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2.
Artigo em Inglês | MEDLINE | ID: mdl-32160015

RESUMO

The extracellular matrix (ECM) increasingly emerges as an active driver in several diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins. In pulmonary arteries, the BM is in close contact and direct proximity to vascular cells including endothelial cells. So far, the role of the BM has remained under-investigated in IPAH. Here, we aimed to shed light on the involvement of the BM in IPAH, by addressing its structure, composition and function. On an ultrastructural level, we observed a marked increase in BM thickness in IPAH pulmonary vessels. BM composition was distinct in small and large vessels and altered in IPAH. Proteoglycans were mostly responsible for distinction between smaller and larger vessels, while BM collagens and laminins were more abundantly expressed in IPAH. Type IV collagen and laminin both strengthened endothelial barrier integrity. However, only type IV collagen concentration dependently increased cell adhesion of both donor and IPAH-derived pulmonary arterial endothelial cells (PAEC), and induced nuclear translocation of mechanosensitive transcriptional co-activator of the hippo pathway Yes-activated protein (YAP). On the other hand, laminin caused cytoplasmic retention of YAP in IPAH PAEC. Accordingly, silencing of COL4A5 and LAMC1, respectively, differentially affected tight junction formation and barrier integrity in both donor and IPAH PAEC. Collectively, our results highlight the importance for a well-maintained BM homeostasis. By linking changes in BM structure and composition to altered endothelial cell function, we here suggest an active involvement of the BM in IPAH pathogenesis. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

3.
Br J Pharmacol ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31976545

RESUMO

Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long-term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Further research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to affect COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies.

4.
Am J Respir Crit Care Med ; 201(5): 575-585, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31661308

RESUMO

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

5.
Thorac Cancer ; 11(2): 205-215, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31799812

RESUMO

Lung cancer incidence has increased worldwide over the past decades, with non-small cell lung cancer (NSCLC) accounting for the vast majority (85%) of lung cancer specimens. It is estimated that lung cancer causes about 1.7 million global deaths per year worldwide. Multiple trials have been carried out, with the aim of finding new effective treatment options. Lately, special focus has been placed on immune checkpoint (PD1/PD-L1) inhibitors which impact the tumor immune microenvironment. Tumor mutational burden (TMB) has been found to predict response to immune checkpoint inhibitors. Conversely, recent studies have weakened the significance of TMB as a predictor of response to therapy and survival. In this review article, we discuss the significance of TMB, as well as possible limitations. Furthermore, we give a concise overview of mutations frequently found in NSCLC, and discuss the significance of oncogene addiction in lung cancer as an essential driver of tumorigenesis and tumor progression.

6.
Cancer Lett ; 469: 266-276, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31697978

RESUMO

Lung cancer is one of the deadliest cancers worldwide. Late diagnosis at an advanced, inoperable stage makes chemotherapy a treatment of choice, yet, with low response rates. The hedgehog signaling pathway (HHSP) is often reactivated in cancer. We identified miR-182-5p as a regulator of GLI2, a transcriptional regulator of the HHSP, and explored the role of the miR-182-5p/GLI2 axis in carcinogenesis and cisplatin resistance of lung adenocarcinoma (LADC). Expression of miRNAs and target genes was analyzed by RT-qPCR, expression of the GLI-protein family in LADC and adjacent lung tissue (n = 27 pairs) by immunohistochemistry. MiR-182-5p was manipulated, and data were generated by immunoblotting, immunofluorescence, apoptosis, proliferation/viability, dual-luciferase-, and colony forming assays. MiR-182-5p was down-regulated in cisplatin-resistant LADC cells and directly targeted GLI2. Interference with miR-182-5p or GLI2 silencing resulted in modulation of cell proliferation, clonogenic potential, and cisplatin-sensitivity. HHSP was markedly reactivated in LADC tissue compared to adjacent non-malignant lung tissue. Our results indicate that the miR-182-5p/GLI2 axis modulates tumorigenesis and cisplatin-resistance in LADC cells, by influencing the HHSP. Therefore, this axis might be considered as a potential biomarker and future therapeutic target in LADC patients.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31812575

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E2 exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE2 metabolism under the control of TGF-ß and microRNA 218. OBJECTIVE: We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue. METHODS: In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis. RESULTS: We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE2 levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro. CONCLUSIONS: These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.

