Immunoglobulin-driven Complement Activation Regulates Proinflammatory Remodeling in Pulmonary Hypertension.

Area of Science:

• Immunology
• Cardiopulmonary Medicine
• Pathobiology

Background:

• Pulmonary hypertension (PH) is a severe condition where inflammation and immunity play key roles in its early development.
• The precise initiating mechanisms of inflammation in PH and pulmonary arterial hypertension (PAH) are not fully understood.

Purpose of the Study:

• To investigate if complement cascade activation is essential for initiating inflammation and proliferation in experimental hypoxic PH.
• To determine if complement activation can predict clinical outcomes in human PAH patients.

Main Methods:

• Immunostaining of lung tissues from PH models and PAH patients.
• Analysis of genetically modified mice lacking complement components or immunoglobulins.
• Culturing human pulmonary adventitial fibroblasts and network medicine analysis of plasma biomarkers in PAH patients.

Main Results:

• Complement cascade activation in pulmonary perivascular areas is a critical factor in both experimental PH and human PAH.
• Pro-inflammatory and pro-proliferative responses in hypoxic PH depend on complement (alternative pathway, C5) and immunoglobulins (IgG).
• Complement signaling acts as a prognostic factor for clinical outcomes in PAH, with Csf2/GM-CSF identified as a key mediator.

Conclusions:

• Dysregulated, immunoglobulin-driven complement activation is a key mechanism in initiating experimental hypoxic PH.
• Complement signaling is a critical determinant of clinical outcomes in human PAH.