Durch die Fortschritte bei der Transplantation wird zunehmend ein längeres Überleben der Patienten ermöglicht. Vor diesem Hintergrund gewinnen während der Zeit der chronischen Erkrankung erworbene Störungen sowie die im Verlauf nach der Transplantation auftretenden Nebenwirkungen an Bedeutung. Bei Beschränkung auf Veränderungen an der Lunge konnte bei Patienten mit chronischem Organversagen (Herz, Leber und Niere) gezeigt werden, dass lungenfunktionell messbare Störungen nachweisbar sind. Diese manifestieren sich vorrangig als Veränderungen der Diffusion, gefolgt von restriktiven und obstruktiven Ventilationsstörungen. Es bisher ungeklärt, inwieweit an deren Ausprägung interstitielle Lungenerkrankungen beteiligt sind. Gegenstand der Arbeit war die Analyse der Art, der Häufigkeit und des Umfanges lungenfunktioneller Störungen sowie die Bestimmung des Anteils computertomografisch nachweisbarer interstitieller Lungenveränderungen (ILD) bei transplantierten Patienten. Dazu wurden 79 Patienten nach Nierentransplantation (NTX), 40 Patienten nach Lebertransplantation (LTX), 40 Patienten nach Herztransplantation (HTX) zwischen 45-83 Monaten nach Transplantation mittels kompletter Lungenfunktionsanalyse und hochauflösender Computertomografie untersucht. Für eine vergleichende Betrachtung wurden 75 Patienten mit einer progressiven systemischen Sklerodermie (als ein Krankheitsbild mit Modellcharakter für ILD) ausgewertet. Die lungenfunktionellen Daten von 642 Patienten, eine spiroergometrische Analyse sowie eine autoptische Untersuchung bei Patienten nach HTX ergänzten die Erhebung. Als Ergebnisse konnten restriktive Ventilationsstörungen bei 2,5 - 10 Prozent in den drei Gruppen transplantierter Patienten nachgewiesen werden. Eine Obstruktion fand sich in vergleichbarer Größenordnung mit Werten zwischen 7,5 - 10 Prozent. Störungen der Diffusion konnten bei Verwendung des Transferfaktors der Lunge (TLCO) bzw. des Transferkoeffizienten (KCO) bei Patienten nach HTX mit 65 bzw. 98 Prozent, nach NTX mit 44 bzw. 68 Prozent und nach LTX mit 32 bzw. 68 Prozent ermittelt werden. Damit waren diese Veränderungen signifikant häufiger bei Patienten nach HTX gegenüber den beiden anderen Gruppen transplantierter Patienten nachweisbar. Computertomografisch nachweisbare ILD wurden nach LTX mit 5 Prozent , nach HTX mit 12 Prozent und nach NTX mit 24 Prozent gefunden. Damit konnte eine signifikant unterschiedliche Häufigkeit bei Patienten nach LTX und NTX festgestellt werden. Bei keiner der untersuchten Gruppen konnte eine signifikante Korrelation zwischen den Befunden der Diffusionsstörungen und dem Nachweis der ILD erfasst werden. Bei der Modellerkrankung waren die radiologischen Befunde häufiger nachweisbar, jedoch qualitativ gleich. Die Daten der 642 Patienten nach HTX zeigten eine konstante Häufigkeit von Diffusionsein-schränkungen, die unabhängig von der Zeit nach Transplantation waren. Die spiroergometrische Analyse nach HTX dokumentierte bei 92 Prozent der Patienten eine eingeschränkte kardiopulmonale Leistungsfähigkeit, wobei daran eine ventilatorische Begrenzung ursächlich nicht beteiligt war. Bei der autoptischen Untersuchung nach HTX fanden sich in 56 Prozent der untersuchten Fälle eine Verbreiterung des Interstitiums der Lunge sowie in 94 Prozent der Fälle Veränderungen an den Blutgefäßen. Die vorliegenden Daten erlauben die Aussage, dass bei transplantierten Patienten Diffusionsstörungen in relevantem Umfang nachweisbar waren. Diese stehen in keinem ursächlichem Zusammenhang mit den geringgradig computertomografisch nachweisbaren interstitiellen Veränderungen. Somit wird mit den Daten die hypothetische Annahme einer vorrangig gefäßbedingten Einschränkung der Diffusion bei den transplantierten Patienten gestützt. / Progress made in transplantation medicine is increasingly leading to longer survival of patients. This means that impairment acquired during the time of chronic illness and side effects during the postoperative course are increasingly significant. Considering pulmonary changes, it was shown that in patients with chronic organ failure (heart, liver, kidneys) impairment of lung function was measurable. This manifests mainly as changes in diffusion, followed by restrictive and obstructive ventilatory impairment. It is to date unclear to what extent interstitial lung disease is involved. This study analyzes