RESUMO
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 hypoxia-inducible 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.
Assuntos
Adenosina/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Idoso , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Fibrose Pulmonar/metabolismo , Remodelação VascularRESUMO
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-ß activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Hipertensão Pulmonar/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Células Cultivadas , Regulação para Baixo , Expressão Gênica , Humanos , Hipertensão Pulmonar/etiologia , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/fisiopatologia , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Isoformas de Proteínas , Interferência de RNARESUMO
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.
Assuntos
Fibrose Pulmonar Idiopática/imunologia , Interleucina-6/imunologia , Macrófagos Alveolares/imunologia , Fibrose Pulmonar/imunologia , Receptores de Interleucina-6/imunologia , Transdução de Sinais/imunologia , Animais , Colágeno/imunologia , Modelos Animais de Doenças , Feminino , Fibronectinas/imunologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/terapia , Interleucina-6/genética , Pulmão/imunologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Masculino , Camundongos , Miofibroblastos/imunologia , Miofibroblastos/patologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologiaRESUMO
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 1α 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 1α 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.
Assuntos
Desoxicitidina Quinase/fisiologia , Hipóxia/complicações , Fibrose Pulmonar Idiopática/etiologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Humanos , Hipóxia/enzimologia , Hipóxia/fisiopatologia , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Alvéolos Pulmonares/enzimologia , Alvéolos Pulmonares/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/enzimologiaRESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.
Assuntos
Apoptose/efeitos dos fármacos , Nucleotídeos de Desoxiadenina/metabolismo , Desoxiadenosinas/metabolismo , Desoxicitidina Quinase/metabolismo , Hipóxia/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , 2-Cloroadenosina/análogos & derivados , 2-Cloroadenosina/farmacologia , Adenosina Desaminase/deficiência , Animais , Células Cultivadas , Desoxiadenosinas/farmacologia , Humanos , Camundongos , Regulação para CimaRESUMO
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.
Assuntos
Ácido Hialurônico/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptor A2B de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Idoso , Animais , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , Purinas/farmacologia , Pirazóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor A2B de Adenosina/genéticaRESUMO
Bleeding can occur as a sequela to cardiac surgery. Surgical products-such as conventional sutures and clips, and somewhat less conventional sealants-have been developed to prevent this event. Among these, CoSeal is a sealant used at our institution; here we report the cases of 2 patients in whom CoSeal was used successfully as either a supplement or an alternative to suture repair. This sealant was found to be useful in attaining hemostasis both in high-pressure ventricular repair and in the rupture of a friable coronary sinus adjacent to vital structures (in this instance, a left circumflex coronary artery).
Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiopatias/cirurgia , Hemostasia Cirúrgica/métodos , Polietilenoglicóis/administração & dosagem , Feminino , Cardiopatias/complicações , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Cardiac paragangliomas are an extremely rare subset of chromaffin cell tumors that develop from neural crest cells. METHODS: Between March 2004 and October 2010, 7 male patients from our two institutions who underwent surgical resection of cardiac paraganglioma were retrospectively reviewed. RESULTS: In 5 patients, paragangliomas originated from the roof of the left atrium, and in 2 patients, they originated from the aortic root. Hospital mortality was 14%. CONCLUSIONS: Complete surgical resection remains the mainstay of therapy and can be curative, but carries a significant risk of intraoperative bleeding and usually requires cardiopulmonary bypass and often complex resection techniques, including cardiac autotransplantation.
Assuntos
Aorta/cirurgia , Átrios do Coração/cirurgia , Neoplasias Cardíacas/cirurgia , Paraganglioma Extrassuprarrenal/cirurgia , Adulto , Aorta/patologia , Angiografia Coronária , Seguimentos , Átrios do Coração/patologia , Neoplasias Cardíacas/irrigação sanguínea , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patologia , Humanos , Masculino , Neoplasia Residual/irrigação sanguínea , Neoplasia Residual/diagnóstico , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Paraganglioma Extrassuprarrenal/irrigação sanguínea , Paraganglioma Extrassuprarrenal/diagnóstico , Paraganglioma Extrassuprarrenal/patologia , Reoperação , Estudos Retrospectivos , Transplante AutólogoRESUMO
The aortic root is often affected by aneurysmal degeneration of the ascending aorta or dissection. It is important for the clinician to be familiar with current guidelines and recommendations for detection, monitoring, and intervention of the aneurysmal aortic root. Timely surgical referral to an experienced aortic center allows for close monitoring and possible intervention that may preserve the aortic valve in appropriate cases and avoid disastrous complications such as aortic dissection, rupture, or death. Patients with bicuspid aortic valve syndrome or connective tissue disorders (e.g. Marfan syndrome) are particularly at risk and should be followed aggressively. Whenever possible, attempts should be made to preserve or repair the aortic valve using valve-sparing aortic root replacement techniques. This article provides an overview of recent advances in management of the aortic root, including guidelines for surgical intervention, technical procedures, and outcomes.