RESUMO
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.
Assuntos
Fibrose Pulmonar Idiopática/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Diagnóstico Diferencial , Humanos , Pulmão , PrognósticoRESUMO
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.
RESUMO
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.
Assuntos
Infecção Hospitalar , Pneumonia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Humanos , Pneumonia/tratamento farmacológico , Pneumonia/etiologiaRESUMO
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.
Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Humanos , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico , Prognóstico , Medição de RiscoRESUMO
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.
Assuntos
Hipercalcemia , Hiperparatireoidismo Primário , Osteíte Fibrosa Cística , Neoplasias das Paratireoides , Refugiados , Adulto , Humanos , Hipercalcemia/complicações , Hipercalcemia/diagnóstico , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Osteíte Fibrosa Cística/diagnóstico , Osteíte Fibrosa Cística/etiologia , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/diagnósticoRESUMO
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.
Assuntos
Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Dispneia/diagnóstico , Dispneia/tratamento farmacológico , Dispneia/etiologia , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Guanilato Ciclase , Humanos , Hipertensão Pulmonar/etiologia , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Prognóstico , Prostaglandinas/efeitos adversos , Prostaglandinas/uso terapêutico , Receptores de Epoprostenol/agonistas , Fatores de Risco , Remodelação Vascular/fisiologia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/etiologiaRESUMO
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.
Assuntos
Inflamação/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Aspirina/farmacologia , Azepinas/farmacologia , Células CACO-2 , Calcimicina/farmacologia , Humanos , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/efeitos dos fármacos , Elastase Pancreática/metabolismo , Explosão Respiratória/efeitos dos fármacos , Triazóis/farmacologia , ômega-N-Metilarginina/farmacologiaRESUMO
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.
Assuntos
Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Lesão Pulmonar/complicações , Lesão Pulmonar/terapia , Guias de Prática Clínica como Assunto , Pneumologia/normas , Cardiologia/normas , Alemanha , Humanos , Hipertensão Pulmonar/diagnóstico , Lesão Pulmonar/diagnósticoRESUMO
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.
Assuntos
Hipertensão Pulmonar/terapia , Inibidores Enzimáticos/uso terapêutico , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas I/uso terapêutico , Receptores de Endotelina/efeitos dos fármacos , Guanilil Ciclase Solúvel/antagonistas & inibidoresRESUMO
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.
Assuntos
Eletrocardiografia Ambulatorial/estatística & dados numéricos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/epidemiologia , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Causalidade , Comorbidade , Reações Falso-Negativas , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Distribuição por Sexo , Adulto JovemRESUMO
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.
Assuntos
Anti-Hipertensivos/administração & dosagem , Antagonistas dos Receptores de Endotelina/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Prostaglandinas/administração & dosagem , Receptores Citoplasmáticos e Nucleares/agonistas , Medicina Baseada em Evidências , Guanilato Ciclase , Humanos , Hipertensão Pulmonar/diagnóstico , Guanilil Ciclase Solúvel , Resultado do TratamentoRESUMO
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.
Assuntos
Paniculite/diagnóstico , Paniculite/etiologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/etiologia , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Diagnóstico Diferencial , Humanos , Pessoa de Meia-Idade , Paniculite/terapia , Enfisema Pulmonar/terapia , Coxa da Perna , Deficiência de alfa 1-Antitripsina/terapiaAssuntos
Comportamento Cooperativo , Hipertensão Pulmonar/tratamento farmacológico , Comunicação Interdisciplinar , Terapia de Alvo Molecular/métodos , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Terapia Combinada , Aprovação de Drogas , Quimioterapia Combinada , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Medicina Baseada em Evidências , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoAssuntos
Benzamidas/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Benzamidas/efeitos adversos , Alemanha , Humanos , Hipertensão Pulmonar/mortalidade , Mesilato de Imatinib , Uso Off-Label , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Disfunção Ventricular Direita/tratamento farmacológico , Disfunção Ventricular Direita/mortalidadeRESUMO
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.
Assuntos
Anti-Hipertensivos/farmacologia , Benzamidas/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Paxilina/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-sis/farmacologia , Pirimidinas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Animais , Apoptose/efeitos dos fármacos , Becaplermina , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mesilato de Imatinib , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Paxilina/genética , Fosforilação , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Interferência de RNA , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , TirosinaRESUMO
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.
Assuntos
Exercício Físico/fisiologia , Forame Oval Patente/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Adulto , Pressão Arterial/fisiologia , Teste de Esforço/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiologia , Circulação Pulmonar/fisiologiaRESUMO
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.
Assuntos
Dispneia/etiologia , Dispneia/fisiopatologia , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Capacidade Inspiratória , Mecânica Respiratória , Volume de Ventilação Pulmonar , Tolerância ao Exercício , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , AMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Camundongos , Camundongos Nus , Inibidores da Fosfodiesterase 4/farmacologia , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transplante HeterólogoRESUMO
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.