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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease without significant disease-modifying treatment
One additional factor contributing to death associated with IPF is the development of secondary pulmonary hypertension, defined as WHO group III pulmonary hypertension – associated with lung diseases and/or hypoxia
Prevalence of secondary pulmonary hypertension in IPF ranges from 32% to 85%, and importantly is associated with worse exercise capacity, quality of life and survival compared to patients with IPF and no evidence of pulmonary hypertension [1]
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease without significant disease-modifying treatment. One additional factor contributing to death associated with IPF is the development of secondary pulmonary hypertension, defined as WHO group III pulmonary hypertension – associated with lung diseases and/or hypoxia. The available medical therapies for treatment of primary pulmonary arterial hypertension are either ineffective in the treatment of secondary pulmonary hypertension [2], or provide only a small potential benefit in secondary trial outcomes [3]. To this end, there is a large need for novel therapies based on alternative mechanistic pathways in disease development
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