RESUMEN
Fibrosing lung diseases describe a heterogeneous group of interstitial lung diseases (ILD) of highly variable etiology, but with a unifying terminal process of irreversible, fibroproliterative destruction of the alveolar surface, loss of compliance and progressive impairment of gas exchange. In view of the heterogeneity, the disastrous prognoses in some cases and the treatment consequences, a thorough differential diagnosis is essential in all patients. Antifibrotic therapies are currently only indicated in idiopathic pulmonary fibrosis (IPF). The only curative therapeutic option is lung transplantation. Therefore, suitable patients should be promptly evaluated.
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Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Fibrosis Pulmonar/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Diagnóstico Diferencial , Humanos , Pulmón , PronósticoRESUMEN
Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH.
RESUMEN
Hospital-acquired pneumonia (HAP) is a frequent complication of hospitalisation. Due to rising multidrug resistant bacteria an appropriate, empiric and targeted therapy is essential and requires an accurate assessment of risk for multidrug resistant bacteria. A targeted, temporal therapy is indispensable and should begin after a focussed diagnosis. Re-evaluation of therapy is important, as clinical course, microbiological and laboratory results might lead to de-escalation of therapy. In this review article the current German guidelines on the diagnosis and therapy of hospital-acquired pneumonia are summarized. Special focus is put on targeted, risk-adapted therapy.
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Infección Hospitalaria , Neumonía , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Humanos , Neumonía/tratamiento farmacológico , Neumonía/etiologíaRESUMEN
Community-acquired pneumonia (CAP) is a frequent and potentially fatal disorder. Due to the notably high mortality within the first days, the immediate initiation of rational diagnostic pathways and treatment is of tremendous prognostic impact. In this review article, the current German guideline on the diagnosis and therapy of CAP is presented. Special focus is put on structured patient management based on the individual risk for early identification of critically ill patients. In particular, risk assessment directly influences rational diagnostics and adequate therapy. New recommendations concerning preventive strategies are also discussed in this article.
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Infecciones Comunitarias Adquiridas , Neumonía , Antibacterianos/uso terapéutico , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Humanos , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Pronóstico , Medición de RiesgoRESUMEN
A 28-year-old Syrian refugee presented with right-sided knee pain and progressive deterioration of the general condition over the past months. Laboratory diagnostics revealed severe hypercalcemia due to primary hyperparathyroidism, and computed tomography (CT) scanning demonstrated disseminated osteolytic lesions throughout the skeleton. Histologically, these lesions were characterized by multinuclear giant cells (defining these lesions as so-called brown tumors). Finally, surgical removal of a jugular mass allowed the histopathologic diagnosis of a sporadic parathyroid carcinoma. In the patient, this condition was associated with a mutation in the HPRT2 gene locus.
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Hipercalcemia , Hiperparatiroidismo Primario , Osteítis Fibrosa Quística , Neoplasias de las Paratiroides , Refugiados , Adulto , Humanos , Hipercalcemia/complicaciones , Hipercalcemia/diagnóstico , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/diagnóstico , Osteítis Fibrosa Quística/diagnóstico , Osteítis Fibrosa Quística/etiología , Neoplasias de las Paratiroides/complicaciones , Neoplasias de las Paratiroides/diagnósticoRESUMEN
The term pulmonary arterial hypertension comprises a group of pulmonary vascular diseases of different etiologies that are characterized by similar precapillary vascular remodeling processes and result in exertional dyspnea and right heart insufficiency. The specific pharmacological treatment approach considers the risk of mortality and phenotypical properties and includes treatment with phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostanoids, as well as with more novel substances, such as a soluble guanylyl cyclase stimulator and an oral prostacyclin receptor agonist. The prognosis of the disease is mainly determined by the right heart insufficiency for which there is currently no specific pharmacological treatment. Lung transplantation may be offered as a last option. This review provides an overview of the current European guidelines from 2015 and the recommendations of the Cologne Consensus Conference for pulmonary hypertension from 2016.
