Pulmonary arterial remodeling induced by a Th2 immune response

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH

Renal Denervation Reduces Pulmonary Vascular Remodeling and Right Ventricular Diastolic Stiffness in Experimental Pulmonary Hypertension

Neurohormonal overactivation plays an important role in pulmonary hypertension (PH). In this context, renal denervation, which aims to inhibit the neurohormonal systems, may be a promising adjunct therapy in PH. In this proof-of-concept study, we have demonstrated in 2 experimental models of PH that renal denervation delayed disease progression, reduced pulmonary vascular remodeling, lowered right ventricular afterload, and decreased right ventricular diastolic stiffness, most likely by suppression of the renin-angiotensin-aldosterone system

Dendritic Cells in Pulmonary Hypertension: Foot Soldiers or Hidden Enemies?

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Multiple roles of macrophage migration inhibitory factor in pulmonary hypertension

International audiencePulmonary hypertension (PH) is a life-threatening condition arising from the loss and obstructive remodeling of the pulmonary arteries, leading to the sustained elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) and subsequently right ventricular (RV) failure and death. PH encompasses a group of multifactorial diseases, such as pulmonary arterial hypertension (PAH) and chronic thromboembolic PH, for which there is no treatment that can stop or reverse the progression of remodeling of the pulmonary vasculature. The identification of new molecular targets for the development of more effective drugs is thus urgently needed. In this context, macrophage migration inhibitory factor (MIF), a pleiotropic upstream proinflammatory mediator, is emerging as a promising molecular target, as it contributes to perivascular inflammation and pulmonary arterial remodeling, two key hallmarks of PAH that are not specifically targeted by currently approved therapies. The objective of this review is to summarize the scientific evidence on the pathogenic roles of MIF and its potential as a biomarker and therapeutic target in PH/PAH

Targeting Transforming Growth Factor Beta Receptors in Pulmonary Hypertension

International audienceThe transforming growth factor (TGF)-β superfamily includes several groups of multifunctionalproteins that form two major branches, namely the TGF-β/activin/nodal branch and the bonemorphogenetic protein (BMP)/growth differentiation factor (GDF) branch. The response to theactivation of these two branches, acting through canonical (Smad 2/3 and Smad 1/5/8, respectively)and noncanonical signaling pathways, are diverse and vary amongst different environmentalconditions and cell types. An extensive body of data gathered in recent years has demonstrated a centralrole for the cross-talk between these two branches in a number of cellular processes that include theregulation of cell proliferation and differentiation, as well as the transduction of signaling cascades forthe development and maintenance of different tissues and organs. Importantly, alterations in thesepathways that include heterozygous germline mutations and/or alterations in the expression of severalconstitutive members have been identified in patients with familial/heritable or idiopathic pulmonaryarterial hypertension (PAH). Consequently, loss or dysfunctions in the delicate, finely tuned balancebetween the TGF-β/activin/nodal branch and the BMP/GDF branch are currently viewed as the majormolecular defect playing a critical role in PAH predisposition and disease progression. Here we reviewthe role of the TGF-β/activin/nodal branch in PAH and illustrate how this knowledge has not onlyprovided insight to understand its pathogenesis, but also paved the way for possible novel therapeuticapproaches