“A small leak will sink a great ship”: hypoxia-inducible factor and group III pulmonary hypertension

Abstract

Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) – a regulatory protein that is vital in adaptation to hypoxic conditions – in the development of secondary pulmonary hypertension. HIF influences development of hypoxia-induced pulmonary hypertension through alteration in voltage-gated potassium channels and homeostatic calcium regulation, resulting in disruption of endothelial cell-cell communication, and eventual vascular remodeling. This article summarizes salient literature related to HIF and secondary pulmonary hypertension, in addition to proposing a final common pathway in known mechanistic pathways that result in endothelial barrier integrity loss – vascular “leak” – primarily through a shared endothelial-epithelial signaling protein family, CCN.