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1.
Crit Care Med ; 49(5): 760-769, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33590996

RESUMO

OBJECTIVE: Management of patients experiencing massive pulmonary embolism-related cardiac arrest is controversial. Venoarterial extracorporeal membranous oxygenation has emerged as a potential therapeutic option for these patients. We performed a systematic review assessing survival and predictors of mortality in patients with massive PE-related cardiac arrest with venoarterial extracorporeal membranous oxygenation use. DATA SOURCES: A literature search was started on February 16, 2020, and completed on March 16, 2020, using PubMed, Embase, Cochrane Central, Cinahl, and Web of Science. STUDY SELECTION: We included all available literature that reported survival to discharge in patients managed with venoarterial extracorporeal membranous oxygenation for massive PE-related cardiac arrest. DATA EXTRACTION: We extracted patient characteristics, treatment details, and outcomes. DATA SYNTHESIS: About 301 patients were included in our systemic review from 77 selected articles (total screened, n = 1,115). About 183 out of 301 patients (61%) survived to discharge. Patients (n = 51) who received systemic thrombolysis prior to cannulation had similar survival compared with patients who did not (67% vs 61%, respectively; p = 0.48). There was no significant difference in risk of death if PE was the primary reason for admission or not (odds ratio, 1.62; p = 0.35) and if extracorporeal membranous oxygenation cannulation occurred in the emergency department versus other hospital locations (odds ratio, 2.52; p = 0.16). About 53 of 60 patients (88%) were neurologically intact at discharge or follow-up. Multivariate analysis demonstrated three-fold increase in the risk of death for patients greater than 65 years old (adjusted odds ratio, 3.08; p = 0.03) and six-fold increase if cannulation occurred during cardiopulmonary resuscitation (adjusted odds ratio, 5.67; p = 0.03). CONCLUSIONS: Venoarterial extracorporeal membranous oxygenation has an emerging role in the management of massive PE-related cardiac arrest with 61% survival. Systemic thrombolysis preceding venoarterial extracorporeal membranous oxygenation did not confer a statistically significant increase in risk of death, yet age greater than 65 and cannulation during cardiopulmonary resuscitation were associated with a three- and six-fold risks of death, respectively.

3.
ERJ Open Res ; 6(4)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33043049

RESUMO

Background: Idiopathic pulmonary fibrosis (IPF) is characterised by constant threat of acute exacerbation of IPF (AE-IPF). It would be significant to identify risk factors of AE-IPF. We sought to determine the prognostic value of lung transplantation candidacy testing for AE-IPF and describe explant pathology of recipients with and without AE-IPF before lung transplantation. Methods: Retrospective cohort study of 89 IPF patients listed for lung transplantation. Data included pulmonary function testing, echocardiography, right heart catheterisation, imaging, oesophageal pH/manometry and blood tests. Explanted tissue was evaluated by pulmonary pathologists and correlated to computed tomography (CT) findings. Results: Out of 89 patients with IPF, 52 were transplanted during stable IPF and 37 had AE-IPF before transplantation (n=28) or death (n=9). There were no substantial differences in candidacy testing with and without AE-IPF. AE-IPF had higher rate of decline of forced vital capacity (FVC) (21±22% versus 4.8±14%, p=0.00019). FVC decline of >15% had a hazard ratio of 7.2 for developing AE-IPF compared to FVC decline of <5% (p=0.004). AE-IPF had more secondary diverse histopathology (82% versus 29%, p<0.0001) beyond diffuse alveolar damage. There was no correlation between ground-glass opacities (GGO) on chest CT at any point to development of AE-IPF (p=0.077), but GGO during AE-IPF predicted secondary pathological process beyond diffuse alveolar damage. Conclusions: Lung transplantation candidacy testing including reflux studies did not predict AE-IPF besides FVC absolute decline. CT did not predict clinical or pathological AE-IPF. Secondary diverse lung pathology beyond diffuse alveolar damage was present in most AE-IPF, but not in stable IPF.

4.
Clin Chest Med ; 41(3): 547-557, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32800205

RESUMO

Patients with severe chronic obstructive pulmonary disease who fail maximal medical therapy have bronchoscopic options that can improve lung function, quality of life, and exercise performance. Those with upper lobe predominant emphysema can consider bronchoscopic lung volume reduction with endobronchial valves. Select patients with diffuse emphysema and severe hyperinflation can also be considered for endobronchial valves. Bronchoscopic techniques targeting cholinergic pathways and mucus hypersecretion are under development. Ultimately, patients with advanced chronic obstructive pulmonary disease who are not eligible for or have failed bronchoscopic interventions can consider lung volume reduction surgery or even lung transplantation, if free from major comorbidities.