the kind, prevalence and extent of lung impairment and the role of interstitial lung disease (ILD) revealed by computed tomography in transplanted patients. For this purpose we examined 79 patients after kidney transplantation (KTX), 40 patients after liver transplantation (LTX) and 40 patients after heart transplantation (HTX) between 45 and 83 months after transplantation by means of comprehensive lung function analysis and high-resolution computed tomography. For purposes of comparison, 75 patients with progressive systemic sclerodermia (chosen because of its exemplary nature for ILD) were evaluated. The study also includes lung function data for 642 patients, an analysis of exercise testing and an autopsy investigation of 73 patients after HTX. The results showed restrictive ventilatory impairment of 2.5-10% in the three groups of transplanted patients. The values for obstruction were similar at between 7.5 and 10%. Taking into account the lung transfer factor (TLCO) and the transfer coefficient (KCO), diffusion impairment was calculated to be 65 and 98% respectively in HTX patients, 44 and 68 % in KTX patients and 32 and 68% in LTX patients. These changes were therefore shown to be significantly more common in patients after HTX than in the other two patient groups. ILD revealed by computed tomography was 5% after LTX, 12% after HTX and 24% after KTX, i.e. a significantly different occurrence was found in patients after LTX and KTX. In none of the groups was a significant correlation between diffusion impairment data and ILD shown. In the sclerodermia group ILD could be shown more often than in the transplanted patients but corresponded in quality. The data of the 642 patients after HTX showed a constant incidence of diffusion impairment independent of the posttransplant time. The analysis of exercise testing established in patients after HTX restricted cardiopulmonary function, of which ventilatory impairment was not the cause. The autopsy investigation of patients after HTX showed widening of the pulmonary interstitium in 56% and changes in the blood vessels in 94% of the cases investigated. The data studied show that diffusion impairment was present to a relevant extent in transplanted patients. This impairment has no causative correlation with the interstitial changes shown by computed tomography to be minimal. Therefore the data support the hypothesis of diffusion impairment in transplanted patients being caused mainly by vascular changes.

No laboratório de investigação médica da disciplina de Cirurgia Torácica do Departamento de Cardio-pneumologia da Faculdade de Medicina da Universidade de São Paulo vem sendo desenvolvida uma linha de pesquisa experimental sobre transplante pulmonar, visando elucidar os efeitos que a cirurgia sobre o brônquio e o uso de drogas imunossupressoras têm sobre o aparelho mucociliar. O presente estudo tem por objetivo avaliar os efeitos da azatioprina e da transecção brônquica sobre o aparelho mucociliar em ratos. Utilizamos 36 ratos machos da raça Wistar, não isogênicos, pesando de 200 a 250g, obtidos no biotério da Faculdade de Medicina da Universidade de São Paulo. Todos os animais foram submetidos à anestesia geral, intubação orotraqueal e ventilação mecânica. Em seguida foi realizada uma toracotomia esquerda com transecção e reanastomose do brônquio principal esquerdo. Por fim síntese do tórax e drenagem fechada, que era retirada quando o animal acordava. Os animais foram divididos em dois grupos: com administração de azatioprina e com administração de solução de salina. Eles foram sacrificados aos 7, 15 e 30 dias para retirada dos pulmões e árvore brônquica. O muco foi coletado do brônquio direito e esquerdo. Foi realizada a medida da velocidade do transporte mucociliar à direita e esquerda dos dois grupos e posterior análise das propriedades dos mucos através da medida da velocidade de transporte relativa no palato de rã e da medida do ângulo de contato. As medidas das variáveis dos brônquios direito e esquerdo com e sem azatioprina nos três tempos de avaliação foram submetidas ao teste de Análise de Variância de Duplo Fator. Nos resultados a velocidade do transporte à esquerda foi significativamente reduzida pela transecção brônquica quando comparada entre os grupos: mostrando-se pior aos 30 dias. A velocidade relativa e o ângulo de contato dos mucos coletados à esquerda mostraram com significado estatístico uma piora nas propriedades do muco pela transecção, pricipalmente aos 30 dias. Com a azatioprina e a transecção observamos piora na velocidade do transporte mucociliar significativa ao longo do tempo, maior aos sete dias e com uma progressiva melhora até os 30 dias. O estudo mostrou que a azatioprina não acarretou piora quando associada à transecção. Na presença de azatioprina houve melhora das propriedades do muco, tendo a velocidade do transporte relativo e o ângulo de contato melhora significativa ao longo do tempo. A azatioprina previne uma piora da qualidade do muco. Concluímos que a transecção brônquica piora o transporte mucociliar; a azatioprina preserva as propriedades do muco; a azatioprina piora o transporte até os sete dias; a azatioprina não interage com a transecção para a redução da velocidade do transporte mucociliar e para a piora do muco / At the Experimental Thoracic Surgery Laboratory, Department of Cardio-Pneumology , Department of Pathology, Experimental Air Pollution Laboratory, in the Medical School, São Paulo University, research in lung transplantation, administration of imunossupression drugs and their effects on the mucociliary system are carried out. We develop models of bronchial transeccion and reanastomosis, unilateral lung transplantation, mucociliary transport velocity and mucus transportability in rats, which allow us to observe the resulting alterations. The mechanisms involved in the impairment of the mucociliary function after lung transplantation and immunosuppression therapy are not yet completely understood. The purpose of the present study was to evaluate the effects of azathioprine on the mucociliary system in a model of bronchial transeccion and reanastomosis in rats. We used 36 rats, submitted to general anesthesia, tracheal tube, mechanical ventilation and left thoracotomy, followed by a left main stem bronchus transeccion and reanastomosis. The animals were separated into 2 groups that received or not azathioprine (AZA), and being sacrificed at 7, 15 and 30 days after the surgical procedure. In situ bronchial mucociliary transport (MCT) was determined distal to the anastomosis of the left main stem transected bronchus (LTB) and in the right intact bronchus (RIB). We also studied the surface properties of mucus by using in vitro mucus transportability with a frog palate preparation and mucus contact angle (mucus adhesively) collecting mucus from LTB and RIB. The measures obtained were submitted to statistical analysis. The results showed that the MCT velocity (mm/min) was significantly lower (p<0.01) in the LTB without the AZA administration compared with the RIB with or without AZA. At the LTB with AZA administration there was significant difference (p<0.05) at 7 days compared with the RIB with and without AZA and no significant difference at 15 and 30 days (p>0.05). Mucus in vitro transportability and adhesiveness showed the worst result at the LTB without AZA (p<0.05). In the group that received AZA on 30 days of LTB there was no significantly difference in mucus properties (p>0.05) compared with the RIB groups (with and without AZA). We concluded that AZA led to a temporary marked impairment of MCT, while this occurrence was maintained up to 30 days in the transected bronchus. In addition, AZA contributes to preventing alterations in the mucus surface properties

No laboratório de investigação médica da disciplina de Cirurgia Torácica do Departamento de Cardio-pneumologia da Faculdade de Medicina da Universidade de São Paulo vem sendo desenvolvida uma linha de pesquisa experimental sobre transplante pulmonar, visando elucidar os efeitos que a cirurgia sobre o brônquio e o uso de drogas imunossupressoras têm sobre o aparelho mucociliar. O presente estudo tem por objetivo avaliar os efeitos da azatioprina e da transecção brônquica sobre o aparelho mucociliar em ratos. Utilizamos 36 ratos machos da raça Wistar, não isogênicos, pesando de 200 a 250g, obtidos no biotério da Faculdade de Medicina da Universidade de São Paulo. Todos os animais foram submetidos à anestesia geral, intubação orotraqueal e ventilação mecânica. Em seguida foi realizada uma toracotomia esquerda com transecção e reanastomose do brônquio principal esquerdo. Por fim síntese do tórax e drenagem fechada, que era retirada