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Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológico , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Disnea/diagnóstico , Disnea/tratamiento farmacológico , Disnea/etiología , Antagonistas de los Receptores de Endotelina/efectos adversos , Antagonistas de los Receptores de Endotelina/uso terapéutico , Guanilato Ciclasa , Humanos , Hipertensión Pulmonar/etiología , Inhibidores de Fosfodiesterasa 5/efectos adversos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Pronóstico , Prostaglandinas/efectos adversos , Prostaglandinas/uso terapéutico , Receptores de Epoprostenol/agonistas , Factores de Riesgo , Remodelación Vascular/fisiología , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/etiologíaRESUMEN
Polymorphonuclear granulocytes (PMN) are activated in inflammatory reactions. Intestinal epithelial cells are relevant for maintaining the intestinal barrier. We examined interactions of PMN and intestinal epithelial cell-like CaCo-2 cells to elucidate their regulation of inflammatory signalling and the impact of cyclooxygenase (COX), nitric oxide (NO) and platelet-activating factor (PAF). Human PMN and CaCo-2 cells, separately and in co-incubation, were stimulated with the calcium ionophore A23187 or with N-Formyl-methionyl-leucyl-phenylalanin (fMLP) that activates PMN only. Human neutrophil elastase (HNE) and respiratory Burst were measured. To evaluate the modulation of inflammatory crosstalk we applied inhibitors of COX (acetyl salicylic acid; ASA), NO-synthase (N-monomethyl-L-arginin; L-NMMA), and the PAF-receptor (WEB2086). Unstimulated, co-incubation of CaCo-2 cells and PMN led to significantly reduced Burst and elevated HNE as compared to PMN. After stimulation with A23187, co-incubation resulted in an inhibition of Burst and HNE. Using fMLP co-incubation failed to modulate Burst but increased HNE. Without stimulation, all three inhibitors abolished the effect of co-incubation on Burst but did not change HNE. ASA partly prevented modulation of Burst L-NMMA and WEB2086 did not change Burst but abolished mitigation of HNE. Without stimulation, co-incubation reduced Burst and elevated HNE. Activation of PMN and CaCo-2 cells by fMLP as compared to A23187 resulted in a completely different pattern of Burst and HNE, possibly due to single vs. dual cell activation. Anti-inflammatory effect of co-incubation might in part be due to due to COX-signalling governing Burst whereas NO- and PAF-dependent signalling seemed to control HNE release.
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Inflamación/patología , Neutrófilos/metabolismo , Neutrófilos/patología , Aspirina/farmacología , Azepinas/farmacología , Células CACO-2 , Calcimicina/farmacología , Humanos , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/efectos de los fármacos , Elastasa Pancreática/metabolismo , Estallido Respiratorio/efectos de los fármacos , Triazoles/farmacología , omega-N-Metilarginina/farmacologíaRESUMEN
The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.
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Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Lesión Pulmonar/complicaciones , Lesión Pulmonar/terapia , Guías de Práctica Clínica como Asunto , Neumología/normas , Cardiología/normas , Alemania , Humanos , Hipertensión Pulmonar/diagnóstico , Lesión Pulmonar/diagnósticoRESUMEN
Pulmonary hypertension (PH) comprises a group of pulmonary vascular diseases that are characterized by progressive exertional dyspnea and right heart insufficiency ultimately resulting in right heart decompensation. The classification is into five clinical subgroups that form the absolutely essential basis for decisions on the indications for different pharmacological and non-pharmacological forms of treatment. The guidelines were updated in 2015 and in addition to the hitherto existing pharmacological treatment options of phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclins, the soluble guanylate cyclase stimulator riociguat has now been incorporated for treatment of certain forms of PH. This article provides an overview of the new treatment recommendations in the current guidelines, e. g. for PH patients who are in intensive care units due to surgical interventions or progressive right heart insufficiency.
