Elsevier

Progress in Cardiovascular Diseases

Volume 55, Issue 2, September–October 2012, Pages 218-228
Progress in Cardiovascular Diseases

Immune and inflammatory mechanisms in pulmonary arterial hypertension

https://doi.org/10.1016/j.pcad.2012.07.006Get rights and content

Abstract

Altered immunity and inflammation are increasingly recognized features of pulmonary arterial hypertension (PAH). This is suggested by infiltration of various inflammatory cells (e.g., macrophages, T and B lymphocytes), increased cytokine and growth factor (e.g., VEGF and PDGF) expression in remodeled pulmonary vessels, and the presence of circulating chemokines and cytokines. In certain diseases associated with PAH, increased expression of growth and transcriptional (e.g., Nuclear Factor of Activated T cells or NFAT) factors, and viral protein components (e.g., HIV-1 Nef), appear to contribute directly to recruitment of inflammatory cells in remodeled vessels, and may potentially serve as specific therapeutic targets. This section provides an overview of inflammatory pathways highlighting their potential role in pulmonary vascular remodeling in PAH and the possibility of future targeted therapy.

Section snippets

The role of inflammation in human PAH

Inflammation appears to be a prominent pathologic feature in PAH as suggested by infiltration of inflammatory cells, including macrophages and T and B lymphocytes, and dendritic cells in pulmonary perivascular spaces and around the plexiform lesions in PAH.8, 9 In addition, levels of macrophage inflammatory protein-1 alpha, IL-1β and IL-67, 10 and P-selectin11 (expressed on leukocytes and platelets and able to bind to their ligands on endothelial cells (EC)), are increased in severe IPAH.

Growth factors in PAH: tyrosine kinase signalling as a potential target in PAH

Several growth factors, including platelet-derived growth factor (PDGF),27, 28 basic fibroblast growth factor (b-FGF),29 epidermal growth factor (EGF)30 and VEGF,31, 32, 33 have been implicated in the abnormal proliferation and migration of PA vascular cells. These growth factors form homo- or heterodimers, stimulate cell surface receptors which activate the major signaling transduction pathways like the Ras-mitogen activated protein kinase pathway, and act as potent mitogens and

The NFAT in inflammation and vascular remodeling

The nuclear factor of activated T cells (NFAT) increases the transcription of multiple inflammatory mediators, such as interleukins and tumor necrosis factor. NFAT also activates T and B cells.67 An increase in [Ca2 +]i, in response to hypoxia or other stimulus, activates calcineurin, which dephosphorylates cytoplasmic NFAT, allowing its entry to the nucleus where it forms complexes with other important transcription factors (e.g., activator protein-1) regulating gene transcription.67

NFAT

Human immunodeficiency virus and PAH

PAH associated with HIV infection is classified in WHO Group 1 along with IPAH and CTD-associated PAH. Perhaps even more so than for other syndromes in this group (with the exception of CTD-PAH), there is strong evidence for underlying inflammatory mechanisms in the pathogenesis of the pulmonary vascular remodeling in HIV-PAH.

Although the exact mechanisms of pathogenesis of HIV-PAH are not well understood, several facts have been established, including the lack of evidence of a direct role for

Autoantibodies in PAH

Several autoantibodies have been reported in PAH, in particular IPAH and SSc-PAH. For example, PAH-SSc patients have been found to have antifibrillarin antibodies,90 and the poorly characterized anti-EC antibodies which correlate with digital infarcts.92 Nicolls et al. suggested that anti-EC antibodies can activate EC, induce the expression of adhesion molecules, and trigger apoptosis, thus contributing to the pathogenesis of PAH.9 Other antibodies reported in PAH-SSc include antibodies to

Conclusion

Inflammatory processes appear to play an important role in the vascular remodeling characteristic of PAH and might be important targets for PAH therapy. While preclinical trials targeting specific inflammatory pathways have shown promising results in animal models, translating these findings to human PAH remains largely unexplored except in the case of the tyrosine kinase pathway where clinical trials are on-going. Recognizing the complexity of specific inflammatory pathways in animal models

Statement of Conflict of Interest

This work was supported by a grant from the National Heart, Lung and Blood Institute (NIH/NHLBI HL084946).

The authors have no conflicts of interest regarding this manuscript. PMH is supported by a grant from the National Heart, Lung and Blood Institute (NIH/NHLBI HL084946). Otherwise, he serves on scientific advisory boards for Gilead, Pfizer, Novartis, and Merck. He has also received research funding from Actelion/United Therapeutics for the REVEAL registry of PAH patients.

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