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Molecular Medicine

, Volume 18, Issue 2, pp 215–223 | Cite as

Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

  • Yinzhong Zhang
  • Arunabh Talwar
  • Donna Tsang
  • Annette Bruchfeld
  • Ali Sadoughi
  • Maowen Hu
  • Kennedy Omonuwa
  • Kai Fan Cheng
  • Yousef Al-Abed
  • Edmund J. Miller
Research Article

Abstract

Pulmonary hypertension (PH) is a devastating disease leading to progressive hypoxemia, right ventricular failure, and death. Hypoxia can play a pivotal role in PH etiology, inducing pulmonary vessel constriction and remodeling. These events lead to increased pulmonary vessel wall thickness, elevated vascular resistance and right ventricular hypertrophy. The current study examined the association of the inflammatory cytokine macrophage migration inhibitory factor (MIF) with chronic lung disease and its role in the development of hypoxia-induced PH. We found that plasma MIF in patients with primary PH or PH secondary to interstitial lung disease (ILD) was significantly higher than in the control group (P = 0.004 and 0.007, respectively). MIF involvement with hypoxia-induced fibroblast proliferation was examined in both a human cell-line and primary mouse cells from wild-type (mif+/+) and MIF-knockout (mif−/−) mice. In vitro, hypoxia-increased MIF mRNA, extracellular MIF protein accumulation and cell proliferation. Inhibition of MIF inflammatory activity reduced hypoxia-induced cell proliferation. However, hypoxia only increased proliferation of mif−/− cells when they were supplemented with media from mif+/+ cells. This growth increase was suppressed by MIF inhibition. In vivo, chronic exposure of mice to a normobaric atmosphere of 10% oxygen increased lung tissue expression of mRNA encoding MIF and accumulation of MIF in plasma. Inhibition of the MIF inflammatory active site, during hypoxic exposure, significantly reduced pulmonary vascular remodeling, cardiac hypertrophy and right ventricular systolic pressure. The data suggest that MIF plays a critical role in hypoxia-induced PH, and its inhibition may be beneficial in preventing the development and progression of the disease.

Notes

Acknowledgments

The authors wish to thank following for their support: Pulmonary Hypertension Association (Fellowship, Y Zhang); The Empire Clinical Research Investigator Program (Fellowships, A Sadoughi and K Omonuwa) and The Feinstein Institute for Medical Research, for intramural funding (EJ Miller, A Talwar).

