Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

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

doi:10.2119/molmed.2011.00094

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.

Highlights

Pulmonary hypertension (PH) is a devastating disease associated with progressive hypoxemia and right ventricular failure
Median resting plasma migration inhibitory factor (MIF) concentrations were higher in patients with primary PH alone (1061 pg/mL; range: 762–3140; P = 0.004), interstitial lung disease (ILD) alone (803 pg/mL; range: 292–1845; P = 0.076) or PH secondary to ILD (1424 pg/mL; range 519–4396; P = 0.007) than in a randomly recruited population-based control group (365 pg/mL range: 142-4707) that we have described previously [16]
In all seven individuals of the PH secondary to ILD the plasma MIF was significantly increased after exercise (P = 0.02) (Figure 1)

Summary

Introduction

Pulmonary hypertension (PH) is a devastating disease associated with progressive hypoxemia and right ventricular failure. PH is usually classified as primary (idiopathic) or secondary. The World Health Organization (WHO) has proposed a classification system for PH based on common clinical features [1]. This classification adds to our understanding of the mechanisms involved and provides a good starting point in developing a rational clinical approach to the management of PH. The diagnosis of pulmonary arterial hypertension (primary PH) is made when these secondary causes have been clinically excluded. A major factor in the rapid progression of PH symptoms may be due in part to the creation of a vicious cycle: PH can be initiated by hypoxia, itself causes hypoxia, and hypoxia in return exacerbates PH

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