Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights
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REVIEW
Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights Grégoire Ruffenach1 , Jason Hong1,2, Mylène Vaillancourt3, Lejla Medzikovic1 and Mansoureh Eghbali1*
Abstract Pulmonary hypertension (PH) developing secondarily in pulmonary fibrosis (PF) patients (PF-PH) is a frequent comorbidity. 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 hypertension, Pulmonary fibrosis, Vascular diseases Background Interstitial lung disease, which will be referred to hereafter as pulmonary fibrosis (PF), is an umbrella term that encompasses a wide range of lung diseases which culminate in fibrotic destruction of the lung parenchyma [1]. In the PF patient population, a major determinant of allcause mortality is the development of pulmonary hypertension (PH) secondary to PF (PF-PH) [2], making PH a potential cornerstone of PF patients care. PH is characterized by sustained elevation of pulmonary pressure as a result of severe pulmonary vascular remodeling and loss of capillary density. In the World Health Organization classification of PH, group 3 includes all PH secondary to
*Correspondence: [email protected] 1 Division of Molecular Medicine, Department of Anesthesiology and Perioperiative Medicine, David Geffen School of Medicine, University of California, BH‑550CHS, Los Angeles, CA 90095‑7115, USA Full list of author information is available at the end of the article
lung disease and PF-PH is a subclass (group 3.2) of this group [3, 4]. Our understanding of PH pathogenesis in PF patients primarily relies on data from idiopathic pulmonary fibrosis (IPF) [5]. In the recent years, new pathophysiological concepts emerged that primarily relate to IPF but may also have implications for PH in other forms of PF. In PH, sustained elevation of pulmonary pressures is driven, at least in part, by sustained inflammation, vascular smooth muscle cell proliferation and angiogenic dysfunction. Different pulmonary vascular remodeling morphologies can be observed in PH [6, 7]. These various morphological changes can both be present in multiple forms of PH or be characteristic of one specif
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