RESUMO
High-altitude pulmonary edema (HAPE) is a life-threatening, noncardiogenic pulmonary edema that occurs in unacclimatized individuals rapidly ascending to high altitudes above 2,500 m above sea level. Until the entity of HAPE was first identified in a case report published in Japan in 1966, the symptoms of severe dyspnea or coma occurring in climbers of the Japan Alps were incorrectly attributed to pneumonia or congestive heart failure. The Shinshu University Hospital serves as the central facility for rescuing and treating patients with HAPE in the region. Over the past 50 years, a series of studies have been conducted at Shinshu University to gain a better understanding of the characteristics of HAPE. This review summarizes the major achievements of these studies, including their clinical features, management, and pathogenesis of HAPE, particularly in the Japanese population.
RESUMO
Patients with end-stage lung disease can undergo living-donor lobar lung transplantation (LDLLT), with survival rates improving every year. We herein report the 20-year follow-up findings of the first patient who underwent LDLLT in Japan. A 24-year-old woman with primary ciliary dyskinesia became ventilator-dependent after severe respiratory failure and right-sided heart failure following repeated respiratory infections. In 1998, she underwent LDLLT and received her sister's right lower lobe and her mother's left lower lobe. Although the patient required 21 hospitalizations and developed unilateral bronchiolitis obliterans syndrome, she is in good physical condition and lives without restriction at 20 years after undergoing LDLLT.
Assuntos
Transtornos da Motilidade Ciliar/cirurgia , Doadores Vivos , Transplante de Pulmão , Bronquiolite Obliterante/etiologia , Transtornos da Motilidade Ciliar/complicações , Feminino , Seguimentos , Volume Expiratório Forçado , Hospitalização/estatística & dados numéricos , Humanos , Japão , Pulmão/diagnóstico por imagem , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias , Radiografia Torácica , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Serum soluble interleukin-2 (IL-2) receptor (sIL-2R) might reflect disease activity in immunoglobulin G4-related disease (IgG4-RD). We aimed to elucidate the clinical significance of blood markers, including sIL-2R, in patients with IgG4-RD. METHODS: We enrolled 59 patients with IgG4-RD and investigated the association between blood markers (white blood cells, C-reactive protein, sIL-2R, IgG, IgG4, IgE, total hemolytic complement), and clinical indices. RESULTS: At baseline, serum sIL-2R (Rs = 0.532, p < .001) and IgG4 (Rs = 0.545, p < .001) levels showed significant correlation to the number of organs involved. During follow-up period (median, 70 months; range, 7-195 months), 40 patients were treated with corticosteroids. Receiver operating characteristic (ROC) analysis showed that baseline sIL-2R levels most accurately predicted patients requiring glucocorticoid treatment (area under the ROC curve, 0.807). Among the 46 patients who improved, sIL-2R and IgG4 levels decreased in 42 and 41 patients, respectively. Among them, serum sIL-2R levels decreased to a normal range in 42 patients (91%), whereas IgG4 levels normalized in 19 (41%). CONCLUSION: The serum sIL-2R level is a potential biomarker for IgG4-RD that may reflect the number of involved organs and may predict patients requiring glucocorticoid treatment.
