The effects of genetic deletion of Macrophage migration inhibitory factor on the chronically hypoxic pulmonary
Lili Li1, Maojia Xu1, Simon C Rowan1
1UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Abstract:
While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout (MIF ) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice (MIF ). Following exposure to hypoxia for three weeks, isolated lungs from MIF mice had significantly higher pulmonary vascular resistance than those from MIF mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF-/- mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.
Insights
Macrophage migration inhibitory factor (MIF) is crucial for normal pulmonary vascular responses to hypoxia. Lacking MIF impairs the lung
Area of Science:
- Pulmonary Hypertension Research
- Molecular Pathogenesis
- Cytokine Signaling
Background:
- Hypoxic pulmonary hypertension stems from increased pulmonary vascular resistance.
- The molecular mechanisms driving this resistance are not fully understood.
- Macrophage migration inhibitory factor (MIF) is a cytokine implicated in inflammatory diseases.
Purpose of the Study:
- To elucidate the role of Macrophage migration inhibitory factor (MIF) in the development of hypoxic pulmonary hypertension.
- To investigate the integrated actions of MIF in response to chronic alveolar hypoxia.
Main Methods:
- Comparison of isolated lungs from Macrophage migration inhibitory factor (MIF) knockout mice and wild-type mice under normoxic and hypoxic conditions.
- Assessment of pulmonary vascular resistance and alveolar capillary network expansion.
Main Results:
- Macrophage migration inhibitory factor (MIF) knockout lungs exhibited greater acute hypoxic vasoconstriction.
- Chronic hypoxia led to significantly higher pulmonary vascular resistance in Macrophage migration inhibitory factor (MIF) knockout mice.
- Impaired alveolar capillary network expansion was the primary mechanism for increased resistance in hypoxic Macrophage migration inhibitory factor (MIF) knockout mice.
Conclusions:
- Macrophage migration inhibitory factor (MIF) plays a critical role in regulating pulmonary vascular remodeling in response to chronic hypoxia.
- MIF is essential for the normal hypoxia-induced expansion of the alveolar capillary bed.
