Novelty in Treatment of Pulmonary Fibrosis: Pulmonary Hypertension Drugs and Others

Correale, Michele; Totaro, Antonio; Lacedonia, Donato; Montrone, Deodata; Foschino, Maria Pia; Brunetti, Natale Daniele

doi:10.2174/187152571131100086

Cited by 6 publications

(6 citation statements)

References 53 publications

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“…Interestingly, immunosuppressive peptidyl-prolyl isomerase inhibitors like FK506 have been ascribed potent antifibrotic effects in lung fibrosis (40)(41)(42)(43). FK506 suppresses collagen synthesis and expression of the TGF-b 1 receptor in dermal and lung fibroblasts, but the underlying mechanisms are largely unclear (41,44,45).…”

Section: Discussionmentioning

confidence: 99%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).Objectives: To assess the expression and function of FKBP10 in IPF. Methods:We assessed FKBP10 expression in bleomycininduced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-b 1 , was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68 1 macrophages. Transforming growth factor-b 1 , but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and a-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.Conclusions: FKBP10 might be a novel drug target for IPF.

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Section: Discussionmentioning

confidence: 99%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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“…ET-1 receptor antagonists, bosentan, macitentan and ambrisentan are currently approved for the treatment of PAH, preventing the aberrant activity of ET-1 observed in patients. Bosentan and macitentan are dual ET A and ET B receptor antagonist, whereas ambrisentan is a selective ET A receptor antagonist (Correale et al, 2013).…”

Section: Endothelin Receptor Antagonistsmentioning

confidence: 99%

The Role of Sex in the Pathophysiology of Pulmonary Hypertension

Docherty

Harvey

Mair

et al. 2018

Advances in Experimental Medicine and Biology

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Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin.

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“…As such, ERAs can be distinguished into two types, based on the action on the ET receptor, with relative differences in pharmacologic effects: selective drugs (eg, ambrisentan) and unselective (eg, Bosentan and macitentan). 13 If these drugs bind to ET 1 receptors, the latter cannot be activated by ET 1 , which cannot exert its effects on vascular structures within the lungs. The rationale for the selective blockade of ET A receptors is the ability to maintain the potential beneficial effects mediated by ET B receptors (vasodilatation and ET 1 clearance) by blocking only the adverse effects (vasoconstriction and proliferation) of ET A receptors.…”

Section: Resultsmentioning

confidence: 99%

Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

Correale

Ferraretti

Monaco

et al. 2018

VHRM

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Pulmonary arterial hypertension, a disease largely neglected until a few decades ago, is presently the object of intense studies by several research teams. Despite considerable progress, pulmonary arterial hypertension remains a major clinical problem, because it is not always easy to diagnose, treat, and prevent. The disease was considered incurable until the late 1990s, when Epoprostenol was introduced as the first tool against this illness. More recently, therapy for pulmonary arterial hypertension gained momentum after publication of the SERAPHIN and AMBITION trials, which also highlighted the importance of upfront therapy. This review also focuses on recent substudies from these trials and progress in drugs targeting the endothelin pathway. Future perspectives with regard to endothelin-receptor antagonists are also discussed.

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Novelty in Treatment of Pulmonary Fibrosis: Pulmonary Hypertension Drugs and Others

Cited by 6 publications

References 53 publications

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

The Role of Sex in the Pathophysiology of Pulmonary Hypertension

Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

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