Assuntos
Broncoscopia/métodos , Doença Pulmonar Obstrutiva Crônica/terapia , Qualidade de Vida/psicologia , Humanos
5.
Clin Chest Med ; 41(3): 559-566, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32800206

RESUMO

Patients with severe chronic obstructive pulmonary disease who fail maximal medical therapy and bronchoscopic interventions have surgical options to improve lung function, quality of life, and exercise performance. Carefully selected patients with upper lobe predominant emphysema can consider lung volume reduction surgery. Patients with upper lobe-predominant emphysema and low exercise performance have a survival advantage. Patients with large bulla compressing adjacent lung tissue occupying more than one-third of the lung benefit from bullectomy. Patients with advanced chronic obstructive pulmonary disease ineligible for or failing other surgical or bronchoscopic interventions can consider lung transplantation if free from major comorbidities.


Assuntos
Doença Pulmonar Obstrutiva Crônica/cirurgia , Qualidade de Vida/psicologia , Humanos
6.
BMJ Open Respir Res ; 7(1)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32661103

RESUMO

BACKGROUND: Pulmonary hypertension (PH) causes increased morbidity and mortality in patients with interstitial lung diseases (ILD). Classification schemes, while well-characterised for the vasculopathy of idiopathic PH, have been applied, unchallenged, to ILD-related PH. We evaluated pulmonary arterial histopathology in explanted human lung tissue from patients who were transplanted for advanced fibrotic ILD. METHODS: Lung explants from 38 adult patients who underwent lung transplantation were included. Patients were divided into three groups: none, mild/moderate and severe PH by mean pulmonary artery pressure (mPAP) measured at pre lung transplantation right heart catheterisation (RHC). Grading of pulmonary vasculopathy according to Heath and Edwards scheme, and prelung transplantation evaluation data were compared between the groups. RESULTS: 38 patients with fibrotic ILDs were included, the majority (21) with idiopathic pulmonary fibrosis. Of the 38 patients, 18 had severe PH, 13 had mild/moderate PH and 7 had no PH by RHC. 16 of 38 patients had severe pulmonary arterial vasculopathy including vascular occlusion with intimal fibrosis and/or plexiform lesions. There were no correlations between mPAP and lung diffusion with the severity of pulmonary arterial pathological grade (Spearman's rho=0.14, p=0.34, rho=0.11, p=0.49, respectively). CONCLUSIONS: Patients with end stage ILD had severe pulmonary arterial vasculopathy in their explanted lungs irrespective of the presence and/or severity of PH as measured by RHC. These findings suggest that advanced pulmonary arterial vasculopathy is common in patients with advanced fibrotic ILD and may develop prior to the clinical detection of PH by RHC.


Assuntos
Hipertensão Pulmonar/etiologia , Doenças Pulmonares Intersticiais/cirurgia , Transplante de Pulmão , Complicações Pós-Operatórias/etiologia , Artéria Pulmonar/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonectomia , Estudos Retrospectivos , Índice de Gravidade de Doença
7.
Respir Res ; 21(1): 164, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605574

RESUMO

RATIONALE: Patients with combined pulmonary fibrosis and emphysema (CPFE) may develop acute exacerbations of IPF (AE-IPF) or COPD (AE-COPD). The incidence and the characteristics of exacerbations in patients with CPFE (e.g., COPD vs IPF) have not been well described. OBJECTIVES: To compare the incidence and rate of exacerbations in patients with CPFE vs. IPF and evaluate their effect on clinical outcomes. METHODS: Comprehensive clinical data from CPFE and IPF patients were retrospectively reviewed. Baseline characteristics including lung function data, oxygen requirements, and pulmonary hemodynamics, were collected. Acute exacerbation events in both groups were defined clinically and radiographically. In the CPFE group, two patterns of exacerbations were identified. AE-COPD was defined clinically by symptoms of severe airflow obstruction causing respiratory failure and requiring hospitalization. Radiographic data were also defined based on previously published literature. AE-IPF was defined clinically as an acute hypoxic respiratory failure, requiring hospitalization and treatment with high dose corticosteroids. Radiographically, patients had to have a change in baseline imaging including presence of ground-glass opacities, interlobular septal thickening or new consolidations; that is not fully explained by other etiologies. RESULTS: Eighty-five CPFE patients were retrospectively compared to 112 IPF patients. Of 112 patients with IPF; 45 had AE-IPF preceding lung transplant (40.18%) compared to 12 patients in the CPFE group (14.1%) (p < 0.05). 10 patients in the CPFE group experienced AE-COPD (11.7%). Patients with AE-IPF had higher mortality and more likely required mechanical ventilation and extracorporeal membrane oxygenation (ECMO) compared to patients with AE-COPD, whether their underlying disease was IPF or CPFE. CONCLUSIONS: CPFE patients may experience either AE-IPF or AE-COPD. Patients with CPFE and AE-COPD had better outcomes, requiring less intensive therapy compared to patients with AE-IPF regardless if underlying CPFE or IPF was present. These data suggest that the type of acute exacerbation, AE-COPD vs AE-IPF, has important implications for the treatment and prognosis of patients with CPFE.