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Hipertensión Pulmonar/terapia , Inhibidores Enzimáticos/uso terapéutico , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Prostaglandinas I/uso terapéutico , Receptores de Endotelina/efectos de los fármacos , Guanilil Ciclasa Soluble/antagonistas & inhibidoresRESUMEN
BACKGROUND: Sudden cardiac death (SCD) accounts for approximately 30 % in patients with pulmonary arterial hypertension (PAH). The exact circumference for SCD in this patient population is still unclear. Malignant cardiac arrhythmias are reported to be rarely present. There are no systematic data concerning long-term electrocardiographic (ECG) recording in patients with PAH. OBJECTIVES: We sought to investigate the rate of potentially relevant arrhythmias in patients with pulmonary hypertension (PH). METHODS: Consecutive patients without diagnosis of known cardiac arrhythmias followed in our outpatient clinic for PH were enrolled in the study. All patients underwent a 72-h Holter ECG. Clinical data, 6-min walk distance, laboratory values, and echocardiography were collected/performed. RESULTS: Ninety-two consecutive patients (New York Heart Association class (NYHA) III/IV: 65.2 %/5.4 %, PH Group 1: 35.9 %, Group 3: 10.9 %, Group 4: 28.3 %, Group 5: 2.2 %) were investigated. Relevant arrhythmias were newly detected in 17 patients: non-sustained ventricular tachycardia (n = 12), intermittent second-degree heart block (n = 1), intermittent third-degree heart block (n= 3), and atrial flutter (n = 1). Echocardiographic systolic pulmonary pressure and diameter of the right heart were elevated in patients with relevant arrhythmias. Right heart catheterization revealed higher pulmonary vascular resistance (672 vs. 542 dyn · s · cm(-5), p = 0.247) and lower cardiac index (2.46 vs. 2.82 l/min/m(2), p = 0.184). CONCLUSIONS: Ventricular tachycardias occur more often in PH patients than previously reported. However, the prognostic relevance of non-sustained ventricular tachycardias in this cohort remains unclear. As a large number of PH patients die from SCD, closer monitoring, e.g., using implantable event recorders, might be useful to identify patients at high risk.
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Electrocardiografía Ambulatoria/estadística & datos numéricos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/epidemiología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Enfermedades Asintomáticas , Causalidad , Comorbilidad , Reacciones Falso Negativas , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Reproducibilidad de los Resultados , Medición de Riesgo , Sensibilidad y Especificidad , Distribución por Sexo , Adulto JovenRESUMEN
Pulmonary hypertension (PH) is a chronic progressive disease of the pulmonary circulation of multifactorial causes. The current diagnostic classification of PH distinguishes five main groups, which have as a common feature an increased pulmonary arterial pressure and pulmonary resistance. The classification differentiates pulmonary arterial hypertension (PAH), PH due to left heart disease, PH in lung diseases and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), and PH with unclear/multifactorial mechanisms. Recent advances in basic research with the approval of new drugs and the establishment of therapeutic strategies, mainly in PAH and CTEPH, require a differentiated view of the disease, a careful diagnosis and initiation of therapy, and regular follow-ups. In this article, we provide an overview of the complex drug therapy currently available for PAH patients.
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Antihipertensivos/administración & dosificación , Antagonistas de los Receptores de Endotelina/administración & dosificación , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Prostaglandinas/administración & dosificación , Receptores Citoplasmáticos y Nucleares/agonistas , Medicina Basada en la Evidencia , Guanilato Ciclasa , Humanos , Hipertensión Pulmonar/diagnóstico , Guanilil Ciclasa Soluble , Resultado del TratamientoRESUMEN
This article reports a case of febrile, symmetrical and painful soft tissue swelling on both thighs in a 54-year-old otherwise healthy male patient. Histologically, necrotizing panniculitis of subcutaneous adipose tissue was described as a marker manifestation of a previously unknown alpha-1-antitrypsin (A1AT) deficiency with pulmonary emphysema and low plasma A1AT levels. The PiZZ homozygous form of A1AT could be diagnosed by gene sequencing. Complete remission of panniculitis could be achieved by A1AT replacement therapy.
