Kennedy Omonuwa

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.

Repeated phlebotomies improve and stabilise renal function in cyanotic nephropathy.

Patients over 10 years of age with cyanotic congenital heart disease (CCHD) risk developing significant glomerular proteinuria, a condition called cyanotic nephropathy. Even though the pathogenesis of glomerulopathy associated with CCHD is still unclear, a potential mechanism is hyperviscosity-induced decrease in peritubular capillary blood flow leading to an increase in glomerular capillary pressure, in turn resulting in proteinuria. Although angiotensin-converting enzyme (ACE) inhibitors have been traditionally used in the treatment of these patients with cyanotic nephropathy, they may, however, not be well tolerated. Here we present a case of an adult patient with CCHD who could not tolerate an ACE inhibitor but showed improvement and stabilisation of her renal function following treatment with repeated phlebotomies.