Arun Jose Clinical Research Program

Portopulmonary Hypertension (PoPH) is a particularly lethal lung disease that occurs in those with underlying liver disease. It has very poor treatment response and survival, with a 5-year survival of only 40% even with treatment. Some patients can undergo liver transplantation, and some lucky few are able to cure their PoPH following liver transplant. Unfortunately, we know very little about who is at risk of developing PoPH, why some people get PoPH and others do not, how the lungs react to liver transplant, and how best to treat PoPH to get the best outcomes for patients.

The major focus of our lab is understanding how liver disease can cause lung disease in PoPH, and ultimately how to better diagnose and treat this condition. Given the rare disease we study, we have taken a multidisciplinary collaborative team-science approach, and work closely with the University of Cincinnati Pulmonary Hypertension Clinic, Liver Transplant Program, core facilities at the Cincinnati Children’s Hospital Medical Center (Research Flow Cytometry Facility, Single Cell Genomics Core, Translational Metabolomics Core Facility), and a number of basic science laboratories both at the University of Cincinnati and the Cincinnati Children’s Hospital Medical Center. We also conduct ongoing collaborative research projects with a number of institutions both national and international. By building large-scale biorepositories of biological samples and clinical data, using next-generation “-omics” technology including single cell and single nuclear RNA sequencing, discovery proteomics, unbiased metabolomics, and shotgun metagenomics, and conducting novel “N of 1” research studies applying molecular medicine analytic techniques to new clinical paradigms, we hope to better understand the link between the gut, liver, lung, and circulation in pulmonary arterial hypertension and PoPH.

Our work to date has uncovered interesting links between certain signaling pathways (estrogen, arginine, GDF’s, inflammation) and development of PoPH in liver cirrhosis, as well as identified cardiac function and vascular resistance as key determinant of both mortality and post-liver-transplant outcomes in PoPH. We have also identified unique differences in the gut microbiome and circulating metabolome in patients with pulmonary arterial hypertension (PAH) that may have implications for treatment of PoPH.

Key Contributions of the Lab

1. Advancing understanding of pathophysiology and prognostication in PoPH:
   

   Using the national liver transplantation database, we identified pulmonary vascular resistance as an important determinant of outcomes following liver transplantation in PoPH, and hypoxemia as a determinant of outcomes following transplant in HPS. Expanding upon this finding, we applied single cell sequencing techniques to identify several unique characteristics of the PoPH liver transcriptome and candidate PoPH-specific biomarkers for further validation. Using the national Veteran cardiac catheterization database (VA CART), we also identified cardiac function as the major determinant of outcomes, and discovered low uptake of targeted therapy in Veterans with PoPH.

   Potential projects for students and fellows: analysis of existing “-omic” data to further understand potential pathways that define a liver-lung axis of communication in PoPH

2. Identification of candidate metabolic markers of disease severity and treatment response in pulmonary hypertension and PAH:
   Studying the intestinal gut microbial composition in PAH, we identified several promising new markers of disease severity and treatment response that might link the intestinal microbiome with the circulating metabolome and pulmonary vascular disease severity
3. Potential projects for students and fellows: analysis of existing data to further link together the gut microbiome, circulating metabolome, and disease severity in PAH