References

  1. 1.
    McLaughlin VV, et al. (2009) ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J. Am. Coll. Cardiol. 53:1573–1619.CrossRefGoogle Scholar
  2. 2.
    Stenmark KR, Fagan KA, Frid MG. (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ. Res. 99:675–91.CrossRefGoogle Scholar
  3. 3.
    Tuder RM, Yun JH, Bhunia A, Fijalkowska I. (2007) Hypoxia and chronic lung disease. J Mol. Med. 85:1317–24.CrossRefGoogle Scholar
  4. 4.
    Dorfmuller P, Perros F, Balabanian K, Humbert M. (2003) Inflammation in pulmonary arterial hypertension. Eur. Respir. J. 22:358–63.CrossRefGoogle Scholar
  5. 5.
    Sadoughi A, Zhang Y, Miller EJ, Talwar A. (2010) Inflammatory mechanisms in pulmonary hypertension. CML Pulm. Hypertens. 1:93–106.Google Scholar
  6. 6.
    Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J. (2002) Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect. 4:449–460.CrossRefGoogle Scholar
  7. 7.
    Sakuragi T, et al. (2007) Lung-derived macrophage migration inhibitory factor in sepsis induces cardio-circulatory depression PMID: 17381395. Surg Infect. (Larchmt). 8:29–40.CrossRefGoogle Scholar
  8. 8.
    Baugh JA, et al. (2006) Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. Biochem. Biophys. Res. Commun. 347:895–903.CrossRefGoogle Scholar
  9. 9.
    Welford SM, et al. (2006) HIF1alpha delays premature senescence through the activation of MIF. Genes. Dev. 20:3366–71.CrossRefGoogle Scholar
  10. 10.
    Oda S, et al. (2008) Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLoS One 3: e2215CrossRefGoogle Scholar
  11. 11.
    Winner M, Koong AC, Rendon BE, Zundel W, Mitchell RA. (2007) Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res. 67:186–93.CrossRefGoogle Scholar
  12. 12.
    Mitchell RA, Metz CN, Peng T, Bucala R. (1999) Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J. Biol. Chem. 274:18100–6.CrossRefGoogle Scholar
  13. 13.
    Amin MA, et al. (2003) Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ. Res. 93:321–9.CrossRefGoogle Scholar
  14. 14.
    Pan JH, et al. (2004) Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 109:3149–53.CrossRefGoogle Scholar
  15. 15.
    Chen Z, et al. (2004) Evidence for a role of macrophage migration inhibitory factor in vascular disease. Arterioscler. Thromb. Vasc. Biol. 24:709–14.CrossRefGoogle Scholar
  16. 16.
    Bruchfeld A, et al. (2009) Elevated serum macrophage migration inhibitory factor (MIF) concentrations in chronic kidney disease (CKD) are associated with markers of oxidative stress and endothelial activation PMC2600496. Mol. Med. 15:70–5.CrossRefGoogle Scholar
  17. 17.
    Bozza M, et al. (1999) Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 189:341–6.CrossRefGoogle Scholar
  18. 18.
    Kumar RK, O’Grady R, Li W, Smith LW, Rhodes GC. (1991) Primary culture of adult mouse lung fibroblasts in serum-free medium: responses to growth factors. Exp. Cell Res. 193:398–404.CrossRefGoogle Scholar
  19. 19.
    Cheng KF, Al-Abed Y. (2006) Critical modifications of the ISO-1 scaffold improve its potent inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity. Bioorg. Med. Chem. Lett. 16:3376–9.CrossRefGoogle Scholar
  20. 20.
    Li FH, Xia W, Li AW, Zhao CF, Sun RP. (2007) Inhibition of rho kinase attenuates high flow induced pulmonary hypertension in rats. Chin. Med. J. (Engl) 120:22–9.Google Scholar
  21. 21.
    Le Pavec J, Launay D, Mathai SC, Hassoun PM, Humbert M. (2011) Scleroderma lung disease. Clin. Rev. Allergy Immunol. 40:104–16.CrossRefGoogle Scholar
  22. 22.
    Akgul F, et al. (2007) Pulmonary hypertension in sickle-cell disease: Comorbidities and echocardiographic findings. Acta Haematol. 118:53–60.CrossRefGoogle Scholar
  23. 23.
    Ryu JH, Krowka MJ, Pellikka PA, Swanson KL, McGoon MD. (2007) Pulmonary hypertension in patients with interstitial lung diseases. Mayo Clin. Proc. 82:342–50.CrossRefGoogle Scholar
  24. 24.
    Domenighetti G. (2007) Prognosis, screening, early detection and differentiation of arterial pulmonary hypertension. Swiss Med. Wkly 137:331–6.PubMedGoogle Scholar
  25. 25.
    Dalonzo GE, et al. (1991) Survival in patients with primary pulmonary-hypertension—Results from a National Prospective Registry. Ann Intern Med 115:343–9.CrossRefGoogle Scholar
  26. 26.
    Jing ZC, et al. (2007) Registry and survival study in Chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest 132:373–9.CrossRefGoogle Scholar
  27. 27.
    Puri A, McGoon MD, Kushwaha SS. (2007) Pulmonary arterial hypertension: current therapeutic strategies. Nat. Clin. Pract. Cardiovasc. Med. 4:319–29.CrossRefGoogle Scholar
  28. 28.
    Calandra T, et al. (1995) MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377:68–71.CrossRefGoogle Scholar
  29. 29.
    Bacher M, et al. (1997) Migration inhibitory factor expression in experimentally induced endotoxemia. Am. J. Pathol. 150:235–46.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Metz CN, Bucala R. (1997) Role of macrophage migration inhibitory factor in the regulation of the immune response. Adv. Immunol. 66:197–223.CrossRefGoogle Scholar
  31. 31.
    Calandra T, et al. (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat. Med. 6:164–70.CrossRefGoogle Scholar
  32. 32.
    Al-Abed Y, et al. (2005) ISO-1 binding to the tautomerase active site of MIF inhibits its proinflammatory activity and increases survival in severe sepsis. J. Biol. Chem. 280:36541–4.CrossRefGoogle Scholar
  33. 33.
