Project Grant F32HL186556

INVESTIGATING INFLAMMATORY PATHWAYS IN PULMONARY VASCULAR DISEASE - PROJECT SUMMARY/ABSTRACT PULMONARY ARTERIAL HYPERTENSION (PAH) IS A PROGRESSIVE AND FATAL DISEASE RESULTING FROM DYSFUNCTION OF THE PULMONARY VASCULATURE, THAT IF UNTREATED, MAY LEAD TO DEATH FROM RIGHT HEART FAILURE. THE PREVALENCE OF PAH HAS INCREASED OVER THE PAST 30 YEARS, UP TO APPROXIMATELY 2 PER 100,000 WORLDWIDE IN 2021. DESPITE ADVANCES IN TREATMENT, PATIENTS WITH PAH REPORT A POOR QUALITY OF LIFE, AND TRANSPLANT-FREE SURVIVAL REMAINS DIRE AT 6 YEARS, WITHOUT SIGNIFICANT IMPROVEMENT OVER THE PAST 15 YEARS. THUS, THERE IS AN URGENT NEED TO IMPROVE CURRENT PREVENTIVE, THERAPEUTIC, AND DISEASE MONITORING APPROACHES TO ADDRESS PERSISTENT ADVERSE OUTCOMES. DESPITE THE RECOGNIZED CENTRAL ROLE OF INFLAMMATION IN PAH, INTERVENTIONS DIRECTLY TARGETING INFLAMMATION (E.G. IL-6 RECEPTOR ANTIBODY TOCILIZUMAB) HAVE NOT PROVEN SUCCESSFUL, UNDERSCORING A CRITICAL NEED TO BETTER UNDERSTAND SPECIFIC MOLECULAR PATHWAYS THAT UNDERLIE INFLAMMATORY ACTIVITY IN PULMONARY VASCULAR (PV) DISEASE. EICOSANOIDS ARE A CLASS OF BIOACTIVE LIPIDS THAT SERVE AS UPSTREAM REGULATORS OF KEY PHYSIOLOGIC PROCESSES RELEVANT TO PAH INCLUDING INFLAMMATION, VASCULAR TONE, AND ENDOTHELIAL CELL (EC) FUNCTION. REGARDING THE LATTER, EC DYSFUNCTION IS A HALLMARK OF PAH DRIVEN IN PART BY INFLAMMATORY SIGNALING. EXISTING APPROACHES TO STUDYING EC IN PAH ARE LIMITED BY THEIR RELEVANCE TO IN VIVO PATHOPHYSIOLOGY, RESTRICTION TO SEVERE DISEASE, AND INVASIVE NATURE. OUR LAB HAS EXPERTISE WITH AN ESTABLISHED METHOD OF FRESH HUMAN PERIPHERAL EC COLLECTION FOR GENE EXPRESSION PROFILING THAT HAS BEEN USED TO ASSESS EC HEALTH IN ~1,000 ADULTS IN THE COMMUNITY. WE NOW SEEK TO DEFINE THE SYSTEMIC AND EC INFLAMMATORY PATHWAYS THAT UNDERLIE PV DYSFUNCTION AND TO DETERMINE THEIR RELATIONSHIP TO CLINICAL RESPONSE TO PAH-SPECIFIC THERAPIES. IN AIM 1, IN A SAMPLE OF 549 PATIENTS WITH DYSPNEA WHO UNDERWENT INVASIVE HEMODYNAMIC EVALUATION WITH MULTI-SITE BLOOD SAMPLING, WE WILL EXAMINE THE ASSOCIATION OF TRANSPULMONARY INFLAMMATORY EICOSANOID GRADIENTS, WHICH REFLECT LUNG METABOLITE UPTAKE AND RELEASE, WITH MEASURES OF REST AND EXERCISE PV FUNCTION. IN AIM 2, WE PROPOSE A LONGITUDINAL PILOT STUDY OF 20 PATIENTS WITH PAH OVER 6 MONTHS TO INVESTIGATE THE CHANGE IN CIRCULATING EICOSANOID PROFILES AND EC PHENOTYPING BEFORE AND AFTER INITIATION OF PAH- SPECIFIC THERAPY. THESE FINDINGS HAVE THE POTENTIAL TO PROVIDE IMPORTANT INSIGHTS INTO THE INFLAMMATORY MECHANISMS DRIVING PV DYSFUNCTION AND PAH AND MAY INFORM DEVELOPMENT OF THERAPIES TARGETING IMMUNE PATHWAYS IN THIS COMPLEX DISEASE. THIS PROJECT IS SUPPORTED BY AN OUTSTANDING, MULTIDISCIPLINARY TEAM OF EXPERTS WITH EXPERTISE IN CARDIOMETABOLIC DISEASE, PULMONARY VASCULAR DISEASE, INFLAMMATION, AND ADVANCED BIOSTATISTICS. THESE MENTORS WILL PROVIDE RIGOROUS HANDS-ON TRAINING COMPLEMENTED BY FORMAL COURSEWORK FOR ALL ASPECTS OF THE PROPOSED WORK, IN ADDITION TO FORMAL CAREER DEVELOPMENT. THE PROJECT WILL BE PRIMARILY BASED AT BETH ISRAEL DEACONESS MEDICAL CENTER, WITH SUPPORT FROM THE MASSACHUSETTS GENERAL HOSPITAL CENTER FOR IMMUNOLOGY AND INFLAMMATION, THE HARVARD SCHOOL OF PUBLIC HEALTH, AND THE HARVARD PULMONARY FELLOWSHIP PROGRAM, FORMING A ROBUST ENVIRONMENT WITH UNIQUE RESOURCES TO SUPPORT THE PROPOSED TRAINING AND RESEARCH.