8.
BMC Pulm Med ; 19(1): 230, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783745

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is a severe rheumatic disease of the interstitial tissue, in which heart and lung involvement can lead to disease-specific mortality. Our study tests the hypothesis that in addition to established prognostic factors, cardiopulmonary exercise testing (CPET) parameters, particularly peak oxygen uptake (peakVO2) and ventilation/carbon dioxide (VE/VCO2)-slope, can predict survival in patients with SSc. SUBJECTS AND METHODS: We retrospectively assessed 210 patients (80.9% female) in 6 centres over 10 years with pulmonary testing and CPET. Survival was analysed with Cox regression analysis (adjusted for age and gender) by age, comorbidity (Charlson-Index), body weight, body-mass index, extensive interstitial lung disease, pulmonary artery pressure (measured by echocardiography and invasively), and haemodynamic, pulmonary and CPET parameters. RESULTS: Five- and ten-year survival of SSc patients was 93.8 and 86.9%, respectively. There was no difference in survival between patients with diffuse (dcSSc) and limited cutaneous manifestation (lcSSc; p = 0.3). Pulmonary and CPET parameters were significantly impaired. Prognosis was worst for patients with pulmonary hypertension (p = 0.007), 6-min walking distance < 413 m (p = 0.003), peakVO2 < 15.6 mL∙kg- 1∙min- 1, and VE/VCO2-slope > 35. Age (hazard ratio HR = 1.23; 95% confidence interval CI: 1.14;1.41), VE/VCO2-slope (HR = 0.9; CI 0.82;0.98), diffusion capacity (Krogh factor, HR = 0.92; CI 0.86;0.98), forced vital capacity (FVC, HR = 0.91; CI 0.86;0.96), and peakVO2 (HR = 0.87; CI 0.81;0.94) were significantly linked to survival in multivariate analyses (Harrell's C = 0.95). This is the first large study with SSc patients that demonstrates the prognostic value of peakVO2 < 15.6 mL∙kg- 1∙min- 1 (< 64.5% of predicted peakVO2) and VE/VCO2-slope > 35.

9.
JACC Heart Fail ; 7(10): 823-833, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31521680

RESUMO

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) coincide in a significant number of patients. Recent population-based registries suggest that spirometry is largely underused in patients with HF to diagnose comorbid COPD and that patients with COPD frequently do not receive the recommended beta-blocker (BB) treatment. This state-of-the-art review summarizes: 1) current challenges in the implementation of recommended spirometry for COPD diagnosis in patients with HF; and 2) current underuse and underdosing of BBs in patients with HF and COPD despite guideline recommendations. Open issues in the therapeutic management of patients with HF and COPD are discussed in the third section, including the use of the nonselective BB carvedilol, target BB doses in patients with HF and COPD, BB and bronchodilator management during HF hospitalization with and without COPD exacerbation, and the use of BBs in patients with COPD with right HF or free from cardiovascular disease. The whole scenario described herein advocates for a bipartisan initiative to drive immediate attention to the translation of guideline recommendations into clinical practice for patients with HF with co-occurring COPD.

12.
Eur Respir J ; 54(3)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31320452

RESUMO

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1ß in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1ß were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg-1·day-1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitroFra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1ß was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.

13.
Dtsch Med Wochenschr ; 144(19): 1367-1372, 2019 09.
Artigo em Alemão | MEDLINE | ID: mdl-31277079

RESUMO

The ESC/ERS guidelines (published at the end of 2015) and other international recommendations defined pulmonary hypertension (PH) by an invasively measured mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest. At the 6th World Symposium on Pulmonary Hypertension in Nice a modification of this hemodynamic definition in the sense of lowering the threshold to > 20 mmHg was proposed. A pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU) is additionally required for the diagnosis of pre-capillary PH. This modification must be critically reviewed with regard to the underlying rationale and possible consequences. Therefore, a detailed explanation is required. In particular, it must be made clear that this change currently has no influence on the evidence-based and approval-compliant prescription of drugs for the targeted therapy of pulmonary arterial hypertension (PAH).


Assuntos
Hemodinâmica/fisiologia , Hipertensão Pulmonar , Anti-Hipertensivos/uso terapêutico , Cardiologia/organização & administração , Europa (Continente) , Humanos , Hipertensão Pulmonar/classificação , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Guias de Prática Clínica como Assunto , Pneumologia/organização & administração , Resistência Vascular
14.
Biochim Biophys Acta Rev Cancer ; 1872(1): 24-36, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152822

RESUMO

Cancer cells constantly face a fluctuating nutrient supply and interference with adaptive responses might be an effective therapeutic approach. It has been discovered that in the absence of glucose, cancer cells can synthesize crucial metabolites by expressing phosphoenolpyruvate carboxykinase (PEPCK, PCK1 or PCK2) using abbreviated forms of gluconeogenesis. Gluconeogenesis, which in essence is the reverse pathway of glycolysis, uses lactate or amino acids to feed biosynthetic pathways branching from glycolysis. PCK1 and PCK2 have been shown to be critical for the growth of certain cancers. In contrast, fructose-1,6-bisphosphatase 1 (FBP1), a downstream gluconeogenesis enzyme, inhibits glycolysis and tumor growth, partly by non-enzymatic mechanisms. This review sheds light on the current knowledge of cancer cell gluconeogenesis and its role in metabolic reprogramming, cancer cell plasticity, and tumor growth.


