Abstract
Pulmonary arterial hypertension (PAH) pathobiology involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to enhanced pulmonary vascular resistance and pressure, to right heart failure and death. The exact mechanisms accounting for PAH development remain unknown, but growing evidence demonstrate that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Not surprisingly, PAH is often associated with diverse inflammatory disorders. Furthermore, pathologic specimens from PAH patients reveal an accumulation of inflammatory cells in and around vascular lesions, including macrophages, T and B cells, dendritic cells, and mast cells. Circulating levels of autoantibodies, chemokines, and cytokines are also increased in PAH patients and some of these correlate with disease severity and patients’ outcome. Moreover, preclinical experiments demonstrated the key role of inflammation in PAH pathobiology. Immunosuppressive agents have also demonstrated beneficial effects in animal PAH models. In humans, observational studies suggested that immunosuppressive drugs may be effective in treating some PAH subtypes associated with marked inflammation. The present chapter reviews experimental and clinical evidence suggesting that inflammation is involved in the pathogenesis of PAH, as well the therapeutic potential of immunosuppressive agents in PAH.
Jolyane Meloche and Sébastien Renard have equally contributed to this work.
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Abbreviations
- BMPRII:
-
Bone morphogenetic protein receptor 2
- CCL:
-
C-C motif ligand
- CsA:
-
Ciclosporin A
- CTD:
-
Connective tissue disease
- CYC:
-
Cyclophosphamide
- DHEA:
-
Dehydroepiandrosterone
- EC:
-
Endothelial cells
- HAART:
-
Highly active antiretroviral therapy
- HHV-8:
-
Human herpes virus 8
- HIF-1α:
-
Hypoxia inducible factor 1 alpha
- HIV:
-
Human immunodeficiency virus
- IL:
-
Interleukin (i.e., IL-6, IL-2)
- iPAH:
-
Idiopatic pulmonary arterial hypertension
- MCP-1:
-
Monocyte chemotactic protein 1
- MCT:
-
Monocrotaline (induced PAH)
- MIP-1α:
-
Macrophage inflammatory protein 1 alpha
- MMF:
-
Mycophenolate mofetil
- MTX:
-
Methotrexate
- NFAT:
-
Nuclear factor for activated T cells
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- PA:
-
Pulmonary artery
- PAH:
-
Pulmonary arterial hypertension
- PASMC:
-
Pulmonary artery smooth muscle cells
- PDGF:
-
Platelet-derived growth factor
- PH:
-
Pulmonary hypertension
- RANTES:
-
Regulated upon activation normal T cell expressed and secreted
- RV:
-
Right ventricle/ventricular
- SLE:
-
Systemic lupus erythematosus
- SSc:
-
Systemic scleroderma
- Tc:
-
Cytotoxic T lymphocytes
- Th:
-
Helper T lymphocytes
- TNF-α:
-
Tumor necrosis factor alpha
- Treg:
-
Regulatory T lymphocytes
- VEGF:
-
Vascular endothelial growth factor
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Meloche, J., Renard, S., Provencher, S., Bonnet, S. (2013). Anti-inflammatory and Immunosuppressive Agents in PAH. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_18
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