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


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.



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).


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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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