Description: Pulmonary hypertension (PH) is a devastating disease associated with progressive low blood oxygen levels, heart failure, and a mortality rate of 50% within three years of diagnosis. PH can occur in association with chronic lung disorders including Interstitial Lung Disease (ILD), Chronic Obstructive Pulmonary Disease (COPD) and scleroderma.
Hypoxia – a condition in which oxygen concentrations fall below the level that can sustain life – plays a pivotal role in PH etiology through inducing elevated pulmonary vascular resistance (constriction), increased pulmonary vessel wall thickness (remodeling) and increased heart volume (right ventricle hypertrophy). Recently, the Miller laboratory has discovered that the inflammatory cytokine, macrophage migration inhibitory factor (MIF), plays a critical role in PH. Relative to healthy subjects, patients with PH have elevated plasma MIF concentrations that increase further following exercise. In animal models of PH, plasma MIF and lung tissue MIF mRNA levels are increased following hypoxia. Hypoxia also increases the proliferation of fibroblasts (a component cell of the pulmonary blood vessels), and this proliferation is associated with increased MIF mRNA and accumulation of MIF in the culture medium. MIF plays a causative role in this hypoxia-mediated proliferation since fibroblasts from mice genetically deficient in MIF (mif -/-) do not increase proliferation unless supplemented with media from hypoxia-cultured wildtype fibroblasts. Finally, administration of an orally-available small molecule MIF inhibitor, ISO-92, prevents many of the adverse sequelae of hypoxia: ISO-92 inhibits hypoxia-induced, but not normal cell proliferation; ISO-92 significantly reduces right ventricular systolic pressure, pulmonary vascular remodeling and hypoxia-induced right ventricular hypertrophy in vivo.
These data demonstrate that MIF plays a critical role in hypoxia-induced pulmonary vascular remodeling and hypertension, and that inhibition of the MIF inflammatory active site may be beneficial in preventing the development and progression of the disease.
Area of Application: Inflammatory diseases
Lead Investigator: Edmund Miller, PhD
References: Zhang et al. Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension Mol Med. 2012 Mar 27;18:215-23.
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