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1.
J Immunol ; 205(5): 1393-1405, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32727891

RESUMO

Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1ß, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1ß prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1ß is a novel potential target for treating and preventing this disorder.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Células Endoteliais/metabolismo , Inflamassomos/metabolismo , Pulmão/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Caspase 1/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Am J Respir Crit Care Med ; 196(6): 713-726, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28245134

RESUMO

RATIONALE: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with high mortality and morbidity. Although inflammatory responses triggered by infection are crucial for host defense against invading microbes, the excessive inflammation often causes tissue damage leading to organ dysfunction. Resolution of inflammation, an active immune process mediated by endogenous lipid mediators (LMs), is important to maintain host homeostasis. OBJECTIVES: We sought to determine the role of the nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in polymicrobial sepsis and regulation of LM biosynthesis. METHODS: We performed cecal ligation and puncture (CLP) using mice lacking NLRP3 inflammasome-associated molecules to assess mortality. Inflammation was evaluated by using biologic fluids including plasma, bronchoalveolar, and peritoneal lavage fluid. Local acting LMs in peritoneal lavage fluid from polymicrobacterial septic mice were assessed by mass spectrometry-based metabololipidomics. MEASUREMENTS AND MAIN RESULTS: Genetic deficiency of NLRP3 inhibited inflammatory responses and enhanced survival of CLP-induced septic mice. NLRP3 deficiency reduced proinflammatory LMs and increased proresolving LM, lipoxin B4 (LXB4) in septic mice, and in macrophages stimulated with LPS and ATP. Activation of the NLRP3 inflammasome induced caspase-7 cleavage and pyroptosis. Caspase-7 deficiency similarly reduced inflammation and mortality in CLP-induced sepsis, and increased LXB4 production in vivo and in vitro. Exogenous application of LXB4 reduced inflammation, pyroptosis, and mortality of mice after CLP. CONCLUSIONS: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7-dependent repression of LXB4 biosynthesis, and increased survival potentially via LXB4 production and inhibition of proinflammatory cytokines.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Lipoxinas/metabolismo , Sepse/imunologia , Sepse/microbiologia , Animais , Camundongos , Substâncias Protetoras , Transdução de Sinais
3.
Respir Med Case Rep ; 51: 102103, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39286411

RESUMO

Anti-neutrophil cytoplasmic antibody-associated vasculitis is triggered by infection, dust exposure, and drugs. A 73-year-old male presented with dyspnea. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection was confirmed upon admission. Exacerbation of interstitial pneumonia and renal dysfunction were observed. Analysis revealed positivity for myeloperoxidase-anti-neutrophil cytoplasmic antibody, other anti-aminoacyl transfer RNA synthetase antibodies, and anti-melanoma differentiation-associated gene 5. Renal biopsy confirmed crescentic glomerulonephritis, leading to the diagnosis of microscopic polyangiitis. Combination therapy with prednisolone and cyclophosphamide was initiated, resulting in improved respiratory and renal failure. There is a potential association between SARS-CoV-2 infection and the onset of autoimmune diseases.

4.
Intern Med ; 63(8): 1167-1172, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38296478

RESUMO

A 45-year-old woman was hospitalized with severe coronavirus disease 2019 pneumonia. Following cytokine storm-induced multiorgan failure and lethal arrhythmia, the patient developed a sustained coma with flaccid quadriplegia. A cerebrospinal fluid examination excluded infectious and immunogenic encephalopathies, and diffusion-weighted magnetic resonance imaging demonstrated high-intensity areas in the white matter with a cortex-sparing distribution, suggesting delayed post-hypoxic leukoencephalopathy. As a result of intensive cardiopulmonary support for a month, the neurological function gradually recovered. Based on the reversible clinical course noted in this patient, accurate diagnosis and persistent medical approaches are important for the management of coronavirus disease 2019-related delayed post-hypoxic leukoencephalopathy.


Assuntos
COVID-19 , Leucoencefalopatias , Feminino , Humanos , Pessoa de Meia-Idade , COVID-19/complicações , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/etiologia , Hipóxia/etiologia , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Imageamento por Ressonância Magnética
5.
Heliyon ; 9(3): e13829, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36895411

RESUMO

Cancer cells harbor many genetic mutations and gene expression profiles different from normal cells. Patient-derived cancer cells (PDCC) are preferred materials in cancer study. We established patient-derived spheroids (PDSs) and patient-derived organoids (PDOs) from PDCCs isolated from the malignant pleural effusion in 8 patients. The morphologies suggested that PDSs may be a model of local cancer extensions, while PDOs may be a model of distant cancer metastases. The gene expression profiles differed between PDSs and PDOs: Gene sets related to inflammatory responses and EMT were antithetically regulated in PDSs or in PDOs. PDSs demonstrated an attenuation of the pathways that contribute to the enhancement of transforming growth factor beta (TGF-ß) induced epithelial mesenchymal transition (EMT), while PDOs demonstrated an attenuation of it. Taken together, PDSs and PDOs have differences in both the interaction to the immune systems and to the stroma. PDSs and PDOs will provide a model system that enable intimate investigation of the behavior of cancer cells in the body.

6.
Respir Investig ; 61(4): 498-507, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37263115

RESUMO

BACKGROUND: TAS-115, a novel oral multi-kinase inhibitor, showed antifibrotic effects in in vitro and in vivo animal models of idiopathic pulmonary fibrosis (IPF). METHODS: In this exploratory phase 2 study, IPF patients with a percent predicted forced vital capacity (%FVC) decline ≥5% acquired within the previous 6 months were enrolled. Patients were divided into three pre-treatment cohorts, namely, treatment-naïve, pirfenidone, or nintedanib. TAS-115 was administered orally at 200 mg/day with a 5-day on and 2-day off regimen. After 13 weeks of treatment, patients entered a 13-week extension treatment period where the efficacy was evaluated. The primary endpoint was the difference in slope of %FVC decline at Week 13 from baseline. Safety was also evaluated. RESULTS: Between June 2018 and July 2019, 46 patients were enrolled, and 30 (65.2%) patients completed the 13-week treatment. Of these, 22 (47.8%) proceeded to extension treatment. For the primary endpoint, TAS-115 treatment lowered the slope of the %FVC decline of 0.0750%/day (95% confidence interval: 0.0341-0.1158%/day) at Week 13. Efficacy was also demonstrated at Week 26. Treatment-related adverse events were reported in 40 (88.9%) patients, but most were manageable by dose reduction, dose interruption, or symptomatic treatment. CONCLUSIONS: TAS-115 treatment was effective, assessed using intra-patient change in slope of %FVC decline as a surrogate endpoint in patients with IPF pre-treated with pirfenidone or nintedanib and treatment-naïve patients. TAS-115 showed acceptable tolerability and a manageable safety profile. TRIAL REGISTRATION: Japic-Clinical Trials Information, JapicCTI-183898 (first registered: March 15, 2018).


Assuntos
Fibrose Pulmonar Idiopática , Quinolinas , Humanos , Resultado do Tratamento , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/induzido quimicamente , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Capacidade Vital , Piridonas/uso terapêutico
7.
Respir Investig ; 61(1): 95-102, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36580379

RESUMO

BACKGROUND: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs). METHODS: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated. DISCUSSION: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs. ETHICS AND DISSEMINATION: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017).


Assuntos
Pneumonias Intersticiais Idiopáticas , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Biomarcadores , Pneumonias Intersticiais Idiopáticas/diagnóstico , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/terapia , Pulmão , Sistema de Registros , Japão
8.
J Cell Biol ; 178(5): 843-60, 2007 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-17724123

RESUMO

Neurotrophins, such as NGF and BDNF, induce sustained activation of Rap1 small G protein and ERK, which are essential for neurite outgrowth. We show involvement of a GDP/GTP exchange factor (GEF) for Rap1, PDZ-GEF1, in these processes. PDZ-GEF1 is activated by GTP-Rap1 via a positive feedback mechanism. Upon NGF binding, the TrkA neurotrophin receptor is internalized from the cell surface, passes through early endosomes, and arrives in late endosomes. A tetrameric complex forms between PDZ-GEF1, synaptic scaffolding molecule and ankyrin repeat-rich membrane spanning protein which interacts directly with the TrkA receptor. At late endosomes, the complex induces sustained activation of Rap1 and ERK, resulting in neurite outgrowth. In cultured rat hippocampal neurons, PDZ-GEF1 is recruited to late endosomes in a BDNF-dependent manner involved in BDNF-induced neurite outgrowth. Thus, the interaction of PDZ-GEF1 with an internalized neurotrophin receptor transported to late endosomes induces sustained activation of both Rap1 and ERK and neurite outgrowth.


Assuntos
Endossomos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuritos/metabolismo , Receptor trkA/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/genética , Retroalimentação Fisiológica , Fatores de Troca do Nucleotídeo Guanina/genética , Fator 2 de Liberação do Nucleotídeo Guanina/genética , Fator 2 de Liberação do Nucleotídeo Guanina/metabolismo , Guanosina Trifosfato/metabolismo , Guanilato Quinases , Hipocampo/citologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Complexos Multiproteicos , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Neuritos/ultraestrutura , Células PC12 , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Receptor trkA/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas rap1 de Ligação ao GTP/genética
9.
BMJ Open Respir Res ; 9(1)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36162917

RESUMO

BACKGROUND: Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO. METHODS: We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO. RESULTS: Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1 s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. CONCLUSIONS: IDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO.


Assuntos
Fibrose Pulmonar Idiopática , Osteogênese , Progressão da Doença , Feminino , Humanos , Masculino , Fenótipo , Capacidade Vital
10.
Cancer Med ; 10(23): 8595-8603, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34617674

RESUMO

BACKGROUND: Bronchoscopy is a minimally invasive procedure for establishing the diagnosis of lung cancer. It sometimes fails to obtain tissue samples but readily collects cytological samples. METHODS: We developed PNA-LNA dual-PCR (PLDP), which amplified mutant sequences by a high-fidelity DNA polymerase in the presence of a peptide nucleic acid (PNA) oligomer having a wild-type sequence. Mutations are detected either by locked nucleic acid (LNA) probes for quick detection of a limited number of mutations, which are EGFR, KRAS, and BRAF mutations in the current study, or by direct sequencing for a comprehensive screening. In a total of 233 lung cancer samples, the results for cytological samples by PLDP were compared with those for tissue samples by cobas® EGFR mutation test (cobas) or by the PNA-LNA PCR clamp method (P-LPC). Moreover, the performance of PLDP using cell-free DNA (cfDNA) was investigated. RESULTS: Peptide nucleic acid-LNA dual-PCR was able to detect each synthesized mutant sequence with high sensitivity. PLDP detected EGFR mutations in 80 out of 149 clinical samples, while the cobas or the P-LPC detected in 66 matched. The correctness of PLDP was confirmed both by clinical response and by the results of sequencing using a next-generation sequencer. PLDP detected mutations from cfDNA in approximately 70% of patients who harbors mutations in the tumor. CONCLUSIONS: Peptide nucleic acid-LNA dual-PCR exhibited an excellent performance, even using cytological samples. PLDP is applicable for the investigation of cfDNA. The combination of bronchoscopy and PLDP is attractive and will expand the utility of bronchoscopy in clinical practice.


Assuntos
Broncoscopia/métodos , Neoplasias Pulmonares/genética , Ácidos Nucleicos Livres , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patologia , Mutação , Estadiamento de Neoplasias , Técnicas de Amplificação de Ácido Nucleico , Ácidos Nucleicos Peptídicos/análise , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA
11.
Respir Investig ; 59(6): 819-826, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33994347

RESUMO

BACKGROUND: Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited. METHODS: The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records. RESULTS: Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax). CONCLUSIONS: Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.


Assuntos
Fibrose Pulmonar Idiopática , Piridonas , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis , Japão/epidemiologia , Piridonas/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
12.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34287647

RESUMO

Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich α-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.


Assuntos
Células Endoteliais/patologia , Pulmão/patologia , Enfisema Pulmonar/patologia , Administração Intravenosa , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Células Endoteliais/transplante , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Elastase Pancreática/metabolismo , Fenótipo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Fumar , Transcriptoma/genética
13.
Respir Med Case Rep ; 31: 101279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33209578

RESUMO

A 65-year-old woman had a ground glass nodule, which was suspicious for lung cancer, in her right lung S6 by chest computed tomography. For diagnosis, video-assisted thoracoscopic surgery was performed, and the specimen showed a pathological pattern of lymphocytic interstitial pneumonia (LIP). Four years after surgery, new localized ground glass shadows gradually increased on the base of the lung. However, because she had no respiratory symptoms and had normal respiratory function, she was observed with no medication. Subsequently, no other underlying diseases associated with LIP developed. The ground glass nodule was the initial lesion of LIP.

14.
Respir Investig ; 58(2): 102-109, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883998

RESUMO

BACKGROUND: The presence of histologically evident epithelioid granuloma is required for the diagnosis of sarcoidosis worldwide. The Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 diagnostic criteria (JSSOG 2015 criteria) includes "clinically proven diagnosis" (involvement of at least 2 of 3 systems confirmed solely by clinical assessment) because of the frequency of sarcoidosis with ocular, cardiac, and respiratory involvement in Japan and the difficulty of obtaining specimens. Here, we describe in detail the clinical presentation of clinically diagnosed sarcoidosis. METHODS: We enrolled 68 consecutive patients with clinically diagnosed sarcoidosis (12 men, 56 women) based on the JSSOG 2015 criteria who were treated at Jichi Medical University between December 2018 and January 2000. We analyzed age at diagnosis, organ involvement, and laboratory findings. RESULTS: Age at diagnosis was unimodal in women. Ocular, splenic, cardiac, and skin involvement, and hypercalcemia were observed in 95.6%, 8.8%, 7.4%, 5.9%, and 35.0% of patients, respectively. High serum lysozyme and soluble interleukin-2 receptor (sIL-2R) levels, bilateral hilar lymphadenopathy on chest radiography, high-grade atrioventricular block or fatal ventricular arrhythmia, and bundle branch block were found in 18.8%, 48.3%, 95.6%, 5.0%, and 10.0% of patients, respectively. CONCLUSIONS: The age-specific distribution of clinically diagnosed sarcoidosis was similar to histologically diagnosed sarcoidosis in women, as previously reported. Rates of elevated serum lysozyme and sIL-2R levels were lower in this study than previously reported in histologically diagnosed patients in Japan.


