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 output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)215-223
Number of pages9
JournalMolecular medicine (Cambridge, Mass.)
Volume18
Issue number1
StatePublished - 2012
Externally publishedYes

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Macrophage Migration-Inhibitory Factors
Pulmonary Hypertension
Lung
Cell Proliferation
Right Ventricular Hypertrophy
Messenger RNA
Hypoxia
Interstitial Lung Diseases
Cardiomegaly
Ventricular Pressure
Atmosphere
Constriction
Knockout Mice
Vascular Resistance
Lung Diseases
Disease Progression
Catalytic Domain
Chronic Disease
Fibroblasts
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, Y., Talwar, A., Tsang, D., Bruchfeld, A., Sadoughi, A., Hu, M., ... Miller, E. J. (2012). Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension. Molecular medicine (Cambridge, Mass.), 18(1), 215-223.

Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension. / Zhang, Yinzhong; Talwar, Arunabh; Tsang, Donna; Bruchfeld, Annette; Sadoughi, Ali; Hu, Maowen; Omonuwa, Kennedy; Cheng, Kai Fan; Al-Abed, Yousef; Miller, Edmund J.

In: Molecular medicine (Cambridge, Mass.), Vol. 18, No. 1, 2012, p. 215-223.

Research output: Contribution to journalArticle

Zhang, Y, Talwar, A, Tsang, D, Bruchfeld, A, Sadoughi, A, Hu, M, Omonuwa, K, Cheng, KF, Al-Abed, Y & Miller, EJ 2012, 'Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension.', Molecular medicine (Cambridge, Mass.), vol. 18, no. 1, pp. 215-223.
Zhang, Yinzhong ; Talwar, Arunabh ; Tsang, Donna ; Bruchfeld, Annette ; Sadoughi, Ali ; Hu, Maowen ; Omonuwa, Kennedy ; Cheng, Kai Fan ; Al-Abed, Yousef ; Miller, Edmund J. / Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension. In: Molecular medicine (Cambridge, Mass.). 2012 ; Vol. 18, No. 1. pp. 215-223.
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