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.
Persistent perivascular inflammation is observed in many forms of pulmonary hypertension and is now thought to contribute significantly to both the overall vascular remodeling and high pulmonary artery pressures that characterize this lethal disease process. We show that early activation of complement occurs in PH and that this activation is critical in the early recruitment and persistence of inflammatory cells. The purpose of our project is to determine the mechanisms contributing to early and persistent complement activation and to determine if complement activation, in the vessel wall, can ultimately be targeted to ameliorate the disease process.