Assuntos
Sarcoidose/diagnóstico , Sociedades Médicas/organização & administração , Fatores Etários , Biomarcadores/sangue , Feminino , Humanos , Japão , Masculino , Muramidase/sangue , Receptores de Interleucina-2/sangue , Fatores de Tempo
15.
Nat Commun ; 10(1): 3390, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358769

RESUMO

Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung.


Assuntos
GTP Fosfo-Hidrolases/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Metabolismo dos Lipídeos , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Células Cultivadas , Colesterol/metabolismo , GTP Fosfo-Hidrolases/genética , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Camundongos Knockout , Camundongos Transgênicos , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/genética , Fosfolipídeos/biossíntese
17.
Ann Am Thorac Soc ; 14(8): 1298-1304, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28421817

RESUMO

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.


Assuntos
Autoanticorpos/uso terapêutico , Lavagem Broncoalveolar , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Macrófagos Alveolares/efeitos dos fármacos , Proteinose Alveolar Pulmonar/terapia , Administração por Inalação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Respiratória , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Antioxid Redox Signal ; 23(17): 1329-50, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26067258

RESUMO

SIGNIFICANCE: Mitochondria, vital cellular power plants to generate energy, are involved in immune responses. Mitochondrial damage-associated molecular patterns (DAMPs) are molecules that are released from mitochondria to extracellular space during cell death and include not only proteins but also DNA or lipids. Mitochondrial DAMPs induce inflammatory responses and are critically involved in the pathogenesis of various diseases. RECENT ADVANCES: Recent studies elucidate the molecular mechanisms by which mitochondrial DAMPs are released and initiate immune responses by use of genetically modulated cells or animals. Importantly, the levels of mitochondrial DAMPs in patients are often associated with severity and prognosis of human diseases, such as infection, asthma, ischemic heart disease, and cancer. CRITICAL ISSUES: Although mitochondrial DAMPs can represent proinflammatory molecules in various experimental models, their roles in human diseases may be multifunctional and complex. It remains unclear where and how mitochondrial DAMPs are liberated into extracellular spaces and exert their biological functions particularly in vivo. In addition, while mitochondria can secrete several types of DAMPs during cell death, the interaction of each mitochondrial DAMP (e.g., synergistic effects) remains unclear. FUTURE DIRECTIONS: Regulation of mitochondrial DAMP-mediated immune responses may be important to alter the progression of human diseases. In addition, measuring mitochondrial DAMPs in patients may be clinically useful as biomarkers to predict prognosis or response to therapies. Further studies of the mechanisms by which mitochondrial DAMPs impact the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid.


Assuntos
Inflamação/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Animais , DNA Mitocondrial/metabolismo , Espaço Extracelular/metabolismo , Humanos , Proteínas Mitocondriais/metabolismo , Transdução de Sinais
19.
Cell Rep ; 12(1): 102-115, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26119735

RESUMO

The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1ß maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 inflammasome activation.


Assuntos
Proteínas de Transporte/metabolismo , Glicólise , Hexoquinase/metabolismo , Inflamassomos/metabolismo , Complexos Multiproteicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Caspase 1/metabolismo , Células Cultivadas , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR
20.
Artigo em Inglês | MEDLINE | ID: mdl-26740747

RESUMO

Idiopathic pulmonary fibrosis (IPF) is an intractable disease for which the pathological findings are characterized by temporal and spatial heterogeneity. The pathogenesis is composed of myriad factors, including repetitive injuries to epithelial cells, alterations in immunity, the formation of vascular leakage and coagulation, abnormal wound healing, fibrogenesis, and collagen accumulation. Therefore, the molecular target drugs that are used or attempted for treatment or clinical trials may not cover the myriad therapeutic targets of IPF. In addition, the complicated pathogenesis results in a lack of informative biomarkers to diagnose accurately the status of IPF. These facts point out the necessity of using a combination of drugs, that is, each single drug with molecular targets or a single drug with multiple therapeutic targets. In this review, we introduce a humoral factor, stanniocalcin-1 (STC1), which has myriad functions, including the maintenance of calcium homeostasis, the promotion of early wound healing, uncoupling respiration (aerobic glycolysis), reepithelialization in damaged tissues, the inhibition of vascular leakage, and the regulation of macrophage functions to keep epithelial and endothelial homeostasis, which may adequately cover the myriad therapeutic targets of IPF.

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