Assuntos
Fibrose Pulmonar Idiopática/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/fisiopatologia , Fibrose Pulmonar/fisiopatologia , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/epidemiologia , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/fisiopatologia , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Fibrose Pulmonar Idiopática/complicações , Incidência , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Enfisema Pulmonar/complicações , Fibrose Pulmonar/complicações , Respiração Artificial , Testes de Função Respiratória , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
8.
Transpl Infect Dis ; 22(6): e13364, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32521074

RESUMO

Solid organ transplant recipients are considered at high risk for COVID-19 infection due to chronic immune suppression; little data currently exists on the manifestations and outcomes of COVID-19 infection in lung transplant recipients. Here we report 8 cases of COVID-19 identified in patients with a history of lung transplant. We describe the clinical course of disease as well as preexisting characteristics of these patients.


Assuntos
COVID-19/fisiopatologia , Infecção Hospitalar/fisiopatologia , Imunossupressores/uso terapêutico , Transplante de Pulmão , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Adulto , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico por imagem , COVID-19/imunologia , COVID-19/terapia , Tosse/fisiopatologia , Infecção Hospitalar/diagnóstico por imagem , Infecção Hospitalar/imunologia , Infecção Hospitalar/terapia , Fibrose Cística/cirurgia , Dispneia/fisiopatologia , Feminino , Febre/fisiopatologia , Gastroenteropatias/fisiopatologia , Glucocorticoides/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Humanos , Fibrose Pulmonar Idiopática/cirurgia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Pulmão/diagnóstico por imagem , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Pancreatite Necrosante Aguda , Doença Pulmonar Obstrutiva Crônica/cirurgia , Pulsoterapia , SARS-CoV-2 , Sepse , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
9.
Ann Am Thorac Soc ; 17(7): 829-838, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32223724

RESUMO

Rationale: Bronchoscopic lung volume reduction with Zephyr Valves improves lung function, exercise tolerance, and quality of life of patients with hyperinflated emphysema and little to no collateral ventilation.Objectives: Post hoc analysis of patient-reported outcomes (PROs), including multidimensional measures of dyspnea, activity, and quality of life, in the LIBERATE (Lung Function Improvement after Bronchoscopic Lung Volume Reduction with Pulmonx Endobronchial Valves used in Treatment of Emphysema) study are reported.Methods: A total of 190 patients with severe heterogeneous emphysema and little to no collateral ventilation in the target lobe were randomized 2:1 to the Zephyr Valve or standard of care. Changes in PROs at 12 months in the two groups were compared: dyspnea with the Transitional Dyspnea Index (TDI), focal score; the Chronic Obstructive Pulmonary Disease Assessment Test (CAT; breathlessness on hill/stairs); Borg; the EXAcerbations of Chronic pulmonary disease Tool-PRO, dyspnea domain; activity with the TDI, magnitude of task/effort/functional impairment, CAT (limited activities), and the St. George's Respiratory Questionnaire (SGRQ), activity domain; and psychosocial status with the SGRQ, impacts domain, and CAT (confidence and energy).Results: At 12 months, patients using the Zephyr Valve achieved statistically significant and clinically meaningful improvements in the SGRQ; CAT; and the TDI, focal score, compared with standard of care. Improvements in the SGRQ were driven by the impacts and activity domains (P < 0.05 and P < 0.001, respectively). Reduction in CAT was through improvements in breathlessness (P < 0.05), energy level (P < 0.05), activities (P < 0.001), and increased confidence when leaving home (P < 0.05). The TDI measures of effort, task, and functional impairment were uniformly improved (P < 0.001). The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT)-PRO, dyspnea domain, was significantly improved in the Zephyr Valve group. Improvements correlated with changes in residual volume and residual volume/TLC ratio.Conclusions: Patients with severe hyperinflated emphysema achieving lung volume reductions with Zephyr Valves experience improvements in multidimensional scores for breathlessness, activity, and psychosocial parameters out to at least 12 months.Clinical trial registered with www.clinicaltrials.gov (NCT01796392).


