OC 19.3 - Endothelial-Targeted CD39 Ameliorates Acute Endothelial Toxin-Induced Pulmonary Hypertension in a Murine Model

Sunday, June 25, 2023

11:15 – 11:30 ET

Room: 515

Session Available As: On-Demand

Presenting Author(s)

Abbey Willcox, MBBS BmedSci FRACP FRCPA (she/her/hers)

PhD Student and Haematologist
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia

Co-Author(s)

XW

Xiaowei Wang

Laboratory Head
Baker Institute, University of Melbourne
Melbourne, Victoria, Australia
IS

Ioanna Savvidou

Senior Research Fellow
Alfred Health, Monash University
Melbourne, Victoria, Australia
IC

Ilaria Calvello

Research Assistant
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
NL

Natasha Lee

Post doctoral scientist
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
CS

Carly Selan

Research Assistant
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
VB

Viktoria Bongcaron

Research Assistant
Baker Institute
Melbourne, Victoria, Australia
AW

Aidan Walsh

PhD Student
Baker Institute, University of Melbourne
Melbourne, Victoria, Australia
YS

Yuyang Song

PhD Student
Baker Institute, University of Melbourne
Melbourne, Victoria, Australia
SR

Simon Robson

Professor of Anaesthesia, Charlotte F. & Irving W. Rabb Distinguished Professor of Gastroenterology
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
KP

Karlheinz Peter

Deputy Director, Basic and Translational Science
Baker Institute, University of Melbourne
Melbourne, Victoria, Australia
MS

Maithili Sashindranath

Senior Scientist and Deputy Lab Head
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia

Co-Author(s)

Harshal Nandurkar, MD, PhD, FRACP, FRCPA (he/him/his)

Director of Cancer Program, Alfred Health. Head of the Australian Centre for Blood Diseases
Alfred Health and Monash University
Melbourne, Victoria, Australia

Background: Endothelial lung injury by drugs, toxins, viruses (eg. COVID-19), bacterial sepsis can cause acute pulmonary vasculopathy leading to pulmonary arterial hypertension (PAH) and cardiac compromise. CD39 is integral in maintaining the antithrombotic profile of the endothelium. CD39 is an endothelial cell-anchored enzyme working in concert with CD73 to hydrolyze extracellular ATP (pro-inflammatory) /ADP (pro-thrombotic) to adenosine which is anti-inflammatory, vasodilatory, and anti-thrombotic. CD39 activity and adenosine signaling are disrupted in human PAH. Moreover, CD39-null mice develop severe PAH after hypoxic injury.

Aims: To demonstrate that the endothelial cell-targeted delivery of CD39 will prevent the development of acute-toxin induced pulmonary hypertension.

Methods: A murine model of PAH was established using a single intravenous dose of the endothelial cell (EC) toxin Monocrotaline Pyrrole (MCTP), 8mg/kg. Development of PAH was verified by showing reduced pulmonary acceleration time (PAT): pulmonary ejection (PET) ratio (echocardiogram), raised right ventricular systolic pressure (RVSP) and RV hypertrophy (Fulton’s index; RV/LV+septum).

‘Anti-VCAM1-CD39’ is novel therapeutic containing a scFv recognizing VCAM-1 (receptor expressed on activated ECs) fused to human soluble CD39.

Prior work has demonstrated that intravenous anti-VCAM1-CD39 administration prolongs murine tail bleeding time but only at doses above 1mg/kg. Controls included are non-targeted CD39 and anti-VCAM1 blockade alone.

Results: PAH develops in animals within 10 days of a single dose of MCTP 8mg/kg (Fig.1) demonstrating:
• EC activation with increased VCAM-1 and ICAM-1 expression
• Reduced PAT/PET ratio and elevated RVSP
• RV hypertrophy (increased Fulton’s index)

Single administration of anti-VCAM1-CD39 at doses of 0.4mg/kg and 1.0mg/kg at 72 h post MCTP prevented the development of PAH reflected in preservation of the PAT/PET ratio, normal RVSP and the absence of RV hypertrophy at D10 compared with controls (Fig. 2).

Conclusion(s): Single administration of endothelial targeted CD39 (anti-VCAM1-CD39) ameliorates the development of PAH providing potential for a novel therapeutic target for acute toxin-induced PAH.

Learning Objectives:

Appreciate the clinical implications of pulmonary arterial hypertension and the need for novel therapeutic strategies
Appreciate the role of endothelial dysfunction and altered purinergic signalling in the development of pulmonary arterial hypertension
Appreciate the utility of endothelial targeted CD39 as a novel therapeutic strategy in the treatment of pulmonary arterial hypertension