Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis: A Review

Pitsiou, Georgia; Papakosta, Despina; Bouros, Demosthenes

doi:10.1159/000327918

Cited by 61 publications

(54 citation statements)

References 182 publications

(172 reference statements)

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“…The lungs of patients with IPF are marked with recurrent epithelial injury and remodeling, which can directly affect local blood-gas exchange and result in hypoxia (2,32,33). Our studies confirm previous observations that Hif-1a levels are elevated in experimental pulmonary fibrosis and in IPF (3), and demonstrate that Hif1a-mediated up-regulation of DCK in hyperblastic epithelial cells in the lungs is necessary for the development of extensive fibrosis.…”

Section: Discussionsupporting

confidence: 88%

Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

Weng¹,

Poth

Karmouty‐Quintana³

et al. 2014

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood.Objectives: To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis.Methods: DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice.Measurements and Main Results: DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1a and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1a in the alveolar epithelium.Conclusions: Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation.

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Section: Discussionsupporting

confidence: 88%

Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

Weng¹,

Poth

Karmouty‐Quintana³

et al. 2014

Am J Respir Crit Care Med

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“…Despite the increased mortality due to PH, there are no effective clinical or molecular markers that can be used to predict or evaluate its development or progression (5,7,32,33). In line with this, we report no significant correlations between mPAP values and pulmonary function tests or blood gas values, a phenomenon that has been reported previously and has been ascribed to a lower sensitivity of these tests to detect ORIGINAL RESEARCH changes in pulmonary vascular tone (34).…”

Section: Discussionsupporting

confidence: 86%

Altered Hypoxic–Adenosine Axis and Metabolism in Group III Pulmonary Hypertension

Garcia-Morales¹,

Chen²,

Weng³

et al. 2016

Am J Respir Cell Mol Biol

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Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxiainducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.Keywords: group III pulmonary hypertension; adenosine A2B receptor; idiopathic pulmonary fibrosis; succinate; hypoxiainducible factor-1A Clinical RelevanceThis study shows that alterations in metabolism lead to enhanced activation of the hypoxic-adenosine axis that contribute to the development of pulmonary hypertension associated with idiopathic pulmonary fibrosis. These findings suggest that targeting elements of the hypoxic-adenosine axis could be used therapeutically for group III pulmonary hypertension, for which currently no effective strategies exist.

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“…In a recent study, KIMURA et al [32] confirmed by multivariate analysis that a high mean PAP value measured at the initial evaluation of IPF patients undergoing RHC is an independent predictor of survival. Unlike many other studies [1,33,34], this retrospective analysis focused on IPF patients affected by milder disease (mean FVC 70.2%, and mean DLCO 47.9%) [32]. The study demonstrated the importance of the initial evaluation of PH and supported previous observations indicating that PH is not just a result of restrictive impairment in patients with IPF [1,20,35].…”

Section: Prognostic Significance Of Ph In Ipfsupporting

confidence: 71%

Pulmonary hypertension in chronic interstitial lung diseases

Caminati¹,

Cassandro²,

Harari³

2013

European Respiratory Review

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Pulmonary hypertension (PH) is a common complication of interstitial lung diseases (ILDs), particularly in idiopathic pulmonary fibrosis and ILD associated with connective tissue disease. However, other lung diseases, such as combined pulmonary fibrosis and emphysema syndrome, pulmonary Langerhans cell histiocytosis, and lymphangioleiomyomatosis, may also include PH in their clinical manifestations. In all of these diseases, PH is associated with reduced exercise capacity and poor prognosis. The degree of PH in ILDs is typically mild-to-moderate. However, some of these patients may develop a disproportionate increase in PH that cannot be justified solely by hypoxia and parenchymal injury: this condition has been termed “out-of-proportion” PH. The pathogenesis of PH in these diseases is various, incompletely understood and may be multifactorial. The clinical suspicion (i.e. increased dyspnoea, low diffusion capacity) and echocardiographic assessment are the first steps towards proper diagnosis of PH; however, right heart catheterisation remains the current gold standard for diagnosis of PH. At present, no specific therapies have been approved for the treatment of PH in patients with ILDs

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Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis: A Review

Cited by 61 publications

References 182 publications

Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

Hypoxia-induced Deoxycytidine Kinase Contributes to Epithelial Proliferation in Pulmonary Fibrosis

Altered Hypoxic–Adenosine Axis and Metabolism in Group III Pulmonary Hypertension

Pulmonary hypertension in chronic interstitial lung diseases

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