Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening

Abstract

Pulmonary hypertension (PH) is a progressive disease that arises from multiple etiologies and ultimately leads to right heart failure as the predominant cause of morbidity and mortality. In patients, distinct inflammatory responses are a prominent feature in different types of PH, and various immunomodulatory interventions have been shown to modulate disease development and progression in animal models. Specifically, PH-associated inflammation comprises infiltration of both innate and adaptive immune cells into the vascular wall of the pulmonary vasculature-specifically in pulmonary vascular lesions-as well as increased levels of cytokines and chemokines in circulating blood and in the perivascular tissue of pulmonary arteries (PAs). Previous studies suggest that altered hemodynamic forces cause lung endothelial dysfunction and, in turn, adherence of immune cells and release of inflammatory mediators, while the resulting perivascular inflammation, in turn, promotes vascular remodeling and the progression of PH. As such, a vicious cycle of endothelial activation, inflammation, and vascular remodeling may develop and drive the disease process. PA stiffening constitutes an emerging research area in PH, with relevance in PH diagnostics, prognostics, and as a therapeutic target. With respect to its prognostic value, PA stiffness rivals the well-established measurement of pulmonary vascular resistance as a predictor of disease outcome. Vascular remodeling of the arterial extracellular matrix (ECM) as well as vascular calcification, smooth muscle cell stiffening, vascular wall thickening, and tissue fibrosis contribute to PA stiffening. While associations between inflammation and vascular stiffening are well-established in systemic vascular diseases such as atherosclerosis or the vascular manifestations of systemic sclerosis, a similar connection between inflammatory processes and PA stiffening has so far not been addressed in the context of PH. In this review, we discuss potential links between inflammation and PA stiffening with a specific focus on vascular calcification and ECM remodeling in PH.

Keywords: ECM remodeling; inflammation; pulmonary hypertension; vascular calcification; vascular stiffness.

Figure 1

Proposed role of inflammation in PA stiffening; The development of PH is associated with an inflammatory response in the pulmonary vasculature, characterized by immune cell infiltration and the secretion of immune factors. ECM stiffening, especially proximal large pulmonary vascular sclerosis, occurs in the early stages of PH and has a prognostic value for patient outcome and later calcification, and is driven by inflammation. Prolonged angiosclerosis, in turn, further promotes an inflammatory response that exacerbates pulmonary vascular calcification and thickening. PH, pulmonary hypertension; ECM, extracellular matrix; PA, pulmonary artery.

Figure 2

Potential links between inflammatory mediators and mechanisms of pulmonary arterial ECM remodeling and vascular calcification in PH. As described in detail in the manuscript text, perivascular accumulation of immune cells is a characteristic feature of PH. Inflammatory cells such as macrophages produce MMPs that promote ECM degradation and remodeling. Inflammatory cytokines such as IL-6 and TGF-β drive the proliferation of PA SMCs. Stimulation of fibroblasts by inflammatory mediators increases the expression of collagens, elastin, and fibronectin, further promoting PA stiffness. Activated immune cells and inflammatory mediators promote SMC transdifferentiation and enhance the expression of biomineralization genes, thus driving vascular calcification. BMPR2 downregulation, especially in response to the inflammatory factor TNF, promotes endothelial cell mesenchymalization and may as such contribute to the development of pulmonary vascular calcification. A detailed discussion of the proposed signaling pathways is provided in the manuscript text. ECM, extracellular matrix; MMPs, matrix metalloproteinases; SMC, smooth muscle cells; PH, pulmonary hypertension; PA, pulmonary artery; BM, basement membrane.