Vascular Remodeling in Pulmonary Arterial Hypertension: The Potential Involvement of Innate and Adaptive Immunity

Abstract

Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell—mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.

Favorable long term effects of intensified immunosuppression combined with therapeutic plasma exchange in patients with early-onset progressive systemic sclerosis-related interstitial lung disease

“…The mechanism of action remains largely unclear. Persistent injury to endothelial cells, activation of innate and adaptive immunity and downstream effects on smooth muscle cells and fibroblasts results in extracellular matrix production and vascular remodeling [ 18 ]. Different auto-antibodies like anti-endothelial cell antibodies (AECAs) may play an important role in fibroblast activation [ 16 , 19 ].…”

Pathophysiological Involvement of Mast Cells and the Lipid Mediators in Pulmonary Vascular Remodeling

“…In the aortic banding model of Ws/Ws mast cell-deficient rats with a small deletion in the tyrosine kinase domain of the c-kit gene, PH, and pulmonary vascular remodeling in left-sided heart failure were attenuated compared to control rats, suggesting that the presence of mast cells may exacerbate the pathology of PH [ 20 ]. Further, several studies have shown that granule contents released by mast cells are deeply involved in development of PH [ 21 , 22 , 23 ]. Mast cell stabilizers that inhibit degranulation, such as cromolyn and disodium cromoglycate (DSCG), improve pulmonary vascular remodeling in various PH rat models [ 13 , 24 , 25 ].…”

The emerging role of NOTCH3 receptor signalling in human lung diseases

“…The blockage in the pulmonary vessels may progress to right-side heart failure which is the primary cause of high morbidity and mortality associated with PAH (Refs 124 , 125 , 126 ). At the cellular level, the main changes in PAH include proliferation of fibroblasts, infiltration of immune cells and proliferation of PASMCs (Refs 125 , 127 , 128 , 129 , 130 ). The above factors mediate the development of a vascular remodelling phenotype, called ‘neointimal lesions’, resulting in the elevation of pulmonary vascular resistance and ultimately heart failure (Refs 64 , 131 , 132 , 133 ).…”