quando o animal acordava. Os animais foram divididos em dois grupos: com administração de azatioprina e com administração de solução de salina. Eles foram sacrificados aos 7, 15 e 30 dias para retirada dos pulmões e árvore brônquica. O muco foi coletado do brônquio direito e esquerdo. Foi realizada a medida da velocidade do transporte mucociliar à direita e esquerda dos dois grupos e posterior análise das propriedades dos mucos através da medida da velocidade de transporte relativa no palato de rã e da medida do ângulo de contato. As medidas das variáveis dos brônquios direito e esquerdo com e sem azatioprina nos três tempos de avaliação foram submetidas ao teste de Análise de Variância de Duplo Fator. Nos resultados a velocidade do transporte à esquerda foi significativamente reduzida pela transecção brônquica quando comparada entre os grupos: mostrando-se pior aos 30 dias. A velocidade relativa e o ângulo de contato dos mucos coletados à esquerda mostraram com significado estatístico uma piora nas propriedades do muco pela transecção, pricipalmente aos 30 dias. Com a azatioprina e a transecção observamos piora na velocidade do transporte mucociliar significativa ao longo do tempo, maior aos sete dias e com uma progressiva melhora até os 30 dias. O estudo mostrou que a azatioprina não acarretou piora quando associada à transecção. Na presença de azatioprina houve melhora das propriedades do muco, tendo a velocidade do transporte relativo e o ângulo de contato melhora significativa ao longo do tempo. A azatioprina previne uma piora da qualidade do muco. Concluímos que a transecção brônquica piora o transporte mucociliar; a azatioprina preserva as propriedades do muco; a azatioprina piora o transporte até os sete dias; a azatioprina não interage com a transecção para a redução da velocidade do transporte mucociliar e para a piora do muco / At the Experimental Thoracic Surgery Laboratory, Department of Cardio-Pneumology , Department of Pathology, Experimental Air Pollution Laboratory, in the Medical School, São Paulo University, research in lung transplantation, administration of imunossupression drugs and their effects on the mucociliary system are carried out. We develop models of bronchial transeccion and reanastomosis, unilateral lung transplantation, mucociliary transport velocity and mucus transportability in rats, which allow us to observe the resulting alterations. The mechanisms involved in the impairment of the mucociliary function after lung transplantation and immunosuppression therapy are not yet completely understood. The purpose of the present study was to evaluate the effects of azathioprine on the mucociliary system in a model of bronchial transeccion and reanastomosis in rats. We used 36 rats, submitted to general anesthesia, tracheal tube, mechanical ventilation and left thoracotomy, followed by a left main stem bronchus transeccion and reanastomosis. The animals were separated into 2 groups that received or not azathioprine (AZA), and being sacrificed at 7, 15 and 30 days after the surgical procedure. In situ bronchial mucociliary transport (MCT) was determined distal to the anastomosis of the left main stem transected bronchus (LTB) and in the right intact bronchus (RIB). We also studied the surface properties of mucus by using in vitro mucus transportability with a frog palate preparation and mucus contact angle (mucus adhesively) collecting mucus from LTB and RIB. The measures obtained were submitted to statistical analysis. The results showed that the MCT velocity (mm/min) was significantly lower (p<0.01) in the LTB without the AZA administration compared with the RIB with or without AZA. At the LTB with AZA administration there was significant difference (p<0.05) at 7 days compared with the RIB with and without AZA and no significant difference at 15 and 30 days (p>0.05). Mucus in vitro transportability and adhesiveness showed the worst result at the LTB without AZA (p<0.05). In the group that received AZA on 30 days of LTB there was no significantly difference in mucus properties (p>0.05) compared with the RIB groups (with and without AZA). We concluded that AZA led to a temporary marked impairment of MCT, while this occurrence was maintained up to 30 days in the transected bronchus. In addition, AZA contributes to preventing alterations in the mucus surface properties