alveolar and interstitial lung macrophages in rhesus macaques: implications for understanding lung disease in humans. J Immunol 192(6):2821–2829.  https://doi.org/10.4049/jimmunol.1302269 CrossRefGoogle Scholar
  28. 28.
    Glassberg JA, Strunk R, DeBaun MR (2014) Wheezing in children with sickle cell disease. Curr Opin Pediatr 26(1):9–18.  https://doi.org/10.1097/MOP.0000000000000045 CrossRefGoogle Scholar
  29. 29.
    Petrov VP (1966) Complications of sickle-cell anemia. Klin Med (Mosk) 44(1):94–98Google Scholar
  30. 30.
    Siddiqui AK, Ahmed S (2003) Pulmonary manifestations of sickle cell disease. Postgrad Med J 79(933):384–390CrossRefGoogle Scholar
  31. 31.
    Pianosi P, D’Souza SJ, Charge TD, Esseltine DE, Coates AL (1993) Pulmonary function abnormalities in childhood sickle cell disease. J Pediatr 122(3):366–371CrossRefGoogle Scholar
  32. 32.
    Shilo NR, Alawadi A, Allard-Coutu A, Robitaille N, Pastore Y, Berube D, Jacob SV, Abish S, Dauletbaev N, Lands LC (2016) Airway hyperreactivity is frequent in non-asthmatic children with sickle cell disease. Pediatr Pulmonol 51(9):950–957.  https://doi.org/10.1002/ppul.23374 CrossRefGoogle Scholar
  33. 33.
    Galadanci NA, Liang WH, Galadanci AA, Aliyu MH, Jibir BW, Karaye IM, Inusa BP, Vermund SH, Strunk RC, DeBaun MR (2015) Wheezing is common in children with sickle cell disease when compared with controls. J Pediatr Hematol Oncol 37(1):16–19.  https://doi.org/10.1097/MPH.0000000000000239 CrossRefGoogle Scholar
  34. 34.
    Diep RT, Busani S, Simon J, Punzalan A, Skloot GS, Glassberg JA (2015) Cough and wheeze events are temporally associated with increased pain in individuals with sickle cell disease without asthma. Br J Haematol 170(5):732–734.  https://doi.org/10.1111/bjh.13325 CrossRefGoogle Scholar
  35. 35.
    Cohen RT, Madadi A, Blinder MA, DeBaun MR, Strunk RC, Field JJ (2011) Recurrent, severe wheezing is associated with morbidity and mortality in adults with sickle cell disease. Am J Hematol 86(9):756–761.  https://doi.org/10.1002/ajh.22098 CrossRefGoogle Scholar
  36. 36.
    Glassberg J, Spivey JF, Strunk R, Boslaugh S, DeBaun MR (2006) Painful episodes in children with sickle cell disease and asthma are temporally associated with respiratory symptoms. J Pediatr Hematol Oncol 28(8):481–485.  https://doi.org/10.1097/01.mph.0000212968.98501.2b CrossRefGoogle Scholar
  37. 37.
    Boyd JH, Macklin EA, Strunk RC, DeBaun MR (2006) Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood 108(9):2923–2927.  https://doi.org/10.1182/blood-2006-01-011072 CrossRefGoogle Scholar
  38. 38.
    Boyd JH, Moinuddin A, Strunk RC, DeBaun MR (2004) Asthma and acute chest in sickle-cell disease. Pediatr Pulmonol 38(3):229–232.  https://doi.org/10.1002/ppul.20066 CrossRefGoogle Scholar
  39. 39.
    Knight-Madden JM, Forrester TS, Lewis NA, Greenough A (2005) Asthma in children with sickle cell disease and its association with acute chest syndrome. Thorax 60(3):206–210.  https://doi.org/10.1136/thx.2004.029165 CrossRefGoogle Scholar
  40. 40.
    Glassberg J, Minnitti C, Cromwell C, Cytryn L, Kraus T, Skloot GS, Connor JT, Rahman AH, Meurer WJ (2017) Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: a triple-blind, randomized trial. Am J Hematol 92(7):622–631.  https://doi.org/10.1002/ajh.24742 CrossRefGoogle Scholar
  41. 41.
    Kasaian MT, Lee J, Brennan A, Danto SI, Black KE, Fitz L, Dixon AE (2018) Proteomic analysis of serum and sputum analytes distinguishes controlled and poorly-controlled asthmatics. Clin Exp Allergy 48:814–824.  https://doi.org/10.1111/cea.13151 CrossRefGoogle Scholar
  42. 42.
    Niu X, Nouraie M, Campbell A, Rana S, Minniti CP, Sable C, Darbari D, Dham N, Reading NS, Prchal JT, Kato GJ, Gladwin MT, Castro OL, Gordeuk VR (2009) Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease. PLoS One 4(11):e7956.  https://doi.org/10.1371/journal.pone.0007956 CrossRefGoogle Scholar
  43. 43.
    Sarray S, Saleh LR, Lisa Saldanha F, Al-Habboubi HH, Mahdi N, Almawi WY (2015) Serum IL-6, IL-10, and TNFalpha levels in pediatric sickle cell disease patients during vasoocclusive crisis and steady state condition. Cytokine 72(1):43–47.  https://doi.org/10.1016/j.cyto.2014.11.030 CrossRefGoogle Scholar
  44. 44.
    Lanaro C, Franco-Penteado CF, Albuqueque DM, Saad ST, Conran N, Costa FF (2009) Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. J Leukoc Biol 85(2):235–242.  https://doi.org/10.1189/jlb.0708445 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Hematology and OncologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Department of Oncological ScienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of Emergency MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA

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