Introdução: A fibrose pulmonar idiopática (FPI) é uma grave doença pulmonar crônica com sintomas de dispneia progressiva, resultando na diminuição da capacidade de exercício, impactando negativamente na qualidade de vida relacionada à saúde (QVRS). A reabilitação pulmonar (RP) melhora a capacidade funcional (CF) com redução dos sintomas, porém na FPI avançada seus efeitos e magnitudes são pouco conhecidos. Objetivo: Avaliar o impacto da RP sobre a QVRS e a CF em pacientes portadores de FPI. Métodos: Estudo de coorte retrospectiva em que foram revisados dados de 56 prontuários de pacientes em lista de transplante de pulmão com diagnóstico de FPI de acordo com o consenso da American Toracic Society 2011, submetidos a 12 semanas (36 sessões) de RP ambulatorial entre o período de janeiro de 2008 a outubro de 2012. Foram avaliadas a CF e a QVRS através do teste de caminhada de seis minutos (TC6) e do questionário 36-item short-form survey, SF36, respectivamente, antes e imediatamente após a RP. Resultados: Vinte e sete pacientes foram incluídos no estudo, 16 (61%) gênero masculino com idade média de 53 ±13 anos. Dezoito pacientes (68%) tinham diagnóstico histológico por biópsia pulmonar com padrão de pneumonia intersticial usual (PIU), com tempo médio de diagnóstico de 3 ±1,7 anos. Quanto à classificação da dispneia pela escala modified Medical Research Council (mMRC) basal, 59% dos pacientes foram classificados entre 3-4. Houve aumento significativo na distância percorrida de 393 ±88 metros para 453 ±90 metros (p<0,001). As medianas de dispneia sofreram diminuição significativa (p=0,01) na escala do mMRC de 2 (IC95%: 1-4) para 1 (IC95%: 1-4) e de 5 (Mín/Máx:1-10) para 3 (Mín/Máx:0-10) no BORG de dispneia no final do TC6. Apesar de caminharem maiores distâncias, a fadiga em membros inferiores foi menor com uma mediana de 2 (Mín/Máx:0-10) para 1 (Mín/Máx:0-9) (p=0,02). Houve aumento em 5 dos 8 domínios, porém somente a capacidade funcional foi significativa de 26 (IC95%: 19-33) para 37 (IC95%: 27-48) (p<0,05); os demais domínios não tiveram significância estatística. Conclusão: Observaram-se nestes pacientes aumentos da CF, com diminuição dos sintomas dispneia e fadiga; o que não se refletiu em melhora clínica na QVRS em portadores de FPI em lista de transplante de pulmão após um programa de RP. / Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with severe symptoms of progressive dyspnea, resulting in decreased exercise capacity, negatively impacting the health-related quality of life (HRQL). Pulmonary rehabilitation (PR) improves functional capacity (FC) with reduction in symptoms, but in advanced IPF, its effects and magnitudes are unknown. Objective: To evaluate the impact of PR and in HRQL and in FC of patients with IPF. Methods: Coorte study with a retrospective review of data from 56 medical records of patients on lung transplant list diagnosed with IPF according to the American Toracic Society 2011 consensus, submitted to 12 weeks (36 sessions) of outpatient RP between January 2008 and October 2012. The FC and the HRQL were assessed through a six-minute walk test (6MWT) and the 36-item short-form survey (SF36) respectively before and immediately after PR. Results: Twenty-seven patients were included in the study, 16 (61%) male with a mean age of 53 ± 13 years. Eighteen patients (68%) had histologic diagnosis by lung biopsy compatible with usual interstitial pneumonia (UIP), with median time from diagnosis of 3 ± 1.7 years. Regarding the classification of the dyspnea in the modified Medical Research Council (mMRC) scale, 59% of patients were classified between 3-4. There was a significant increase in the distance covered from 393 ± 88 meters to 453 ± 90 meters (p <0.001). The baseline medians of dyspnea had a significant decrease (p = 0.01) in the mMRC scale from 2 (CI 95%: 1-4) to 1 (CI 95%: 1-4) and the median decreased from 5 (Min/Max: 1-10) to 3 (Min/Max :0-10) in the Borg dyspnea index at the end of the 6MWT. Although the patients walked greater distances, they had less fatigue in the legs, with a median decrease from 2 (Min/Max: 0-10) to 1 (Min/Max: 0-9) (p = 0.02). There was an increase in 5 of the 8 domains, but only the functional capacity was significant: from 26 (CI95%: 19-33) to 37 (CI95%: 27-48) (p <0.05), while the remaining areas were not statistically significant. Conclusion: We observed increases of FC in these patients, with decreased symptoms of dyspnea and fatigue; which were not reflected in clinical improvement in HRQL of patients with IPF on lung transplant list after a PR program.