Vasculopathy and Systemic Sclerosis-Associated Interstitial Lung Disease

Project Summary/Abstract
Systemic sclerosis (SSc) is a systemic autoimmune rheumatic disease characterized by vasculopathy,
inflammation, and fibrosis, and has the highest case specific mortality rate of all systemic autoimmune
rheumatic diseases. Interstitial lung disease (ILD), a closely related group of lung disorders characterized by
alveolar inflammation, injury, and fibrosis not due to infection or neoplasia, affects 40-60% of adults with SSc
and is the primary cause of death and hospitalization in this population. Treatments for SSc-ILD are limited,
and no studies have tested interventions to prevent the development of SSc-ILD. Vasculopathy is a hallmark of
SSc and one of its earliest manifestations. We hypothesize that endothelial damage and microvascular injury
are critical inciting events in the pathogenesis of SSc-ILD, and are therefore potential novel treatment targets
for the prevention of SSc-ILD. The overarching goal of this proposal is to elucidate the relationships between
the pulmonary and peripheral microvasculature, endothelial function, lung function, and ILD in adults with SSc.
We will perform a prospective cohort study of 100 adults with SSc in which we will combine structural,
functional, and molecular approaches to understand how the vascular compartment contributes to the
development of ILD in SSc. In Aim 1, we will quantify the pulmonary microvascular perfused blood volume in
SSc and SSc-ILD and determine its relationship to peripheral microvascular structure and lung function. In Aim
2, we will compare peripheral microvascular endothelial function between SSc patients with and without ILD
and determine the relationship between peripheral microvascular endothelial function and pulmonary
microvascular perfusion, peripheral microvascular structure, and lung function in adults with SSc. In Aim 3, we
will perform single cell RNA sequencing of circulating endothelial cells to uncover the molecular mechanisms
that distinguish adults with SSc from those with SSc-ILD. Our study has the potential to generate paradigm-
shifting results that will (1) change the way we conceptualize the putative causal relationship between
microvascular disease and ILD in SSc, (2) identify novel outcome measures for use in SSc-ILD clinical trials,
and (3) enable us to develop new treatments for the primary and secondary prevention of SSc-ILD. We
anticipate that the results of this study will inform and be applicable to other fibrotic lung diseases, thereby
paving the way toward novel therapeutic approaches.

Grant Number: 5R01HL164758-04
NIH Institute/Center: NIH
Principal Investigator: Elana Bernstein