Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease.

Pulmonary Hypertension (PH) and pulmonary vascular remodeling (PVR) are common in a variety of lung diseases leading to right ventricular dysfunction and death. Differences in PVR result in significant prognostic divergences, such as the pulmonary arterial compartment as in pulmonary arterial hypertension (PAH) as well as the venous compartment, as in pulmonary veno-occlusive disease (PVOD). We aimed to identify compartment-specific molecular hallmarks of PVR, considering the risk of life-threatening pulmonary edema in PVOD, if treated by conventional PH-therapy. We undertook a most comprehensive analysis using FFPE tissue of fresh explanted human lungs, of patients suffering from PVOD (n=19), PAH (n=20), idiopathic pulmonary fibrosis (n=13) and chronic obstructive pulmonary disease (n=15), focusing on inflammation and kinome-related gene regulation. We generated a neuronal network which differentiated PVOD from PAH samples with a sensitivity of 100% and a specificity of 92% in a randomly chosen validation set, a level far superior to established diagnostic algorithms. Furthermore, we identified various alterations regarding the gene expression of explanted lungs with PVR, as compared to controls. Specifically, the dysregulation of microtubule associated serine/threonine kinase 2 and protein-o-mannose kinase SGK196 in all disease groups suggests a key role in pulmonary vasculopathy for the first time. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases.