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1.
Ann Am Thorac Soc ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32223724

RESUMO

RATIONALE: Bronchoscopic Lung Volume Reduction (BLVR) with Zephyr® Valves improves lung function, exercise tolerance and quality of life (QoL) of patients with hyperinflated emphysema and little to no collateral ventilation (CV). OBJECTIVES: Post-hoc analysis of patient reported outcomes (PROs) including multidimensional measures of dyspnea, activity, and QoL in the LIBERATE Study are reported. METHODS: 190 patients with severe heterogeneous emphysema and little to no CV in the target lobe were randomized 2:1 to Zephyr Valve or Standard of Care (SoC). Changes in PROs at 12-months in the two groups were compared: Dyspnea: Transitional Dyspnea Index (TDI) focal score, COPD Assessment Test (CAT; breathlessness on hill/stairs), BORG, EXACT-PRO dyspnea domain; activity: TDI magnitude of task/effort/functional impairment, CAT (limited activities), SGRQ-activity domain; and psychosocial status: St George's Respiratory Questionnaire (SGRQ) - impacts domain, CAT (confidence and energy). RESULTS: At 12-months, Zephyr Valve patients achieved statistically significant and clinically meaningful improvements in SGRQ, CAT, and TDI Focal score compared to SoC. Improvements in 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). TDI measures of effort, task, and functional impairment were uniformly improved (p<0.001). The EXACT-PRO dyspnea domain was significantly improved in Zephyr group. Improvements correlated with changes in residual volume (RV) and RV/TLC ratio. CONCLUSION: Severe hyperinflated emphysema patients 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 ClinicalTrials.gov (NCT01796392).

2.
Sci Transl Med ; 11(522)2019 Dec 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.

3.
J Immunol ; 203(9): 2508-2519, 2019 Nov 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.

4.
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.

5.
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
6.
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.

7.
Am J Physiol Lung Cell Mol Physiol ; 317(6): L791-L804, 2019 Dec 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.

8.
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.

9.
Sci Rep ; 9(1): 920, 2019 Jan 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.

11.
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
12.
Am J Respir Cell Mol Biol ; 60(3): 299-307, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30277795

RESUMO

Pulmonary emphysema is characterized by alveolar wall destruction, and cigarette smoking is the main risk factor in this disease development. S100A8 is a member of the S100 protein family, with an oxidative stress-related and antiinflammatory role. The mechanisms of human alveolar type II (ATII) cell injury contributing to emphysema pathophysiology are not completely understood. We wanted to determine whether S100A8 can protect ATII cells against injury induced by cigarette smoke and this disease development. We used freshly isolated ATII cells from nonsmoking and smoking organ donors, as well as patients with emphysema to determine S100A8 function. S100A8 protein and mRNA levels were low in individuals with this disease and correlated with its severity as determined by using lung tissue from areas with mild and severe emphysema obtained from the same patient. Its expression negatively correlated with high oxidative stress as observed by 4-hydroxynonenal levels. We also detected decreased serine phosphorylation within S100A8 by PKAα in this disease. This correlated with increased S100A8 ubiquitination by SYVN1. Moreover, we cultured ATII cells isolated from nonsmokers followed by treatment with cigarette smoke extract. We found that this exposure upregulated S100A8 expression. We also confirmed the cytoprotective role of S100A8 against cell injury using gain- and loss-of-function approaches in vitro. S100A8 knockdown sensitized cells to apoptosis induced by cigarette smoke. In contrast, S100A8 overexpression rescued cell injury. Our results suggest that S100A8 protects ATII cells against injury and cigarette smoke-induced emphysema. Targeting S100A8 may provide a potential therapeutic strategy for this disease.