Assuntos
Proliferação de Células/genética , Gluconeogênese/genética , Redes e Vias Metabólicas/genética , Neoplasias/genética , Aminoácidos/metabolismo , Frutose-Bifosfatase/genética , Frutose-Bifosfatase/metabolismo , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo
16.
Eur Respir J ; 53(6)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31023847

RESUMO

Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl- channel TMEM16A gene. We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing pulmonary arterial hypertension (PAH).We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs).In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl- current in PASMCs (n=9-10). These cells were depolarised and could be repolarised by TMEM16A inhibitors or knock-down experiments (n=6-10). Inhibition/knock-down of TMEM16A reduced the proliferation of IPAH-PASMCs (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMCs produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established pulmonary hypertension.Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying the vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to reverse remodelling in PAH.

19.
Pulm Circ ; 9(3): 2045894019832214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729872

RESUMO

The diagnosis of idiopathic pulmonary arterial hypertension (iPAH) is complex and, besides invasive hemodynamic evaluation, includes several diagnostic steps to exclude any underlying diseases. The role of a decreased diffusion capacity of the lung for carbon monoxide (DLCO) is a matter of discussion. Here, we present a 76-year-old man with a smoking history of 30 pack-years who was diagnosed with iPAH after chronic thromboembolic pulmonary hypertension was excluded based on a negative perfusion scan, an underlying heart disease was excluded based on echocardiography and right heart catheterization, and a significant lung disease was excluded based on lung function test (FVC = 101% predicted, FEV1 = 104% predicted, FEV1/FVC = 77, TLC = 97% predicted) and thin-slice computed tomography (CT) scan. Just DLCO was reduced to 40% predicted, suggesting a possible structural lung disease. Postmortem examination demonstrated severe interstitial lung fibrosis combined with microscopic emphysema. This indicates that both CT imaging and pulmonary function test may be insensitive to a diffuse peripheral combined pattern of fibrosis and emphysema and that DLCO may be the only sensitive marker of this significant lung pathology.

20.
Respirology ; 24(5): 445-452, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30786325

RESUMO

BACKGROUND AND OBJECTIVE: This study aimed to investigate whether quantitative lung vessel morphology determined by a new fully automated algorithm is associated with functional indices in idiopathic pulmonary fibrosis (IPF). METHODS: A total of 152 IPF patients had vessel volume, density, tortuosity and heterogeneity quantified from computed tomography (CT) images by a fully automated algorithm. Separate quantitation of vessel metrics in pulmonary arteries and veins was performed in 106 patients. Results were evaluated against readouts from lung function tests. RESULTS: Normalized vessel volume expressed as a percentage of total lung volume was moderately correlated with functional indices on univariable linear regression analysis: forced vital capacity (R2 = 0.27, P < 1 × 10-6 ), diffusion capacity for carbon monoxide (DLCO ; R2 = 0.12, P = 3 × 10-5 ), total lung capacity (TLC; R2 = 0.45, P < 1 × 10-6 ) and composite physiologic index (CPI; R2 = 0.28, P < 1 × 10-6 ). Normalized vessel volume was correlated with vessel density but not with vessel heterogeneity. Quantitatively derived vessel metrics (and artery and vein subdivision scores) were not significantly linked with the transfer factor for carbon monoxide (KCO ), and only weakly with DLCO . On multivariable linear regression analysis, normalized vessel volume and vessel heterogeneity were independently linked with DLCO , TLC and CPI indicating that they capture different aspects of lung damage. Artery-vein separation provided no additional information beyond that captured in the whole vasculature. CONCLUSION: Our study confirms previous observations of links between vessel volume and functional measures of disease severity in IPF using a new vessel quantitation tool. Additionally, the new tool shows independent linkages of normalized vessel volume and vessel heterogeneity with functional indices. Quantitative vessel metrics do not appear to reflect vasculopathic damage in IPF.

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