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Paniculitis/diagnóstico , Paniculitis/etiología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/etiología , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/diagnóstico , Diagnóstico Diferencial , Humanos , Persona de Mediana Edad , Paniculitis/terapia , Enfisema Pulmonar/terapia , Muslo , Deficiencia de alfa 1-Antitripsina/terapiaAsunto(s)
Conducta Cooperativa , Hipertensión Pulmonar/tratamiento farmacológico , Comunicación Interdisciplinaria , Terapia Molecular Dirigida/métodos , Adulto , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Terapia Combinada , Aprobación de Drogas , Quimioterapia Combinada , Antagonistas de los Receptores de Endotelina/efectos adversos , Antagonistas de los Receptores de Endotelina/uso terapéutico , Medicina Basada en la Evidencia , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/mortalidad , Inhibidores de Fosfodiesterasa 5/efectos adversos , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Benzamidas/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Benzamidas/efectos adversos , Alemania , Humanos , Hipertensión Pulmonar/mortalidad , Mesilato de Imatinib , Uso Fuera de lo Indicado , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/mortalidadRESUMEN
Chronic exposure to hypoxia induces a pronounced remodelling of the pulmonary vasculature leading to pulmonary hypertension (PH). The remodelling process also entails increased proliferation and decreased apoptosis of pulmonary arterial smooth muscle cells (PASMC), processes regulated by the cytoskeletal protein paxillin. In this study, we aimed to examine the molecular mechanisms leading to deregulation of paxillin in PH. We detected a time-dependent increase in paxillin tyrosine 31 (Y31) and 118 (Y118) phosphorylation following hypoxic exposure (1 % O2) or platelet-derived growth factor (PDGF)-BB stimulation of primary human PASMC. In addition, both, hypoxia- and PDGF-BB increased the nuclear localisation of phospho-paxillin Y31 as indicated by immunofluorescence staining in human PASMC. Elevated paxillin tyrosine phosphorylation in human PASMC was attenuated by hypoxia-inducible factor (HIF)-1α depletion or by treatment with the PDGF-BB receptor antagonist, imatinib. Moreover, we observed elevated paxillin Y31 and Y118 phosphorylation in the pulmonary vasculature of chronic hypoxic mice (21 days, 10 % O2) which was reversible by imatinib-treatment. PDGF-BB-dependent PASMC proliferation was regulated via the paxillin-Erk1/2-cyclin D1 pathway. In conclusion, we suggest paxillin up-regulation and phosphorylation as an important mechanism of vascular remodelling underlying pulmonary hypertension.
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Antihipertensivos/farmacología , Benzamidas/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Paxillin/metabolismo , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-sis/farmacología , Pirimidinas/farmacología , Remodelación Vascular/efectos de los fármacos , Transporte Activo de Núcleo Celular , Animales , Apoptosis/efectos de los fármacos , Becaplermina , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipoxia/complicaciones , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Mesilato de Imatinib , Ratones Endogámicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Paxillin/genética , Fosforilación , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Interferencia de ARN , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , TirosinaRESUMEN
A variation in right atrial and pulmonary arterial pressure might result in a shunt dynamic across a patent foramen ovale (PFO). In the present study we tested if peak exercise facilitates a restoration of right to left shunt (RLS) in stroke patients who demonstrated a functional PFO closure (no evidence of RLS across an initially demonstrated PFO). In stroke patients with PFO demonstrating a functional closure, the RLS was reassessed on peak exercise using contrast-enhanced transcranial Doppler sonography. The exercise procedure consisted of a cardiopulmonary exercise test with supplementary stress echocardiography for assessment of pulmonary circulation. Four stroke patients with initially PFO curtain pattern and a subsequent functional PFO closure (no evidence for RLS) underwent the procedure. In all four patients a RLS could be resurrected during peak physical exercise after a Valsalva strain. While in two patients peak exercise led to an RLS in a countable range of microembolic signals, in two patients a curtain pattern was obtained. One patient showed evidence for reoccurrence of RLS on peak exercise without a Valsalva strain. The patients with curtain pattern had a better peak exercise performance. Although the systolic pulmonary arterial pressure increased during exercise in all patients, there was no direct correlation with the detected RLS. After a functional PFO closure peak exercise combined with a Valsalva strain facilitates the reoccurrence of RLS in stroke patients.