Assuntos
Células Epiteliais Alveolares/metabolismo , Calgranulina A/metabolismo , Alvéolos Pulmonares/metabolismo , Enfisema Pulmonar/metabolismo , Células A549 , Idoso , Aldeídos/farmacologia , Células Epiteliais Alveolares/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Fumar Cigarros/efeitos adversos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , RNA Mensageiro/metabolismo , Tabaco/efeitos adversos , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
13.
Chronic Obstr Pulm Dis ; 5(2): 87-96, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30374446

RESUMO

Rationale: Bronchoscopic lung volume reduction utilizing shape-memory nitinol endobronchial coils (EBC) may be safer and more effective in severely hyperinflated homogeneous emphysema compared to medical therapy or lung volume reduction surgery (LVRS). Methods: The effect of bilateral EBC in patients with homogeneous emphysema on spirometry, lung volumes and survival was compared to patients with homogeneous emphysema randomized in the National Emphysema Treatment Trial (NETT) to LVRS or medical therapy. NETT participants were selected to match EBC participants in age, baseline spirometry, and gender. Outcomes were compared from baseline, at 6 and 12 months. Results: There were no significant baseline differences in gender in the EBC, NETT-LVRS or medical treatment patients. At baseline no differences existed between EBC and NETT-LVRS patients in forced expiratory volume in 1 second ( FEV1) or total lung capacity (TLC) %-predicted; residual volume (RV) and diffusing capacity of the lung for carbon monoxide (DLco) %-predicted were higher in the EBC group compared to NETT-LVRS (p < 0.001). Compared to the medical treatment group, EBC produced greater improvements in FEV1 and RV but not TLC at 6 months. FEV1 and RV in the EBC group remained significantly improved at 12-months compared to the medical treatment group. While all 3 therapies improved quality of life, survival at 12 months with EBC or medical therapy was greater than NETT-LVRS. Conclusion: EBC may be a potential therapeutic option in patients with severe homogeneous emphysema and hyperinflation who are already receiving optimal medical treatment.

14.
Ann Am Thorac Soc ; 15(11): 1296-1303, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30063372

RESUMO

RATIONALE: Colder temperatures have been shown to increase hospitalization and mortality rates in adults with chronic obstructive pulmonary disease (COPD) and cardiac disease. Seasonal influences on exacerbation rates in adults with severe COPD but without significant cardiovascular disease are unclear. In addition, regional variations in COPD exacerbations in North America have not yet been explored. OBJECTIVES: In this study, we sought to determine the seasonal and regional variability in exacerbation rates in those with COPD but without significant cardiovascular risk factors. METHODS: We studied adults without cardiovascular risk factors from STATCOPE (Simvastatin in the Prevention of COPD Exacerbations) and placebo arm of MACRO (Azithromycin for the Prevention of Exacerbations of COPD) studies. Forty-five study sites were divided into climate regions in Canada and the United States; seasons were defined as winter, spring, summer, and fall. The primary outcome was the rate of COPD exacerbation. Secondary outcomes included time to first exacerbation, severity of exacerbations, all-cause mortality, and antibiotic and steroid use. RESULTS: We analyzed 1,175 subjects with a mean age of 63.3 ± 8.6 years, forced expiratory volume in 1 second of 41.5 ± 17.1% predicted, and 53.6 ± 29.4 pack-years of smoking history. The COPD exacerbation rate was higher in winter (0.13 exacerbations/person-month) than in spring, summer, and fall (0.11, 0.079, and 0.10 exacerbations/person-month, respectively) (P < 0.001). Summer had the highest proportion of severe exacerbations (40.5%) compared with spring, fall, and winter (32.6%, 34.7%, and 33.1%, respectively) (P = 0.004). Mortality was highest in spring and winter (34% and 30%, respectively). There was significant regional variability in the time to first exacerbation, with the Southeast and West having longer median times to first exacerbation (350 and 342 d, respectively, compared with 184 d in other regions) (P < 0.001). CONCLUSIONS: Significant seasonal and regional variability exist in the rate and severity of exacerbations and overall mortality in adults with COPD without cardiovascular disease.


Assuntos
Doenças Cardiovasculares/etiologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estações do Ano , Idoso , Canadá/epidemiologia , Feminino , Volume Expiratório Forçado , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos/epidemiologia
15.
Chest ; 154(4): 818-826, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29966665

RESUMO

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has an expected median survival of 3 months. Lung transplantation is a potentially lifesaving therapy for AE-IPF. However, the current knowledge of transplantation outcomes during AE-IPF is limited to a few small retrospective studies, reporting only 1-year post-transplantation survival. METHODS: Study population included patients with IPF consecutively listed for lung transplantation at a single institution between the years 2012 and 2016. We collected lung allocation score (LAS), hospitalization, and survival data. The primary outcome was survival among patients transplanted during stable IPF vs during AE-IPF. RESULTS: Of 89 patients with IPF listed for lung transplantation, 52 were transplanted during stable IPF and 37 were hospitalized due to AE-IPF. Of these 37 patients, nine died before transplantation, and 28 were transplanted during AE-IPF. Fifty percent of patients transplanted during AE-IPF died in a mean follow-up of 1.6 ± 1.2 years compared with 12% of patients transplanted during stable IPF who died in a mean follow-up of 2.6 ± 1.2 years. The Kaplan-Meier survival curves post-transplantation after 1 and 3 years for patients who were transplanted during stable IPF were 94% and 90% vs 71% and 60% in patients who were transplanted during AE-IPF (P = .0001). LAS above 80 conferred a 3-year hazard ratio for mortality of 5.7 vs LAS lower than 80 (95% CI, 2.33-14.0; P < .0005). CONCLUSIONS: Patients with IPF transplanted during AE-IPF had significantly worse short-term and long-term survival compared with patients transplanted during stable IPF. Patients with AE-IPF and very high LAS may not experience the survival advantage expected from lung transplantation.


Assuntos
Fibrose Pulmonar Idiopática/mortalidade , Transplante de Pulmão/mortalidade , Doença Aguda , Idoso , Causas de Morte , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/cirurgia , Estimativa de Kaplan-Meier , Masculino , Cuidados Pós-Operatórios/mortalidade , Cuidados Pré-Operatórios/mortalidade , Insuficiência Respiratória/complicações , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Capacidade Vital/fisiologia
17.
Sci Rep ; 8(1): 3555, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29476075

RESUMO

Emphysema is characterized by irreversibly enlarged airspaces and destruction of alveolar walls. One of the factors contributing to this disease pathogenesis is an elevation in extracellular matrix (ECM) degradation in the lung. Alveolar type II (ATII) cells produce and secrete pulmonary surfactants and proliferate to restore the epithelium after damage. We isolated ATII cells from control non-smokers, smokers and patients with emphysema to determine the role of NFE2 (nuclear factor, erythroid-derived 2). NFE2 is a heterodimer composed of two subunits, a 45 kDa (p45 NFE2) and 18 kDa (p18 NFE2) polypeptides. Low expression of p45 NFE2 in patients with emphysema correlated with a high ECM degradation. Moreover, we found that NFE2 knockdown increased cell death induced by cigarette smoke extract. We also studied the cross talk between p45 NFE2 and DJ-1. DJ-1 protein is a redox-sensitive chaperone that protects cells from oxidative stress. We detected that cigarette smoke significantly increased p45 NFE2 levels in DJ-1 KO mice compared to wild-type mice. Our results indicate that p45 NFE2 expression is induced by exposure to cigarette smoke, has a cytoprotective activity against cell injury, and its downregulation in human primary ATII cells may contribute to emphysema pathogenesis.


Assuntos
Enfisema/genética , Pulmão/efeitos dos fármacos , Subunidade p45 do Fator de Transcrição NF-E2/genética , Proteína Desglicase DJ-1/genética , Animais , Proliferação de Células/genética , Fumar Cigarros/efeitos adversos , Enfisema/fisiopatologia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Camundongos Knockout , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiopatologia
18.
J Fam Pract ; 67(2 Suppl): S3-S10, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29443331

RESUMO

Physical inactivity is often considered to be a major contributor to the progression of chronic obstructive pulmonary disease, and is linked to hospitalizations and increased all-cause mortality. There is, therefore, a need to recognize symptoms early and treat them accordingly.


