# Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2021 · $469,957

## Abstract

There is convincing evidence for both inflammatory and autoimmune phenomena to be involved in the
pathogenesis of PAH. However, both the triggering and the disease sustaining mechanisms remain elusive.
Based on emerging evidence in other diseases, including arthritis, kidney disease, and cancer, generated
by Co-Investigators on this project, it has become clear that the Complement system, when dysregulated,
can become a potent instigator of inflammation-driven tissue injury. Our recently published data
demonstrated, we believe for the first time, that the immunoglobulin-driven activation of the complement
cascade, specifically its alternative pathway, in the pulmonary perivascular areas is a critical mechanism
initiating pro-inflammatory and pro-proliferative processes in experimental hypoxic PH (a form of “sterile
inflammation”). We also demonstrated that the activated complement cascade and immunoglobulin G (IgG)
deposition are persistent determinants of the disease. The present proposal builds on these findings and
comprises both mechanistic and translational arms. In Aim 1 we will evaluate the role of immunoglobulins
and complement in initiation of pro-inflammatory processes in PH. In Aim 2 we will evaluate the role of
immunoglobulins and complement in the sustained progression of vascular injury and the disease process. In
a potentially highly translational Aim 3 we will test the efficacy of targeted (local) complement inhibition in
experimental PH using a novel complement inhibitor, human fusion protein termed TT32, which can be used
to target local activated complement signaling.

## Key facts

- **NIH application ID:** 10224331
- **Project number:** 5P01HL152961-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kurt R. Stenmark
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $469,957
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224331

## Citation

> US National Institutes of Health, RePORTER application 10224331, Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression (5P01HL152961-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10224331. Licensed CC0.

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