Article

Regulatory T Cells and Pulmonary Hypertension

VA Palo Alto Health Care System/Stanford University, Palo Alto, CA 94304, USA.
Trends in cardiovascular medicine (Impact Factor: 2.07). 08/2011; 21(6):166-71. DOI: 10.1016/j.tcm.2012.05.004
Source: PubMed

ABSTRACT Pulmonary hypertension (PH) is a disease of high lethality arising from numerous causes. For a significant subset of PH patients, autoimmune biomarkers or frank autoimmune disease are simultaneously present, but the extent to which lung inflammation contributes to PH is unknown. However, emerging experimental and clinical evidence suggests that immune dysregulation may lead to the propagation of vascular injury and PH. A recent preclinical study demonstrated that regulatory T cells are important mediators normally enlisted to control inflammation and that, if absent or dysfunctional, may predispose to the development of PH.

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Available from: Mark R Nicolls, Aug 28, 2015
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    • "T cell deficient rats are more likely to develop PAH and deficiency of CD8+ T cells in PAH patients correlated with a worse survival, which indicate that T cells play a protective role during the development of PH [13]. Various pathways are likely to generate this protective effect, for example Treg (T regulatory) cells might prevent the development of pulmonary hypertension and margin endothelial injuries, through the upregulation of BMPR2 in lung tissue [14]. T cells have been shown to downregulate the macrophage-mediated inflammatory angiogenesis in the lung [7]. "
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    ABSTRACT: Pulmonary hypertension is an “umbrella term” used for a spectrum of entities resulting in an elevation of the pulmonary arterial pressure. Clinical symptoms include dyspnea and fatigue which in the absence of adequate therapeutic intervention may lead to progressive right heart failure and death. The pathogenesis of pulmonary hypertension is characterized by three major processes including vasoconstriction, vascular remodeling and microthrombotic events. In addition accumulating evidence point to a cytokine driven inflammatory process as a major contributor to the development of pulmonary hypertension. This review summarizes the latest clinical and experimental developments in inflammation associated with pulmonary hypertension with special focus on Interleukin-6, and its role in vascular remodeling in pulmonary hypertension.
    Respiratory research 04/2014; 15(1):47. DOI:10.1186/1465-9921-15-47 · 3.38 Impact Factor
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    • "The presence of Tregs in animals being treated with Su5416 is associated with the limitation of peri-arteriolar inflammation and endothelial apoptosis, as well as the upregulation of vascular bone morphogenetic protein receptor-2 (BMPR2). The clinical significance of these findings is that it provided a mechanistic explanation of why patients with autoimmune diseases or viral infections, who also have abnormal Treg activity and immune dysregulation, are possibly predisposed to developing PAH following vascular injury (reviewed in Voelkel et al.[3435) "
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    ABSTRACT: In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for "reverse translation"; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified in the Su5416 VEGFR inhibitor models can be informative about heretofore undescribed processes in human PAH.
    03/2012; 2(4):434-442. DOI:10.4103/2045-8932.105031
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    ABSTRACT: Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism and are markers and mediators of pulmonary inflammation. Research over the past two decades has established that LTs modulate inflammation in pulmonary arterial hypertension (PAH). The purpose of this review was to summarize the current knowledge of LTs in the pathophysiology of PAH and to highlight a recent study that advances our understanding of how leukotriene B4 (LTB4) specifically contributes to pulmonary vascular remodeling. The results of these studies suggest that pharmacological inhibition of LT pathways, especially LTB4, has high potential for the treatment of PAH.
    Immunologic Research 02/2014; 58(2-3). DOI:10.1007/s12026-014-8492-5 · 3.53 Impact Factor
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