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown aetiology, characterised by the progressive and irreversible scarring of parenchymal lung tissue that leads to respiratory failure and death. The disease is understood to be driven by an impaired and aberrant wound healing response, with an inappropriate reactivation of developmental signalling. The greatest risk factor for the disease is age, which is a process intimately associated with an increase in the burden of senescent cells. Such cells acquire a unique secretory phenotype and are known to have a significant impact on their local micro-environment. It was hypothesised that an alteration in epithelial-mesenchymal secretory communication, due to senescent-like changes in the fibroblast phenotype, may detrimentally contribute to lung homeostasis. An in vitro model of the lung airway was established in which primary human lung fibroblasts (HLFs) were co-cultured with human bronchial epithelial cells (HBECs). HBECs were cultured on a semi-permeable, transwell insert and co-cultured with either normal (NHLF), fibrotic (FHLF) or senescent fibroblasts. Over 72 hrs of co-culture, wound healing was assessed, via an epithelial scratch assay, and epithelial regeneration was measured, via trans-epithelial electrical resistance. Co-culture with NHLFs improves epithelial regeneration, however, FHLFs and senescent cells in co-culture show a diminished ability to promote epithelial regeneration and wound repair. The secretory repertoire of these cells contains elevated levels of IL-6, CXCL8, CXCL1 and GCSF (when assessed at both an RNA and protein level), factors strongly associated with the senescent phenotype. Targeting this secretome via treatment with the JAK 1/2 inhibitor Ruxolitinib attenuates these impairments and may point towards a new therapeutic strategy for the treatment of IPF.

Introdução: A fibrose pulmonar idiopática (FPI) é uma grave doença pulmonar crônica com sintomas de dispneia progressiva, resultando na diminuição da capacidade de exercício, impactando negativamente na qualidade de vida relacionada à saúde (QVRS). A reabilitação pulmonar (RP) melhora a capacidade funcional (CF) com redução dos sintomas, porém na FPI avançada seus efeitos e magnitudes são pouco conhecidos. Objetivo: Avaliar o impacto da RP sobre a QVRS e a CF em pacientes portadores de FPI. Métodos: Estudo de coorte retrospectiva em que foram revisados dados de 56 prontuários de pacientes em lista de transplante de pulmão com diagnóstico de FPI de acordo com o consenso da American Toracic Society 2011, submetidos a 12 semanas (36 sessões) de RP ambulatorial entre o período de janeiro de 2008 a outubro de 2012. Foram avaliadas a CF e a QVRS através do teste de caminhada de seis minutos (TC6) e do questionário 36-item short-form survey, SF36, respectivamente, antes e imediatamente após a RP. Resultados: Vinte e sete pacientes foram incluídos no estudo, 16 (61%) gênero masculino com idade média de 53 ±13 anos. Dezoito pacientes (68%) tinham diagnóstico histológico por biópsia pulmonar com padrão de pneumonia intersticial usual (PIU), com tempo médio de diagnóstico de 3 ±1,7 anos. Quanto à classificação da dispneia pela escala modified Medical Research Council (mMRC) basal, 59% dos pacientes foram classificados entre 3-4. Houve aumento significativo na distância percorrida de 393 ±88 metros para 453 ±90 metros (p<0,001). As medianas de dispneia sofreram diminuição significativa (p=0,01) na escala do mMRC de 2 (IC95%: 1-4) para 1 (IC95%: 1-4) e de 5 (Mín/Máx:1-10) para 3 (Mín/Máx:0-10) no BORG de dispneia no final do TC6. Apesar de caminharem maiores distâncias, a fadiga em membros inferiores foi menor com uma mediana de 2 (Mín/Máx:0-10) para 1 (Mín/Máx:0-9) (p=0,02). Houve aumento em 5 dos 8 domínios, porém somente a capacidade funcional foi significativa de 26 (IC95%: 19-33) para 37 (IC95%: 27-48) (p<0,05); os demais domínios não tiveram significância estatística. Conclusão: Observaram-se nestes pacientes aumentos da CF, com diminuição dos sintomas dispneia e fadiga; o que não se refletiu em melhora clínica na QVRS em portadores de FPI em lista de transplante de pulmão após um programa de RP. / Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with severe symptoms