Conference: 2010 International PHA Conference and Scientific Sessions
Release Date: 06.24.2010
Presentation Type: Abstracts
Zhang Y1, Linge HM1, Koga K1, Talwar A1,2, Miller EJ1.
1. The Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA
2. Pulmonary and Critical Care Division, North Shore-LIJ Health System, New Hyde Park, NY, USA
BACKGROUND: Uncontrolled vascular cell proliferation is a key step in the etiology of hypoxic pulmonary vascular remodeling. Inflammation is considered an important factor in inducing cell proliferation. Macrophage migration inhibitory factor (MIF) is a hypoxia inducible pro-inflammatory cytokine that have shown certain abilities in stimulating inflammatory cell proliferation. This study examines the hypothesis that MIF is involved in pulmonary vascular remodeling and mediates hypoxic cell proliferation.
METHODS: Both a mouse model of hypoxic pulmonary hypertension and a cell model of hypoxic proliferation were used to explore MIF expression and the effects of MIF blockade on cell proliferation. In the in vivo setting, C57/BL6 mice were housed in a chamber in a 10% normobaric oxygen atmosphere for 3, 10, or 42 days. MIF expression in the lung was then examined. The pulmonary hypertension (PH) relevant parameters including right ventricular systolic pressure, pulmonary vascular wall thickness, and right ventricular hypertrophy were also recorded. In the in vitro model, human lung fibroblasts (WI-38 or CCL-210) were placed into a 1% oxygen atmosphere for 24 hours. Changes in cell proliferation were assessed using BrDU incorporation. MIF blockade was achieved by gene knock-out or specific inhibition using a synthetic small molecule inhibitor. The effects of MIF blockade on hypoxic cell proliferation were determined.
RESULTS: Hypoxia induced pulmonary hypertension in the mouse model with increased pulmonary vascular remodeling, right ventricular systolic pressure and right ventricular hypertrophy. MIF mRNA increased in the lung from day 3, peaked on day 10, and stayed at a higher level at least until day 42, (7.6, 15.6, and 1.9 fold increases respectively, compared with the normoxia control). MIF protein concentrations in plasma were also increased at days 10 and 42 days of hypoxia (increased 2.01 and 1.58 fold respectively vs. normoxia, p<0.05). In vitro, hypoxia induced a significantly elevated cell proliferation, as well as an increased MIF mRNA level and an increased MIF protein accumulation in the cell culture medium. Specific MIF inhibitor ISO-92, but not the vehicle control, significantly inhibited hypoxia-induced fibroblasts proliferation. MIF gene-deficient (mif-/-) fibroblasts did not have increased proliferation under hypoxic conditions. However, these cells regained the hypoxic proliferation when cultured in the conditioned medium derived from hypoxia treated wild-type (mif+/+) cells.
CONCLUSION: The data suggest that MIF plays a key role in hypoxia-induced cell proliferation and is an important link between hypoxia and PH formation. Further studies are needed to explore its diagnostic and therapeutic significance in PH management.