Assuntos
Doenças Autoimunes/sangue , Imunoglobulina G/sangue , Receptores de Interleucina-2/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Osteoprotegerin (OPG) may play a role in the progression of cardiac hypertrophy and heart failure. However, its pathophysiological role in changes in cardiac structure and function with ageing remains to be elucidated. METHODS AND RESULTS: We conducted experiments using 2.5- and 12-month-old OPG(-/-) mice and age-matched wild-type (WT) mice and compared the morphology and function of the left ventricle (LV). Both 2.5- and 12-month-old OPG(-/-) mice showed a higher systolic blood pressure and a greater heart weight/body weight ratio than age-matched WT mice. Twelve-month-old OPG(-/-) mice had a significantly larger LV chamber and reduced wall thickness compared with age-matched WT mice, and contractile function was decreased. The morphological differences were accompanied by an increase in the number of apoptotic cells and activation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in the LV of 12-month-old OPG(-/-) mice. Correspondingly, OPG small interfering RNA induced the expressions of TRAIL and cleaved caspase-3 in cultured cardiac myocytes. In addition, these mice revealed a decrease in interstitial fibrosis, activation of matrix metalloproteinase (MMP)-2 and tissue inhibitors of MMP-1 and -2, and inactivation of procollagen α1 synthesis. Moreover, intraperitoneal administration of recombinant OPG to either 2.5- or 12-month-old OPG(-/-) mice for 28 days led to partial improvement of LV structure and function without affecting systolic blood pressure. CONCLUSION: These results suggest that OPG plays a role in preserving myocardial structure and function with ageing through a reduction in apoptosis and preservation of the matrix structure. In addition, this appears to be independent of effects on the vasculature.
Assuntos
Cardiomegalia/genética , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Remodelação Ventricular/fisiologia , Envelhecimento , Animais , Pressão Sanguínea/fisiologia , Cardiomegalia/fisiopatologia , Fibrose/metabolismo , Ventrículos do Coração/metabolismo , Camundongos , Camundongos TransgênicosRESUMO
BAL cytokines of IgG4-RRD patients are more characteristic of the Th2 response than those of sarcoidosis patients http://ow.ly/T2gDV.
RESUMO
A 37-year-old woman had undergone bilateral living-donor lobar lung transplantation 11 years previously for idiopathic pulmonary arterial hypertension. Her father donated the right lobe and her brother donated the left lobe. She subsequently developed progressively worsening respiratory dysfunction due to pneumonia. CT showed left dominant pulmonary artery dilatation, bronchial wall thickening and airway stenosis, followed by sudden death. An autopsy showed marked pathologic left dominant rejection of the pulmonary artery, small airway and large airway. Notably, only the left lung showed C4d vascular deposition, thus suggesting that antibody-mediated lung rejection may have occurred.
Assuntos
Antígenos CD4/imunologia , Rejeição de Enxerto/patologia , Doadores Vivos , Transplante de Pulmão , Artéria Pulmonar/patologia , Adulto , Autopsia , Antígenos CD4/metabolismo , Evolução Fatal , Feminino , Rejeição de Enxerto/imunologia , Humanos , Hipertensão Pulmonar/cirurgia , Artéria Pulmonar/imunologia , Artéria Pulmonar/metabolismo , Fatores de TempoAssuntos
Paragonimíase/diagnóstico , Paragonimus westermani , Adulto , Animais , Emigrantes e Imigrantes , Feminino , Humanos , Paragonimíase/etnologia , Irmãos , TailândiaRESUMO
Adrenomedullin (AM) is a vasodilator peptide with pleiotropic effects, including cardiovascular protection and anti-inflammation. Because of these beneficial effects, AM appears to be a promising therapeutic tool for human diseases, while intravenous injection of AM stimulates sympathetic nerve activity due to short-acting potent vasodilation, resulting in increased heart rate and renin secretion. To lessen these acute reactions, we conjugated the N-terminal of human AM peptide with polyethylene glycol (PEG), and examined the biological properties of PEGylated AM in the present study. PEGylated AM stimulated cAMP production, an intracellular second messenger of AM, in cultured human embryonic kidney cells expressing a specific AM receptor in a dose-dependent manner, as did native human AM. The pEC50 value of PEGylated AM was lower than human AM, but no difference was noted in maximum response (Emax) between the PEGylated and native peptides. Intravenous bolus injection of 10nmol/kg PEGylated AM lowered blood pressure in anesthetized rats, but the acute reduction became significantly smaller by PEGylation as compared with native AM. Plasma half-life of PEGylated AM was significantly longer than native AM both in the first and second phases in rats. In summary, N-terminal PEGylated AM stimulated cAMP production in vitro, showing lessened acute hypotensive action and a prolonged plasma half-life in comparison with native AM peptide in vivo.