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Ejercicio Físico/fisiología , Foramen Oval Permeable/fisiopatología , Accidente Cerebrovascular/fisiopatología , Adulto , Presión Arterial/fisiología , Prueba de Esfuerzo/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Pulmonar/fisiología , Circulación Pulmonar/fisiologíaRESUMEN
BACKGROUND: The dynamic decrease in inspiratory capacity (IC) during exercise with restriction of tidal volume (VT) is known as dynamic hyperinflation (DH) and is described mostly in patients with COPD differentiating between a "hyperinflator" and a "non-hyperinflator". Recent studies have revealed DH in patients with idiopathic pulmonary arterial hypertension (iPAH), but the influence of the DH on the reduced exercise capacity with exertional dyspnoae is still being debated. METHODS: We analysed flow-volume curves during cardiopulmonary exercise testing (CPET) in idiopathic PAH (n = 19), in COPD (n = 17), in idiopathic pulmonary fibrosis (IPF) (n = 19) and a control group (n = 30). We measured IC at rest and during maximal exercise and furthermore ventilation, VT and oxygen uptake (VO2 peak). In iPAH a right heart catheter test and a 6-minute walk test (6MWT) were performed, also the B-type naturetic peptide (BNP) and the NYHA/WHO functional class were determined. RESULTS: The IC decreased significantly in 11 PAH "hyperinflators" (PAH-H) (Δ IC: - 0.34 ± 0.14 L, p < 0.001) compared to 8 PAH "non-hyperinflators" (PAH-NH) (Δ IC: 0.08 ± 0.2 L). COPD patients exhibited a characteristic hyperinflation pattern with a decrease in IC throughout exercise (Δ IC: - 0.61 ± 0.3 L, p < 0.001), while patients with IPF (Δ IC: 0.03 ± 0.15 L) and the control group responsed to exercise with a non-hyperinflator pattern (Δ IC: 0.1 ± 0.2 L). Both PAH collectives showed a reduced IC/TLC, while VT/IC was elevated with a decreased peak VO2 and max. performance compared to the control group. Correlations of the IC rest/max (L) were shown in PAH-H and PAH-NH with the VO2 peak, max. performance and VT. CONCLUSION: The analysis of flow-volume curves during CPET can indentify DH in a subgroup of patients with iPAH. The DH contributes significantly but slightly to the development of exertional limitations and dyspnoe in a subgroup of iPAH. Further studies with a larger sample size will be required to definitively measure the impact of the DH seen in these patients.
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Disnea/etiología , Disnea/fisiopatología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/fisiopatología , Capacidad Inspiratoria , Mecánica Respiratoria , Volumen de Ventilación Pulmonar , Tolerancia al Ejercicio , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated. We exposed 10 different lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we analyzed various in silico predicted hypoxia-responsive elements (p-HREs) found in in PDE4A and PDE4D genes. Performing mutation analysis of the p-HRE in luciferase reporter constructs, we identified four functional HRE sites in the PDE4A gene and two functional HRE sites in the PDE4D gene that mediated hypoxic induction of the reporter. Silencing of hypoxia-inducible factor subunits (HIF1α and HIF2α) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i) as a cyclic adenosine monophosphate (cAMP) -elevating agent, cAMP analogs or protein kinase A (PKA)-modulating drugs and an exchange protein directly activated by cAMP (EPAC) activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis enhanced HIF signaling as measured by HRE reporter gene assay, HIF and HIF target genes expression ((lactate dehydrogenase A), LDHA, (pyruvate dehydrogenase kinase 1) PDK1 and (vascular endothelial growth factor A) VEGFA). Notably, inhibition of PDE4 by PDE4i or silencing of PDE4A and PDE4D reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation. Moreover, PDE4i treatment reduced hypoxia-induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. Our findings suggest that PDE4 is expressed in lung cancer, crosstalks with HIF signaling and promotes lung cancer progression. Thus, PDE4 may represent a therapeutic target for lung cancer therapy.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , AMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Ratones , Ratones Desnudos , Inhibidores de Fosfodiesterasa 4/farmacología , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Trasplante HeterólogoRESUMEN
Respiratory diseases are one of the most important causes of mortality with tremendous costs for health care systems, not only in Germany, but worldwide. Up to now treatment options for most of these chronic diseases are limited. The German Ministry for Research and Education (BMBF) - following the example of the US National Institute of Health have supported the foundation of a German Centre for Lung Research (DZL) to speed up the development of preventive, diagnostic and therapeutic measures. Not only universities, but also non-university based research institutes are part of the DZL. To allow the translation from basic research experience into clinical practice to improve patient care, basic research orientated approaches will be combined with disease and patient focused approaches. The DZL is one of six German Centres for Health Care Research (neurological diseases, diabetes, cardiovascular diseases, infectious diseases, cancer, and lung diseases) for the optimisation of translational processes to overcome the burden of major diseases.