# Role of Complement-Driven Pulmonary Vascular Inflammation in PH

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2022 · $488,572

## Abstract

Project Summary/Abstract
Inflammation is central to PH pathogenesis, as a clear trigger of human and experimental disease including
autoimmune scleroderma and schistosomiasis infection. Blocking inflammation prevents PH in pre-clinical
models, including schistosomiasis and hypoxic sterile inflammation. However, targeting inflammation faces
significant challenges, as no therapies have yet been proven to be of clinical benefit. Potential mechanisms
that limit this therapeutic approach include: non-targeted immunosuppression suppressing both deleterious
and protective pathways; patient-to-patient heterogeneity resulting in only some subsets of patients benefiting,
without biomarker identification; and a variable contribution of inflammation to vascular pathology over the
disease course. Our research group, working within the context of this PPG submission, is uniquely poised to
interrogate mechanisms that link innate and adaptive immunity in PH. We focus on the interplay between
complement, monocytes and macrophages in innate immunity, and CD4 T cells in adaptive immunity. Our
body of work has demonstrated that Type 2 adaptive immunity driven by Schistosoma exposure (the cause of
schistosomiasis, a major PAH etiology), triggers an innate immune response with recruitment of Ly6c+
monocytes, resulting in perivascular thrombospondin-1 (TSP-1) expression, leading to latent TGF-β activation
that drives the vascular pathology. We now propose to leverage clearly defined antigenic triggers and
mechanistic intermediate and endpoints in Schistosoma-PH to interrogate how complement activates adaptive
and innate immunity resulting in vascular remodeling. We will study mechanisms underlying disease
persistence versus recovery, focusing on potential dual roles of complement and activated TGF-β as initially
inciting of PH, and subsequently suppressing Schistosoma-triggered inflammation and PH as the antigenic
burden is cleared. Our third Aim is translational, investigating the peripheral blood immune cell phenotype as it
relates to complement and TSP-1 in subjects schistosomiasis, idiopathic and scleroderma-associated
pulmonary arterial hypertension, supporting the overall rigor and impact of our studies. Hypothesis: As an
innate trigger of adaptive immunity, complement activation is necessary for Type 2 inflammation, monocyte
recruitment, and activation of TGF-β by TSP-1, initially contributing to PH and later helping in the resolution of
Schistosoma-induced inflammation and PH. Specific Aim 1: To determine that complement is necessary for
Type 2 inflammation-driven PH. Specific Aim 2: To determine that complement-dependent TSP-1+ monocyte
recruitment contributes to both the initial development and subsequent resolution of Schistosoma-triggered
inflammation and PH. Specific Aim 3: To determine that peripheral blood complement levels correlate with
leukocyte and cytokine signatures in humans with schistosomiasis, scleroderma and idiopathic PAH. Our
overall goal is...

## Key facts

- **NIH application ID:** 10470736
- **Project number:** 5P01HL152961-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Brian Barkley Graham
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $488,572
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470736

## Citation

> US National Institutes of Health, RePORTER application 10470736, Role of Complement-Driven Pulmonary Vascular Inflammation in PH (5P01HL152961-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470736. Licensed CC0.

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