Assuntos
Adrenomedulina/administração & dosagem , AMP Cíclico/biossíntese , Peptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adrenomedulina/química , Adrenomedulina/farmacocinética , Animais , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/metabolismo , Rim/metabolismo , Peptídeos/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Ratos , Receptores de Adrenomedulina/biossínteseRESUMO
INTRODUCTION: The mortality of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is high. Anticoagulation therapy (recombinant human soluble thrombomodulin (rhTM)) is recognized as a potential new strategy for treating disseminated intravascular coagulation in Japan. This preliminary study was to evaluate whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM for AE-IPF-patients has any beneficial effects on inflammatory mediators and activated coagulation. METHODS: We retrospectively compared the clinical data of AE-IPF-patients, idiopathic pulmonary fibrosis (IPF) with pneumonia-patients and slowly progressive IPF-patients. As a subsequent study, AE-IPF-patients were prospectively treated with a bolus of rhTM intravenously for six days under mechanical ventilation. We historically investigated the improvement of the serial clinical data in both oxygenation and intravascular coagulation disturbance between treated AE-IPF-patients and untreated AE-IPF-patients. RESULTS: Eleven AE-IPF, 21 IPF with pneumonia and 16 slowly progressive IPF-patients were enrolled, and the coagulatory levels of the AE-IPF-patients were found to be significantly higher than in the other patients. In 20 treated AE-IPF-patients, the 28-day mortality and in-hospital mortality were 35% and 45%, respectively. The levels of oxygenation rapidly increased on day 1 and continued to improve until day 7 in the survival AE-IPF-patients. The thrombin-antithrombin complex levels and inflammatory cytokine levels in the survivors on day 7 were significantly different from those observed in the nonsurvivors. CONCLUSION: AE-IPF-patients were found to have significantly higher levels of coagulation. The rhTM administration in the surviving AE-IPF-patients led to significant differences in the oxygenation and intravascular coagulation disturbance.
Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Trombomodulina/uso terapêutico , Doença Aguda , Idoso , Proteína C-Reativa/análise , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/mortalidade , L-Lactato Desidrogenase/sangue , Contagem de Leucócitos , Masculino , Estudos Prospectivos , Proteínas Recombinantes , Estudos RetrospectivosRESUMO
PURPOSE: Noninvasive ventilation (NIV) can reduce the need for invasive mechanical ventilation. The aim of this investigation was to determine whether the combination of NIV with administration of a neutrophil elastase inhibitor could improve outcome and respiratory conditions in acute respiratory distress syndrome (ARDS)-patients, according to the Berlin definition. METHODS: ARDS-patients were treated with NIV and a neutrophil elastase inhibitor. Patients were classified as having mild, moderate, and severe ARDS. ARDS-patients were divided into survivors and nonsurvivors on day 28 after the induction of NIV. RESULTS: A total of 47 ARDS-patients received NIV, and 37 of these patients did not require endotracheal intubation. Eight mild, 17 moderate, and 10 severe ARDS-patients were alive on day 28 after the induction of NIV. When ARDS-patients were divided into groups based upon an initial PaO2/FiO2 greater or less than 150 torr, the serial changes of both the PaO2/FiO2 and the lung injury score improved dramatically in those patients with a PaO2/FiO2>150. The survival ratio showed statistically significant differences in mild and moderate ARDS-patients treated with the neutrophil elastase inhibitor. CONCLUSIONS: Administration of neutrophil elastase inhibitor with NIV may be associated with successful outcome in mild-to-moderate ARDS-patients with initial PaO2/FiO2>150.