of progressive dyspnea, resulting in decreased exercise capacity, negatively impacting the health-related quality of life (HRQL). Pulmonary rehabilitation (PR) improves functional capacity (FC) with reduction in symptoms, but in advanced IPF, its effects and magnitudes are unknown. Objective: To evaluate the impact of PR and in HRQL and in FC of patients with IPF. Methods: Coorte study with a retrospective review of data from 56 medical records of patients on lung transplant list diagnosed with IPF according to the American Toracic Society 2011 consensus, submitted to 12 weeks (36 sessions) of outpatient RP between January 2008 and October 2012. The FC and the HRQL were assessed through a six-minute walk test (6MWT) and the 36-item short-form survey (SF36) respectively before and immediately after PR. Results: Twenty-seven patients were included in the study, 16 (61%) male with a mean age of 53 ± 13 years. Eighteen patients (68%) had histologic diagnosis by lung biopsy compatible with usual interstitial pneumonia (UIP), with median time from diagnosis of 3 ± 1.7 years. Regarding the classification of the dyspnea in the modified Medical Research Council (mMRC) scale, 59% of patients were classified between 3-4. There was a significant increase in the distance covered from 393 ± 88 meters to 453 ± 90 meters (p <0.001). The baseline medians of dyspnea had a significant decrease (p = 0.01) in the mMRC scale from 2 (CI 95%: 1-4) to 1 (CI 95%: 1-4) and the median decreased from 5 (Min/Max: 1-10) to 3 (Min/Max :0-10) in the Borg dyspnea index at the end of the 6MWT. Although the patients walked greater distances, they had less fatigue in the legs, with a median decrease from 2 (Min/Max: 0-10) to 1 (Min/Max: 0-9) (p = 0.02). There was an increase in 5 of the 8 domains, but only the functional capacity was significant: from 26 (CI95%: 19-33) to 37 (CI95%: 27-48) (p <0.05), while the remaining areas were not statistically significant. Conclusion: We observed increases of FC in these patients, with decreased symptoms of dyspnea and fatigue; which were not reflected in clinical improvement in HRQL of patients with IPF on lung transplant list after a PR program.

Abstract Interstitial lung diseases (ILD), including interstitial pneumonias (IP), represent disorders with variable degrees of parenchymal inflammation and/or fibrosis offer an ideal model to investigate the histopathological features in relation to the course of these diseases. The most common IP is idiopathic pulmonary fibrosis (IPF) with the histological pattern of usual interstitial pneumonia (UIP) exhibiting the histological hallmark of fibroblast foci (FF). Surgical lung biopsy (SLB) is not usually needed for diagnosis of IPF, but the lung biopsy samples taken by SLB confers the diagnosis in atypical cases. The safety of SLB in IPF/UIP has been a controversial issue. The acute exacerbation occasionally occurs during the course of IPF/UIP, but pathological features related to this event are poorly understood. Recent studies suggest that one important determinant in the pathogenesis of ILDs, as in IPF, is oxidant stress and an imbalance of the redox-state in the lung. Thiol containing redox-regulated proteins which paticipate in the antioxidant defence of the lung include thiorexin (Trx) and gamma-glutamylcysteine synthetase (γGCS), also called glutamate-cysteine ligase (GLCL), the rate-limiting enzyme of glutathione (GSH) synthesis. The goal of this research was to evaluate the safety of SLB and the relationships between the histological findings and the course of IPF/UIP, and to investigate the above mentioned defense mechanisms in a variety of ILDs by means of immmunohistochemical analyses, Western Blotting and immunoelectronmicroscopy. No deaths occurred in the following 30 days after 34 video-assisted thoracoscopic lung biopsy (VATS). The number of FF in the lung sample predicted the survival, but it was not associated with acute exacerbation of IPF/UIP before death. Diffuse alveolar damage was a common feature in autopsy samples. The studied redox regulated defense enzymes were expressed in bronchial epithelium, metaplastic alveolar epithelium and alveolar macrophages, but the fibrotic areas generally showed no expression. In IPF/UIP VATS is a safe diagnostic method and counting the number of FF represents a reproducible and reliable method for predicting patient survival. Alterations in the redox regulated defense enzymes further point to the importance of oxidant burden in the fibrotic lung.