Assuntos
Brônquios/cirurgia , Pneumonectomia/métodos , Próteses e Implantes , Enfisema Pulmonar/cirurgia , Qualidade de Vida , Adulto , Idoso , Broncoscopia , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento
10.
ERJ Open Res ; 5(4)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31857992

RESUMO

Rationale: Alveolar type II (ATII) cells act as adult stem cells contributing to alveolar type I (ATI) cell renewal and play a major role in idiopathic pulmonary fibrosis (IPF), as supported by familial cases harbouring mutations in genes specifically expressed by these cells. During IPF, ATII cells lose their regenerative potential and aberrantly express pathways contributing to epithelial-mesenchymal transition (EMT). The microRNA miR-200 family is downregulated in IPF, but its effect on human IPF ATII cells remains unproven. We wanted to 1) evaluate the characteristics and transdifferentiating ability of IPF ATII cells, and 2) test whether miR-200 family members can rescue the regenerative potential of fibrotic ATII cells. Methods: ATII cells were isolated from control or IPF lungs and cultured in conditions promoting their transdifferentiation into ATI cells. Cells were either phenotypically monitored over time or transfected with miR-200 family members to evaluate the microRNA effect on the expression of transdifferentiation, senescence and EMT markers. Results: IPF ATII cells show a senescent phenotype (p16 and p21), overexpression of EMT (ZEB1/2) and impaired expression of ATI cell markers (AQP5 and HOPX) after 6 days of culture in differentiating medium. Transfection with certain miR-200 family members (particularly miR-200b-3p and miR-200c-3p) reduced senescence marker expression and restored the ability to transdifferentiate into ATI cells. Conclusions: We demonstrated that ATII cells from IPF patients express senescence and EMT markers, and display a reduced ability to transdifferentiate into ATI cells. Transfection with certain miR-200 family members rescues this phenotype, reducing senescence and restoring transdifferentiation marker expression.

11.
Sci Transl Med ; 11(522)2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31826982

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration-approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)-induced lung injury in mice. Like full-length CSP, a seven-amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor-ß1 (Ad-TGF-ß1)-induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases.


Assuntos
Caveolina 1/química , Fibrose Pulmonar Idiopática/tratamento farmacológico , Peptídeos/uso terapêutico , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Bleomicina , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/patologia , Injeções Intraperitoneais , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos , Mutagênicos/toxicidade , Nebulizadores e Vaporizadores , Peptídeos/administração & dosagem , Peptídeos/química , Peptídeos/farmacologia , Fator de Crescimento Transformador beta1 , Proteína Supressora de Tumor p53/metabolismo
12.
Respir Med ; 157: 69-76, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31522032

RESUMO

RATIONALE: Sarcoidosis progresses to end stage fibrotic lung disease in 10% of patients and may necessitate lung transplantation. Organ allocation is currently determined by the Lung Allocation Score (LAS), but its performance in a sarcoidosis population has not been evaluated. OBJECTIVES: To determine sarcoidosis-specific wait list mortality and identify predictive factors of death on the transplantation wait list. METHODS: This was a single-center retrospective study of all sarcoidosis patients listed for lung transplant from March 2012 to February 2019. We compared patients who were transplanted to those who died awaiting organs. We collected baseline listing characteristics, physiologic testing, and outcomes data. Statistical analysis was performed by 2-tailed Student's t-test, Mann-Whitney U test, and Chi-Square analysis (where appropriate). Receiver-operating characteristic curves were constructed for variables reaching statistical significance. RESULTS: Twenty eight sarcoidosis patients were included in analysis. Mortality among wait listed patients was 18%, which exceeded the mortality of COPD and IPF. LAS scores did not differ at initial listing (41 vs. 46, p = 0.35) or at transplant/death (41 vs. 41, p = 0.91); wait list times also did not statistically differ (307 days vs. 177 days, p = 0.19). We identified bilirubin (AUC = 0.92), DLCO (AUC = 0.84), FEV1/FVC at transplant/death (AUC = 0.85), and composite physiologic index (AUC = 0.86) as predictors of death on the transplant list. Pulmonary hypertension was not associated with death. CONCLUSION: Unexpected sudden death was common in our cohort and was associated with markers of advanced fibrotic disease, not pulmonary hypertension.