Assuntos
Ventilação não Invasiva , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Síndrome do Desconforto Respiratório/terapia , Fatores Etários , Idoso , Feminino , Humanos , Intubação Intratraqueal/estatística & dados numéricos , Lesão Pulmonar/diagnóstico , Masculino , Pessoa de Meia-Idade , Ventilação não Invasiva/mortalidade , Respiração Artificial , Síndrome do Desconforto Respiratório/classificação , Síndrome do Desconforto Respiratório/mortalidade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Patients with slowly progressive idiopathic interstitial pneumonia, including idiopathic pulmonary fibrosis, often deteriorate, thus suggesting that the clinical course may be unpredictable. Such episodes are termed acute exacerbation of idiopathic interstitial pneumonia. The etiology of an acute exacerbation of idiopathic interstitial pneumonia is unknown. In this study, we tested the hypothesis that an acute exacerbation of idiopathic interstitial pneumonia is induced by respiratory viral infections. METHODS: Bronchoalveolar lavage fluid obtained from patients with an acute exacerbation of idiopathic interstitial pneumonia was tested for viral nucleic acid using polymerase chain reaction. RESULTS: Only 1 of the 14 patients with an acute exacerbation of idiopathic interstitial pneumonia exhibited evidence of respiratory syncytial virus B, and 2 patients exhibited evidence of cytomegalovirus. Seven patients fulfilled the diagnostic criteria of idiopathic pulmonary fibrosis. CONCLUSIONS: Most cases with an acute exacerbation of idiopathic interstitial pneumonia are not caused by a viral infection.
Assuntos
Infecções por Citomegalovirus/complicações , Pneumonias Intersticiais Idiopáticas , Infecções por Vírus Respiratório Sincicial/complicações , Reação de Fase Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/virologia , Progressão da Doença , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/tratamento farmacológico , Pneumonias Intersticiais Idiopáticas/etiologia , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Pulsoterapia , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/virologiaRESUMO
BACKGROUND: Oxidative stress is implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Analysis of the expired breath condensate (EBC) has been suggested to provide non-invasive inflammatory markers that reflect oxidative stress in the airways. OBJECTIVE: The present study attempts to elucidate whether the hydrogen peroxide (H2O2) levels and pH values in EBC may be useful as biomarkers of the activity or severity of asthma and COPD. METHODS: We measured the H2O2 levels and pH values using a derivatives of reactive oxygen metabolites exhalation test kit (Diacron) and a pH analyser, respectively, in EBC obtained using an EcoScreen from 29 patients with asthma, 33 with COPD, and 33 healthy individuals (all non-smokers). We then examined the relationships among oxidative stress and the asthma control test (ACT) or COPD assessment test (CAT) scores, pulmonary function, fractional exhaled nitric oxide (FeNO), and the extent of low attenuation areas on HRCT. RESULTS: The H2O2 levels were elevated and pH was lower in both asthma (H2O2; 8.75 ± 0.88 µM, p < 0.01, pH; 7.14 ± 0.07, p < 0.05) and COPD (H2O2; 7.44 ± 0.89 µM, p < 0.01, pH; 6.87 ± 0.10, p < 0.01) compared with control subjects (H2O2; 3.42 ± 0.66 µM, pH; 7.35 ± 0.04). Neither the H2O2 levels nor pH correlated with the ACT scores and FeNO in asthma patients. Neither the H2O2 levels nor pH significantly correlated with the pulmonary function in asthma and COPD. However, the CAT scores significantly correlated with the H2O2 levels in patients with COPD (r = 0.52, p < 0.01). CONCLUSIONS: These findings suggest that oxidative stress is involved in the pathogenesis of asthma and COPD and that the H2O2 levels in EBC might reflect the health status in COPD.