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-25T17:34:07Z No. of bitstreams: 1 Paulo Rogerio Pereira.pdf: 773654 bytes, checksum: 098c4df44754fb146e1a3739b5cb13f0 (MD5) / Made available in DSpace on 2016-05-25T17:34:07Z (GMT). No. of bitstreams: 1 Paulo Rogerio Pereira.pdf: 773654 bytes, checksum: 098c4df44754fb146e1a3739b5cb13f0 (MD5) Previous issue date: 2014-12-15 / Background: Idiopathic pulmonary fibrosis (IPF) is characterized by decline of lung function, increased inflammation and fibrosis mainly in the pulmonary interstitium, with serotonin (5-HT) and Akt signaling presenting a role. Aerobic training (AT) reduces lung injury in different models of pulmonary diseases. However, the mechanisms underlying the effects of AT in a model of bleomycin-induced lung fibrosis is unknown. Thus, this study investigated the effects of AT in a model of bleomycin-induced pulmonary fibrosis, as well as the participation of 5HT/Akt signaling. Methods: Seventy-two C57Bl/6 male mice were distributed in Control (Co), Exercise (Ex), Fibrosis (Fi) and Fibrosis+Exercise (Fi+Ex) groups. Bleomycin (1.5UI/Kg) was administered on day 1 and treadmill AT began on day 14 during 4 weeks. Total and differential cells count in bronchoalveolar lavage (BAL), IL-1beta, IL-6, CXCL1/KC, IL-10, TNF-alpha and TGF-beta levels in BAL fluid, collagen content in the lung parenchyma, 5-HT levels in BAL fluid and in serum, and the expression of 5-HT2b receptor and Aktphosphorylation were evaluated. Results: AT reduced bleomycin-increased number of total cells (p<0.001), neutrophils (p<0.01), macrophages (p<0.01) and lymphocytes (p<0.05) in BAL. AT also reduced the levels of IL-1beta (p<0.01), IL-6 (p<0.05), CXCL1/KC (p<0.001), TNF-alpha (p<0.001) and TGF-beta (p<0.001), while increased the levels of IL-10 (p<0.001). Collagen fibers deposition was also reduced by AT (p<0.01). These findings were followed by AT-reduced bleomycin-increased 5-HT levels in BAL fluid (p<0.001) and in serum (p<0.05), as well as the expression of 5-HT2b receptor (p<0.01) and the Aktphosphorylation in lung tissue. Conclusions: We conclude that AT reduces lung inflammation and fibrosis in a model of bleomycin-induced lung fibrosis involving 5-HT/Akt signaling. / Introdução: A fibrose pulmonar idiopática (FPI) é uma doença devastadora com pobre prognóstico e nenhum tratamento efetivo disponível. Estudos recentes demonstram que a serotonina / 5-hidroxitriptamina (5-HT) desempenha um papel importante no processo de fibrose pulmonar. Entretanto, alguns estudos demonstram que o tratamento não farmacológico, como programas de reabilitação pulmonar para pacientes com FPI resulta em melhora da qualidade de vida e do manejo da doença, mas os efeitos sobre os pulmões e os possíveis mecanismos desses efeitos não são conhecidos. Objetivos: Portanto, o presente estudo investigou os efeitos do treinamento físico aeróbio na resposta pulmonar em um modelo de fibrose pulmonar induzida por bleomicina em camundongos, e os possíveis efeitos moduladores do exercício sobre os níveis de 5-HT. Materiais e métodos: Foram utilizados setenta e dois camundongos machos C57/Bl6, os quais foram distribuídos em Controle (Co), Exercício (Ex), Fibrose (Fi) e Fibrose + Exercício (Fi + Ex). Vinte e quatro horas após o último teste físico na esteira, a inflamação pulmonar foi avaliada através da avaliação do lavado broncoalveolar (contagem de células e medidas de citocinas: IL-1beta, IL-6, CXCL1/KC, IL-10, TNF-alfa, TGF-beta), e o remodelamento pulmonar através do acúmulo de fibras colágenas no parênquima pulmonar. Foram avaliados também os níveis de 5-HT no sobrenadante do lavado broncoalveolar e no soro. Além disso, a expressão do receptor para 5-HT (5-HT2B) também foi avaliado no tecido pulmonar. Por fim, a expressão da forma integral e fosforilada da Akt também foi avaliada no tecido pulmonar. Resultados: Os resultados demonstraram que o treinamento aeróbio reduziu o número de células totais (p<0.001), de neutrófilos (p<0.01), de macrófagos (p<0.01) e de linfócitos (p<0.05) no lavado broncoalveolar, assim como reduziu os níveis de IL-1beta (p<0.01), IL-6 (p<0.05), CXCL1/KC (p<0.001), TNF-alfa (p<0.001) e TGF-beta (p<0.001) no lavado broncoalveolar, enquanto aumentou os níveis da citocina anti-inflamatória IL-10 (p<0.001). O treinamento físico