Assuntos
Dispneia/etiologia , Exercício Físico , Indicadores Básicos de Saúde , Atenção Primária à Saúde/métodos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Dispneia/prevenção & controle , Fadiga/etiologia , Nível de Saúde , Humanos , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Qualidade de Vida , Mecânica Respiratória
19.
Am J Respir Crit Care Med ; 197(10): 1275-1284, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29313708

RESUMO

RATIONALE: As the third leading cause of death in the United States, the impact of chronic obstructive pulmonary disease (COPD) makes identification of its molecular mechanisms of great importance. Genome-wide association studies (GWASs) have identified multiple genomic regions associated with COPD. However, genetic variation only explains a small fraction of the susceptibility to COPD, and sub-genome-wide significant loci may play a role in pathogenesis. OBJECTIVES: Regulatory annotation with epigenetic evidence may give priority for further investigation, particularly for GWAS associations in noncoding regions. We performed integrative genomics analyses using DNA methylation profiling and genome-wide SNP genotyping from lung tissue samples from 90 subjects with COPD and 36 control subjects. METHODS: We performed methylation quantitative trait loci (mQTL) analyses, testing for SNPs associated with percent DNA methylation and assessed the colocalization of these results with previous COPD GWAS findings using Bayesian methods in the R package coloc to highlight potential regulatory features of the loci. MEASUREMENTS AND MAIN RESULTS: We identified 942,068 unique SNPs and 33,996 unique CpG sites among the significant (5% false discovery rate) cis-mQTL results. The genome-wide significant and subthreshold (P < 10-4) GWAS SNPs were enriched in the significant mQTL SNPs (hypergeometric test P < 0.00001). We observed enrichment for sites located in CpG shores and shelves, but not CpG islands. Using Bayesian colocalization, we identified loci in regions near KCNK3, EEFSEC, PIK3CD, DCDC2C, TCERG1L, FRMD4B, and IL27. CONCLUSIONS: Colocalization of mQTL and GWAS loci provides regulatory characterization of significant and subthreshold GWAS findings, supporting a role for genetic control of methylation in COPD pathogenesis.


Assuntos
Metilação de DNA/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Epigenômica , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Locos de Características Quantitativas , Estados Unidos/epidemiologia
20.
Hum Genomics ; 12(1): 1, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335020

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) significantly associated with chronic obstructive pulmonary disease (COPD). However, many genetic variants show suggestive evidence for association but do not meet the strict threshold for genome-wide significance. Integrative analysis of multiple omics datasets has the potential to identify novel genes involved in disease pathogenesis by leveraging these variants in a functional, regulatory context. RESULTS: We performed expression quantitative trait locus (eQTL) analysis using genome-wide SNP genotyping and gene expression profiling of lung tissue samples from 86 COPD cases and 31 controls, testing for SNPs associated with gene expression levels. These results were integrated with a prior COPD GWAS using an ensemble statistical and network methods approach to identify relevant genes and observe them in the context of overall genetic control of gene expression to highlight co-regulated genes and disease pathways. We identified 250,312 unique SNPs and 4997 genes in the cis(local)-eQTL analysis (5% false discovery rate). The top gene from the integrative analysis was MAPT, a gene recently identified in an independent GWAS of lung function. The genes HNRNPAB and PCBP2 with RNA binding activity and the gene ACVR1B were identified in network communities with validated disease relevance. CONCLUSIONS: The integration of lung tissue gene expression with genome-wide SNP genotyping and subsequent intersection with prior GWAS and omics studies highlighted candidate genes within COPD loci and in communities harboring known COPD genes. This integration also identified novel disease genes in sub-threshold regions that would otherwise have been missed through GWAS.


Assuntos
Predisposição Genética para Doença , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Receptores de Ativinas Tipo I/genética , Adulto , Idoso , Feminino , Regulação da Expressão Gênica , Genômica , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Humanos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Locos de Características Quantitativas/genética , Proteínas de Ligação a RNA/genética , Proteínas tau/genética
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