Assuntos
Transplante de Pulmão/estatística & dados numéricos , Sarcoidose/mortalidade , Sarcoidose/cirurgia , Listas de Espera/mortalidade , Centros Médicos Acadêmicos , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Morte Súbita/epidemiologia , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/mortalidade , Masculino , Pessoa de Meia-Idade , Philadelphia/epidemiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Sarcoidose/epidemiologia , Sarcoidose/fisiopatologia , Fatores de Tempo
13.
J Immunol ; 203(9): 2508-2519, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31548332

RESUMO

IFN responses to viral infection are necessary to establish intrinsic antiviral state, but if unchecked can lead to heightened inflammation. Recently, we showed that TLR2 activation contributes to limitation of rhinovirus (RV)-induced IFN response in the airway epithelial cells. We also demonstrated that compared with normal airway epithelial cells, those from patients with chronic obstructive pulmonary disease (COPD) show higher IFN responses to RV, but the underlying mechanisms are not known. Initially, RV-induced IFN responses depend on dsRNA receptor activation and then are amplified via IFN-stimulated activation of JAK/STAT signaling. In this study, we show that in normal cells, TLR2 limits RV-induced IFN responses by attenuating STAT1 and STAT2 phosphorylation and this was associated with TLR2-dependent SIRT-1 expression. Further, inhibition of SIRT-1 enhanced RV-induced IFN responses, and this was accompanied by increased STAT1/STAT2 phosphorylation, indicating that TLR2 may limit RV-induced IFN responses via SIRT-1. COPD airway epithelial cells showed attenuated IL-8 responses to TLR2 agonist despite expressing TLR2 similar to normal, indicating dysregulation in TLR2 signaling pathway. Unlike normal, COPD cells failed to show RV-induced TLR2-dependent SIRT-1 expression. Pretreatment with quercetin, which increases SIRT-1 expression, normalized RV-induced IFN levels in COPD airway epithelial cells. Inhibition of SIRT-1 in quercetin-pretreated COPD cells abolished the normalizing effects of quercetin on RV-induced IFN expression in these cells, confirming that quercetin exerts its effect via SIRT-1. In summary, we show that TLR2 is required for limiting RV-induced IFNs, and this pathway is dysregulated in COPD airway epithelial cells, leading to exaggerated IFN production.


Assuntos
Brônquios/imunologia , Interferons/biossíntese , Doença Pulmonar Obstrutiva Crônica/etiologia , Rhinovirus/patogenicidade , Sirtuína 1/fisiologia , Receptor 2 Toll-Like/fisiologia , Células Cultivadas , Células Epiteliais , Humanos , Helicase IFIH1 Induzida por Interferon/fisiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , RNA de Cadeia Dupla/fisiologia , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais/fisiologia , Sirtuína 1/genética , Proteína 1 Supressora da Sinalização de Citocina/fisiologia
14.
EBioMedicine ; 46: 305-316, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383554

RESUMO

BACKGROUND: Cigarette smoke is the main risk factor of pulmonary emphysema development, which is characterized by alveolar wall destruction. Mitochondria are important for alveolar type II (ATII) cell metabolism due to ATP generation. METHODS: We isolated ATII cells from control non-smoker and smoker organ donors, and after lung transplant of patients with emphysema to determine mitochondrial function, dynamics and mitochondrial (mt) DNA damage. FINDINGS: We found high mitochondrial superoxide generation and mtDNA damage in ATII cells in emphysema. This correlated with decreased mtDNA amount. We also detected high TOP1-cc and low TDP1 levels in mitochondria in ATII cells in emphysema. This contributed to the decreased resolution of TOP1-cc leading to accumulation of mtDNA damage and mitochondrial dysfunction. Moreover, we used lung tissue obtained from areas with mild and severe emphysema from the same patients. We found a correlation between the impaired fusion and fission as indicated by low MFN1, OPA1, FIS1, and p-DRP1 levels and this disease severity. We detected lower TDP1 expression in severe compared to mild emphysema. INTERPRETATION: We found high DNA damage and impairment of DNA damage repair in mitochondria in ATII cells isolated from emphysema patients, which contribute to abnormal mitochondrial dynamics. Our findings provide molecular mechanisms of mitochondrial dysfunction in this disease. FUND: This work was supported by National Institutes of Health (NIH) grant R01 HL118171 (B.K.) and the Catalyst Award from the American Lung Association (K.B.).


