Inflammation, Growth Factors, and Pulmonary Vascular Remodeling

Abstract

Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary vascular remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

“…Growth factors, metabolic reprogramming inflammation and NFAT have been implicated in the development of PAH. [3][4][5] The fact that NFAT is activated in both inflammatory cells and pulmonary arterial smooth muscle cells (PASMCs) within pulmonary circulation in both animal and human PAH suggests that NFAT plays a critical role in the pathogenesis of this disease. In this paper, we will discuss how NFAT proteins regulate pulmonary vascular remodeling.…”

Potassium channels in pulmonary arterial hypertension

“…PAH is characterised by proliferation and remodelling of the small pulmonary arteries, leading to increased pulmonary vascular resistance, subsequent right ventricular hypertrophy and ultimately death. It is currently accepted that endothelial cell dysfunction, originating from genetic defects, hypoxia, shear stress or inflammation, promotes the release of vasoconstrictors and mitogens that in turn trigger pulmonary artery smooth muscle cells (PASMCs) contraction, proliferation and resistance to apoptosis [2,3]. Although pathogenesis of PAH is recognised as a complex and multifactorial process, numerous data has accumulated demonstrating the significant role of potassium (K + ) channels in the cellular mechanisms underlying abnormal PASMC behaviour.…”

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

“…1 Resident lung vascular cells, inflammatory cells and cells of the immune system, bone marrow-derived cells, and various precursor or stem cells are all potential participants in the sequence of events leading to vascular remodeling; their particular and interactive roles in pulmonary vascular remodeling are under active investigation in a number of experimental models of PAH. [2][3][4][5][6] The concepts of apoptosis resistance of proliferating vascular cells 1,7 and of misguided angiogenesis have now advanced the field, and we have proposed that angioobliterative PAH is initiated by pulmonary vascular endothelial cell apoptosis. However, by itself endothelial cell apoptosis is insufficient to cause severe PAH.…”