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The broad focus of the Kourembanas laboratory is the elucidation of the vascular responses to hypoxia at the molecular, cellular, and organismal levels. Hypoxia increases the expression of heme oxygenase-1 (HO-1), a cytoprotective enzyme that degrades heme to generate carbon monoxide (CO, a vasodilating gas with anti-inflammatory properties), biliverdin (which is rapidly converted to the antioxidant bilirubin), and iron (sequestered by ferritin). HO-1 activity protects cells and tissues from hypoxia-induced injury, ischemia-reperfusion and the progression of vascular diseases due to inflammation and oxidative stress. Studies in the laboratory using HO-1 null (-/-) mice and transgenic mice with lung-specific constitutive and inducible HO-1 overexpression support this hypothesis. Whereas hypoxia causes severe pulmonary artery hypertension (PAH) with right ventricular dilatation, oxidative damage and infarction in mice lacking HO-1, mice with high lung HO-1 levels are protected from both lung and cardiac injury. Moreover, wild-type mice exposed to hypoxia develop marked lung inflammation with elevated expression of chemokines and cytokines, as well as neutrophil infiltration prior to the manifestation of PAH. Inhibition of early inflammation by transient, inducible, lung-specific expression of HO-1 prevents the later development of PAH. A central line of investigation in the laboratory is the study of the transcriptional and epigenetic mechanisms by which hypoxia induces chemokine gene expression leading to lung inflammation, and the mechanisms by which HO-1 activity resolves inflammation and inhibits the prohypertensive actions of hypoxia to maintain vascular homeostasis.
A related area of investigation in the lab is the study of developmental lung injury, a model of bronchopulmonary dysplasia (BPD). BPD is a disease of the preterm infant characterized by a chronic fibroproliferative process associated with inflammation and disruption of normal vessel growth and alveolization. Our studies in animal physiology and basic molecular biology are validated with parallel studies in infants with BPD using patient-derived material. Linked to this work are genomic approaches to identify genetic markers of predisposition to BPD and PAH.
An overarching new area of research in the laboratory explores the role of mesenchymal stem cells (MSC) in the prevention and treatment of developmental and vascular diseases of the lung, including BPD and PAH. Using several mouse models of lung disease and genetically-modified mice, we have shown that MSC can be isolated, differentiated, transduced, and delivered successfully in the in vivo lung. Via paracrine and immunodulatory pathways, MSC can both prevent and reverse lung vascular disease. The molecular and cellular pathways of MSC action is an active area of investigation.
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