também reduziu a deposição de fibras de colágeno no parênquima pulmonar (p<0.001). Os níveis de 5-HT no sobrenadante do lavado broncoalveolar (p<0.001) e no soro (p<0.05) e a expressão do receptor 5HT2B (p<0.01) no tecido pulmonar demonstraram-se reduzidos no grupo submetido ao treinamento físico. A expressão de Akt na forma total não foi alterada pelo treinamento físico, enquanto que a forma fosforilada foi reduzida pelo treinamento físico (p<0.01). Conclusões: Os resultados do presente estudo demonstram claramente que o treinamento físico aeróbio é capaz de reduzir a inflamação e a fibrose pulmonar em um modelo experimental de fibrose pulmonar induzida pela bleomicina. Os resultados também demonstram que pelo menos em parte, esses efeitos benéficos do treinamento físico aeróbio pode ter sido mediado pelo aumento da liberação de IL-10, assim como pela redução da exacerbação dos níveis de serotonina, levando a uma redução da expressão do receptor de serotonina 5-HT2B, e também da redução da ativação da proteína Akt.

No description available.

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive and severe interstitial lung diseases (ILDs) for which there is no cure. IPF is characterized by an excessive accumulation of fibroblasts which secrete an abundance of extracellular proteins such as collagen. These processes lead to repetitive tissue scarring and fibrosis in the lung parenchyma. As a result, lungs become rigid limiting oxygen intake and gas exchange. Once diagnosed, IPF is fatal within 2-3 years. There is no known cause or proven treatment that significantly improves outcomes. Although the cause is unknown, the current model of IPF suggests that an overactive epithelial repair mechanism caused by genetic and epigenetic factors as well as environmental exposures is responsible for the chronic fibrosis and scarring characteristic of IPF. The transforming growth factor beta (TGF-B) signaling pathway has been implicated as a major contributor in activating this chronic fibrosis. An upstream activator of the TGF-B pathway, avB6, has been identified as a potential therapeutic target. My collaborators in Dr. David Baker's lab at the University of Washington have created a novel avB6 integrin inhibitor (BP2_disulf) whose efficacy in improving IPF outcomes has yet to be tested. In my study, I test the ability of BP2_disulf to combat IPF through the use of the standard IPF murine model and translatable end points like non-invasive uCT scans, pulmonary function tests, bronchoalveolar lavage fluid (BALF) profiles, and histology. With these methods, I demonstrate that intraperitoneal injection of BP2_disulf in bleomycin-injured mice has the ability to decrease rate of fibrotic progression and pulmonary function decline compared to mice treated with bleomycin alone. These results prove that BP2_disulf is a promising therapeutic not only for IPF but other ILDs as well. Further efficacy validation and investigation into an aerosolized delivery method will advance this drug to clinical trials and make it accessible to those in need.

Background: Recent studies have suggested that patients with idiopathic pulmonary fibrosis (IPF) may have a higher risk of venous thromboembolism (VTE) compared to general population even though the results were inconsistent. Objective: To investigate the risk of VTE among patients with IPF. Methods: Comprehensive literature review using MEDLINE and EMBASE database were performed to identify studies that compared the risk of VTE among patients with IPF to general population. Effect estimates from each study were combined together using random effect model, generic inverse variance method of DerSimonian and Laird. Results: Out of 510 retrieved articles, 5 studies met the inclusion criteria and were included in the meta-analysis. A significant risk of VTE in patients with IPF was observed with the pooled risk ratio of 2.11 (95% confidence interval, 1.28-3.48). The heterogeneity was moderate with I2 of 64%. Conclusion: An approximately 2-fold increased risk of VTE among patients with IPF was observed in this meta-analysis.

Final publication is avilable at http://www.sciencedirect.com/science/article/pii/S0954611115300172 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19577号 / 医博第4084号 / 新制||医||1013(附属図書館) / 32613 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 平家 俊男, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.