    Oyama R, Yamamoto H, Titani K. (2000) Glutamine synthetase, hemoglobin alpha-chain, and macrophage migration inhibitory factor binding to amyloid beta-protein: their identification in rat brain by a novel affinity chromatography and in Alzheimer’s disease brain by immunoprecipitation. Biochim. Biophys. Acta 1479:91–102.CrossRefGoogle Scholar
  34. 34.
    Eickhoff R, et al. (2004) Influence of macrophage migration inhibitory factor (MIF) on the zinc content and redox state of protein-bound sulphydryl groups in rat sperm: indications for a new role of MIF in sperm maturation. Mol. Hum. Reprod. 10:605–11.CrossRefGoogle Scholar
  35. 35.
    Balabanian K, et al. (2002) CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 165:1419–25.CrossRefGoogle Scholar
  36. 36.
    Dorfmuller P, et al. (2007) Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum. Pathol. 38:893–902.CrossRefGoogle Scholar
  37. 37.
    Pak O, Aldashev A, Welsh D, Peacock A. (2007) The effects of hypoxia on the cells of the pulmonary vasculature. Eur. Respir. J. 30:364–72.CrossRefGoogle Scholar
  38. 38.
    Preston IR, Hill NS, Warburton RR, Fanburg BL. (2006) Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation. Am. J. Physiol. Lung Cell Mol. Physiol. 290: L367–74.CrossRefGoogle Scholar
  39. 39.
    Frank DB, et al. (2005) Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ. Res. 97:496–504.CrossRefGoogle Scholar
  40. 40.
    Dempsey EC, McMurtry IF, O’Brien RF. (1991) Protein kinase C activation allows pulmonary artery smooth muscle cells to proliferate to hypoxia. Am. J. Physiol. 260: L136–45.PubMedGoogle Scholar
  41. 41.
    Lanner MC, Raper M, Pratt WM, Rhoades RA. (2005) Heterotrimeric G proteins and the platelet-derived growth factor receptor-beta contribute to hypoxic proliferation of smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 33:412–9.CrossRefGoogle Scholar
  42. 42.
    Stiebellehner L, et al. (2003) Bovine distal pulmonary arterial media is composed of a uniform population of well-differentiated smooth muscle cells with low proliferative capabilities. Am. J. Physiol. Lung Cell Mol. Physiol. 285: L819–28.CrossRefGoogle Scholar
  43. 43.
    Benitz WE, Coulson JD, Lessler DS, Bernfield M. (1986) Hypoxia inhibits proliferation of fetal pulmonary arterial smooth muscle cells in vitro. Pediatr. Res. 20:966–72.CrossRefGoogle Scholar
  44. 44.
    Rose F, et al. (2002) Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells: role of hypoxia-inducible transcription factors. FASEB J. 16:1660–1.CrossRefGoogle Scholar
  45. 45.
    Das M, Burns N, Wilson SJ, Zawada WM, Stenmark KR. (2008) Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia. Cardiovasc. Res. 78:440–8.CrossRefGoogle Scholar
  46. 46.
    Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. (2006) Role of the adventitia in pulmonary vascular remodeling. Physiology 21:134–45.CrossRefGoogle Scholar
  47. 47.
    Sartore S, et al. (2001) Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ. Res. 89:1111–21.CrossRefGoogle Scholar
  48. 48.
    Belknap JK, Orton EC, Ensley B, Tucker A, Stenmark KR. (1997) Hypoxia increases bromodeoxyuridine labeling indices in bovine neonatal pulmonary arteries. Am. J. Respir. Cell Mol. Biol. 16:366–71.CrossRefGoogle Scholar
  49. 49.
    Eul B, et al. (2006) Impact of HIF-1alpha and HIF-2alpha on proliferation and migration of human pulmonary artery fibroblasts in hypoxia. FASEB J. 20:163–5.CrossRefGoogle Scholar
  50. 50.
    Stenmark KR, Gerasimovskaya E, Nemenoff RA, Das M. (2002) Hypoxic activation of adventitial fibroblasts: role in vascular remodeling. Chest. 122:326S–34S.CrossRefGoogle Scholar
  51. 51.
    Dewor M, et al. (2007) Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch-wounded monolayers in vitro. FEBS Lett. 581:4734–42.CrossRefGoogle Scholar
  52. 52.
    Hudson JD, et al. (1999) A proinflammatory cytokine inhibits p53 tumor suppressor activity. J. Exp. Med. 190:1375–82.CrossRefGoogle Scholar
  53. 53.
    Lue H, et al. (2006) Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. Cell Signal 18:688–703.CrossRefGoogle Scholar
  54. 54.
    Swant JD, Rendon BE, Symons M, Mitchell RA. (2005) Rho GTPase-dependent signaling is required for macrophage migration inhibitory factor-mediated expression of cyclin D1. J Biol. Chem. 280:23066–72.CrossRefGoogle Scholar
  55. 55.
    Crichlow GV, et al. (2007) Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. J Biol. Chem. 282:23089–95.CrossRefGoogle Scholar
  56. 56.
    Kleemann R, et al. (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J. Mol. Biol. 280:85–102.CrossRefGoogle Scholar
  57. 57.
    Miller EJ, et al. (2008) Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature. 451:578–82.CrossRefGoogle Scholar
  58. 58.
    Koga K, et al. (2011) Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress. Antioxid. Redox. Signal 14:1191–202.CrossRefGoogle Scholar

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Authors and Affiliations

  • Yinzhong Zhang
    • 1
  • Arunabh Talwar
    • 1
    • 3
    • 4
  • Donna Tsang
    • 3
  • Annette Bruchfeld
    • 5
  • Ali Sadoughi
    • 1
    • 3
  • Maowen Hu
    • 1
  • Kennedy Omonuwa
    • 3
  • Kai Fan Cheng
    • 2
  • Yousef Al-Abed
    • 2
    • 4
  • Edmund J. Miller
    • 1
    • 3
    • 4
  1. 1.Centers for Heart and Lung ResearchThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Biomedical SciencesThe Feinstein Institute for Medical ResearchManhassetUSA
  3. 3.Division of Pulmonary, Critical Care and Sleep MedicineNorth Shore LIJ-Health SystemNew YorkUSA
  4. 4.Hofstra University School of MedicineHempsteadUSA
  5. 5.Division of Renal MedicineKarolinska University Hospital, CLINTEC, Karolinska InstituteStockholmSweden

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