Assuntos
Células Epiteliais Alveolares/metabolismo , Mitocôndrias/metabolismo , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Trifosfato de Adenosina/biossíntese , Dano ao DNA , DNA Mitocondrial , Progressão da Doença , Metabolismo Energético , Humanos , Mitocôndrias/genética , Estresse Oxidativo , Diester Fosfórico Hidrolases/metabolismo , Transporte Proteico , Enfisema Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Fumaça/efeitos adversos , Superóxidos/metabolismo
15.
J Thorac Imaging ; 34(6): W131-W140, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31385877

RESUMO

Diaphragmatic dysfunction is a potential cause of dyspnea that can lead to significant morbidity. The purpose of this review article is to provide readers with the essentials for performing diaphragm ultrasonography, image interpretation, and the technical limitations one needs to be aware of. Diaphragm ultrasonography is simple to perform and has proven to be an accurate and safe bedside modality, overcoming many of the traditional limitations of fluoroscopy.


Assuntos
Diafragma/diagnóstico por imagem , Diafragma/fisiopatologia , Dispneia/fisiopatologia , Ultrassonografia/métodos , Humanos , Interpretação de Imagem Assistida por Computador
16.
Am J Physiol Lung Cell Mol Physiol ; 317(6): L791-L804, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31313618

RESUMO

Pulmonary emphysema is characterized by alveolar type II (ATII) cell death, destruction of alveolar wall septa, and irreversible airflow limitation. Cigarette smoke induces oxidative stress and is the main risk factor for this disease development. ATII cells isolated from nonsmokers, smokers, and patients with emphysema were used for this study. ATII cell apoptosis in individuals with this disease was detected. DJ-1 and S100A8 have cytoprotective functions against oxidative stress-induced cell injury. Reduced DJ-1 and S100A8 interaction was found in ATII cells in patients with emphysema. The molecular function of S100A8 was determined by an analysis of the oxidation status of its cysteine residues using chemoselective probes. Decreased S100A8 sulfination was observed in emphysema patients. In addition, its lower levels correlated with higher cell apoptosis induced by cigarette smoke extract in vitro. Cysteine at position 106 within DJ-1 is a central redox-sensitive residue. DJ-1 C106A mutant construct abolished the cytoprotective activity of DJ-1 against cell injury induced by cigarette smoke extract. Furthermore, a molecular and complementary relationship between DJ-1 and S100A8 was detected using gain- and loss-of-function studies. DJ-1 knockdown sensitized cells to apoptosis induced by cigarette smoke extract, and S100A8 overexpression provided cytoprotection in the absence of DJ-1. DJ-1 knockout mice were more susceptible to ATII cell apoptosis induced by cigarette smoke compared with wild-type mice. Our results indicate that the impairment of DJ-1 and S100A8 function may contribute to cigarette smoke-induced ATII cell injury and emphysema pathogenesis.


Assuntos
Células Epiteliais Alveolares/patologia , Apoptose , Calgranulina A/metabolismo , Proteína Desglicase DJ-1/metabolismo , Alvéolos Pulmonares/patologia , Enfisema Pulmonar/patologia , Idoso , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Calgranulina A/genética , Citoproteção , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estresse Oxidativo , Proteína Desglicase DJ-1/genética , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Fumaça/efeitos adversos
17.
Am J Respir Crit Care Med ; 200(5): 575-581, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30794432

