Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension

Abstract

This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.

Keywords: hypertension, pulmonary; leukotriene B4.

Figure 1. Pulmonary vascular changes in PAH includes infiltrating adaptive and innate immune cells

In the top panel is a representative histophathology of a vessel with severe neointimal formation represented below by a diagrammatic illustration. The histopathology shows a single endothelial layer and an eccentric neointima (pale pink) that contains cells that have markers of inflammatory cells and others that stain with markers of smooth muscle but appear poorly differentiated. The medial muscular layer is expanded and there is an abundant adventitial layer. This vessel is decorated with complement and autoantibodies, infiltrated by neutrophils in the lumen attacking the vessel wall and other inflammatory cells binding to the endothelium and infiltrating. The neointima is comprised of pale cells and matrix and infiltrating T and B cells and in the adventitia there are dendritic cells, macrophages and mast cells and in the periadventitial space tertiary lymphoid follicles characterized by T cells, B cells and plamacytoid dendritic cells (APC).

Figure 1. Pulmonary vascular changes in PAH includes infiltrating adaptive and innate immune cells

In the top panel is a representative histophathology of a vessel with severe neointimal formation represented below by a diagrammatic illustration. The histopathology shows a single endothelial layer and an eccentric neointima (pale pink) that contains cells that have markers of inflammatory cells and others that stain with markers of smooth muscle but appear poorly differentiated. The medial muscular layer is expanded and there is an abundant adventitial layer. This vessel is decorated with complement and autoantibodies, infiltrated by neutrophils in the lumen attacking the vessel wall and other inflammatory cells binding to the endothelium and infiltrating. The neointima is comprised of pale cells and matrix and infiltrating T and B cells and in the adventitia there are dendritic cells, macrophages and mast cells and in the periadventitial space tertiary lymphoid follicles characterized by T cells, B cells and plamacytoid dendritic cells (APC).

Figure 2. Distinct roles for reparative and dysregulated immunity following vascular injury

A variety of stimuli can be injurious to pulmonary arterioles; a health-promoting immune response will resolve inflammation after the stimuli has been contained and eliminated. With normal reparative immunity, inflammation is prevented from becoming inappropriately-exuberant and prolonged by the regulatory activity of NK cells and Tregs. In processes not well understood, adaptive immune responses (T cells, B cells) driven by antigen-specific signals coordinate with evolutionarily-ancient innate immune responses (NK cells, macrophages) to dampen immunity once the ‘danger' of the vascular injury has passed. This process may involve the skewing of immune responses with anti-inflammatory molecules, such as IL-10 and HO-1, and the induction of BMPR2; the result is the restoration of vascular health. However, when there is a genetic or acquired predisposition to immune dysregulation, or if the vascular injury itself drives a poorly regulated response (e.g., schistosomiasis infection), vascular injury is not quickly resolved. A useful oversimplification of this situation divides the dysregulated response into two subtypes: TH1/TH17 and TH2 immunity. In the TH1/TH17-skewed response, the arteriole may be invaded by mononuclear cells, including cytotoxic T cells, autoreactive B cells, autoantibodies, mast cells, and activated macrophages expressing GM-CSFR, iNOS and LTB₄. Injurious cytokines liberated in this milieu include TNF-α, IL-1 and IL-6. Additionally, adventitial fibroblasts may play a unique role in skewing and maintaining dysregulated immunity. In TH2-driven responses, there are unique inflammatory patterns. TGF-β-mediated immunity, linked closely with enhanced IL-4 and IL-13 activity, drive a destructive eosinophil and mast cell-rich perivascular infiltrate. IL-6 can be vasoprotective in this setting in contrast to the TH1/TH17-skewed response, where it is likely harmful. With unmitigated immune dysregulation, inflammation is not resolved in a health-promoting manner, and pulmonary vascular disease ensues.