Assuntos
Asma/metabolismo , Peróxido de Hidrogênio/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Adulto , Idoso , Asma/diagnóstico por imagem , Asma/fisiopatologia , Biomarcadores/metabolismo , Testes Respiratórios , Estudos de Casos e Controles , Feminino , Humanos , Concentração de Íons de Hidrogênio , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Tomografia Computadorizada por Raios XAssuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/diagnóstico , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico , Lesão Pulmonar Aguda/epidemiologia , Lesão Pulmonar Aguda/terapia , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Anti-Infecciosos/efeitos adversos , Antineoplásicos/efeitos adversos , Antirreumáticos/efeitos adversos , Biomarcadores/sangue , Testes de Provocação Brônquica , Diagnóstico por Imagem , Medicamentos de Ervas Chinesas/efeitos adversos , Testes Hematológicos , Humanos , Imunossupressores/efeitos adversos , Interferons/efeitos adversos , Japão/epidemiologia , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/terapia , Ativação Linfocitária , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: High-altitude pulmonary edema (HAPE) is a hypoxia-induced, life-threatening, high permeability type of edema attributable to pulmonary capillary stress failure. Genome-wide association analysis is necessary to better understand how genetics influence the outcome of HAPE. MATERIALS AND METHODS: DNA samples were collected from 53 subjects susceptible to HAPE (HAPE-s) and 67 elite Alpinists resistant to HAPE (HAPE-r). The genome scan was carried out using 400 polymorphic microsatellite markers throughout the whole genome in all subjects. In addition, six single nucleotide polymorphisms (SNPs) of the gene encoding the tissue inhibitor of metalloproteinase 3 (TIMP3) were genotyped by Taqman® SNP Genotyping Assays. RESULTS: The results were analyzed using case-control comparisons. Whole genome scanning revealed that allele frequencies in nine markers were statistically different between HAPE-s and HAPE-r subjects. The SNP genotyping of the TIMP3 gene revealed that the derived allele C of rs130293 was associated with resistance to HAPE [odds ratio (OR) = 0.21, P = 0.0012) and recessive inheritance of the phenotype of HAPE-s (P = 0.0012). A haplotype CAC carrying allele C of rs130293 was associated with resistance to HAPE. DISCUSSION: This genome-wide association study revealed several novel candidate genes associated with susceptibility or resistance to HAPE in a Japanese population. Among those, the minor allele C of rs130293 (C/T) in the TIMP3 gene was linked to resistance to HAPE; while, the ancestral allele T was associated with susceptibility to HAPE.
Assuntos
Doença da Altitude/genética , Predisposição Genética para Doença/genética , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único , Inibidor Tecidual de Metaloproteinase-3/genética , Adolescente , Adulto , Idoso , Alelos , Doença da Altitude/etnologia , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Hipertensão Pulmonar/etnologia , Japão , Desequilíbrio de Ligação , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder that has been previously described, and the distinct features of CPFE in comparison with chronic obstructive pulmonary disease (COPD) have been reported. However, the yearly dynamics of pulmonary function parameters in CPFE patients compared with those in COPD patients have not yet been reported. METHODS: We retrospectively enrolled patients with CPFE and COPD who had undergone pulmonary function tests more than five times during a follow-up period of more than five years. The baseline clinical characteristics and the annual changes in pulmonary function during the follow-up period in 16 stable CPFE patients were compared with those in 19 stable COPD patients. Annual changes in pulmonary function were estimated from linear regressions, with assumptions for time-dependency and linearity. We analyzed the time-dependent fluctuations in pulmonary function for the two disorders. RESULTS: Annual decreases in VC and FVC in the CPFE group were significantly higher than those in the COPD group. Annual decrease in FEV1/FVC in the COPD group was significantly higher than in the CPFE group. During the follow-up period, FEV1/FVC in the CPFE group appeared to improve because of annual decrease in FVC. Annual decreases in DLco and DLco/VA in the CPFE group were significantly higher than those in the COPD group. CONCLUSION: This is the first report showing the yearly dynamics of pulmonary function parameters in CPFE patients compared with those in COPD patients during a follow-up period of more than five years. This study revealed that the physiologic consequences of CPFE including the rate of progression of pulmonary function impairment were different from those of COPD.