RESUMO

Rationale: Evidence suggests damage to small airways is a key pathologic lesion in chronic obstructive pulmonary disease (COPD). Computed tomography densitometry has been demonstrated to identify emphysema, but no such studies have been performed linking an imaging metric to small airway abnormality.Objectives: To correlate ex vivo parametric response mapping (PRM) analysis to in vivo lung tissue measurements of patients with severe COPD treated by lung transplantation and control subjects.Methods: Resected lungs were inflated, frozen, and systematically sampled, generating 33 COPD (n = 11 subjects) and 22 control tissue samples (n = 3 subjects) for micro-computed tomography analysis of terminal bronchioles (TBs; last generation of conducting airways) and emphysema.Measurements and Main Results: PRM analysis was conducted to differentiate functional small airways disease (PRMfSAD) from emphysema (PRMEmph). In COPD lungs, TB numbers were reduced (P = 0.01); surviving TBs had increased wall area percentage (P < 0.001), decreased circularity (P < 0.001), reduced cross-sectional luminal area (P < 0.001), and greater airway obstruction (P = 0.008). COPD lungs had increased airspace size (P < 0.001) and decreased alveolar surface area (P < 0.001). Regression analyses demonstrated unique correlations between PRMfSAD and TBs, with decreased circularity (P < 0.001), decreased luminal area (P < 0.001), and complete obstruction (P = 0.008). PRMEmph correlated with increased airspace size (P < 0.001), decreased alveolar surface area (P = 0.003), and fewer alveolar attachments per TB (P = 0.01).Conclusions: PRMfSAD identifies areas of lung tissue with TB loss, luminal narrowing, and obstruction. This is the first confirmation that an imaging biomarker can identify terminal bronchial pathology in established COPD and provides a noninvasive imaging methodology to identify small airway damage in COPD.


Assuntos
Obstrução das Vias Respiratórias/diagnóstico por imagem , Biomarcadores , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Microtomografia por Raio-X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Sci Rep ; 9(1): 920, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696938

RESUMO

Emphysema is characterized by alveolar wall destruction induced mainly by cigarette smoke. Oxidative damage of DNA may contribute to the pathophysiology of this disease. We studied the impairment of the non-homologous end joining (NHEJ) repair pathway and DNA damage in alveolar type II (ATII) cells and emphysema development. We isolated primary ATII cells from control smokers, nonsmokers, and patients with emphysema to determine DNA damage and repair. We found higher reactive oxygen species generation and DNA damage in ATII cells obtained from individuals with this disease  in comparison with controls. We also observed low phosphorylation of H2AX, which activates DSBs repair signaling, in emphysema. Our results indicate the impairement  of NHEJ, as detected by low XLF expression. We also analyzed the role of DJ-1, which has a cytoprotective activity. We detected DJ-1 and  XLF interaction in ATII cells in emphysema, which suggests the impairment of their function. Moreover, we found that DJ-1 KO mice are more susceptible to DNA damage induced by cigarette smoke. Our results suggest that oxidative DNA damage and ineffective the DSBs repair via the impaired NHEJ may contribute to ATII cell death in emphysema.


Assuntos
Células Epiteliais Alveolares/metabolismo , Reparo do DNA por Junção de Extremidades , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Animais , Biomarcadores , Dano ao DNA , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imunofluorescência , Expressão Gênica , Humanos , Camundongos , Estresse Oxidativo , Ligação Proteica , Enfisema Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Fumar/efeitos adversos
20.
Biomarkers ; 24(3): 232-239, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30411980

RESUMO

Background: The aetiology and inflammatory profile of combined pulmonary fibrosis and emphysema (CPFE) remain uncertain currently. Objective: We aimed to examine the levels of inflammatory proteins in lung tissue in a cohort of patients with emphysema, interstitial pulmonary fibrosis (IPF), and CPFE. Materials and methods: Explanted lungs were obtained from subjects with emphysema, IPF, CPFE, (or normal subjects), and tissue extracts were prepared. Thirty-four inflammatory proteins were measured in each tissue section. Results: The levels of all 34 proteins were virtually indistinguishable in IPF compared with CPFE tissues, and collectively, the inflammatory profile in the emphysematous tissues were distinct from IPF and CPFE. Moreover, inflammatory protein levels were independent of the severity of the level of diseased tissue. Conclusions: We find that emphysematous lung tissues have a distinct inflammatory profile compared with either IPF or CPFE. However, the inflammatory profile in CPFE lungs is essentially identical to lungs from patients with IPF. These data suggest that distinct inflammatory processes collectively contribute to the disease processes in patients with emphysema, when compared to IPF and CPFE.


Assuntos
Inflamação/genética , Proteínas/genética , Enfisema Pulmonar/genética , Fibrose Pulmonar/genética , Idoso , Humanos , Inflamação/complicações , Inflamação/diagnóstico por imagem , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Mucina-5B/genética , Polimorfismo de Nucleotídeo Único , Enfisema Pulmonar/complicações , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Tomografia Computadorizada por Raios X
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