Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension
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).
- 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
- 5.Sadoughi A, Zhang Y, Miller EJ, Talwar A. (2010) Inflammatory mechanisms in pulmonary hypertension. CML Pulm. Hypertens. 1:93–106.Google Scholar
- 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
- 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
- 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
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.
The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)