Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights

Abstract

Pulmonary hypertension (PH) developing secondarily in pulmonary fibrosis (PF) patients (PF-PH) is a frequent co-morbidity. The high prevalence of PH in PF patients is very concerning since the presence of PH is a strong predictor of mortality in PF patients. Until recently, PH was thought to arise solely from fibrotic destruction of the lung parenchyma, leading to hypoxic vasoconstriction and loss of vascular bed density. Thus, potential cellular and molecular dysregulation of vascular remodeling as a driver of PF-PH has been under-investigated. The recent demonstrations that there is no correlation between the severity of the fibrosis and development of PH, along with the finding that significant vascular histological and molecular differences exist between patients with and without PH have shifted the etiological paradigm of PF-PH. This review aims to provide a comprehensive translational overview of PH in PF patients from clinical diagnosis and outcome to the latest understanding of the histology and molecular pathophysiology of PF-PH.

Keywords: Pulmonary fibrosis; Pulmonary hypertension; Vascular diseases.

Fig. 1

Prevalence of PH in PF patients. Graphical representation of the prevalence of PH found in the PF patient population in multiple studies. Studies in black used right heart catheterization (RHC) with a mean Pulmonary Arterial Pressure (mPAP) above 25 mmHg to define PH. Studies in blue used transthoracic echography (TTE) to define PH with a calculated systolic pulmonary arterial pressure (SPAP) above 35 mmHg except Song et al. which used a SPAP above 40 mmHg to define PH. PLCH (Pulmonary Langerhans Cell Histiocytosis); CHP (Chronic Hypersensitivity Pneumonitis); Ssc (Systemic Scleroderma); IPF (Idiopathic Pulmonary Fibrosis)

Fig. 2

Schematic representation of molecular mechanisms participating in vascular remodeling that promote PH in PF patients. Depicted in yellow, angiogenesis and endothelial dysfunction are known to be dysregulated in PF patients and to participate in PH development, making PF a fertile ground for PH development. Depicted in green, Adenosine and BMPR2 are known to be dysregulated in PF patients and to be further impaired in patients with PF-PH. Depicted in purple, HIF-1a, Slug and pulmonary arterial smooth muscle cells (SMC) proliferation are three hallmarks of patients with PF-PH