RESUMO
Lung transplantation is currently the only curative treatment for patients with end-stage lung disease; however, donor organ shortage and the need for intense immunosuppression limit its broad clinical application. Bioartificial lungs created by combining native matrix scaffolds with patient-derived cells might overcome these problems. Decellularization involves stripping away cells while leaving behind the extracellular matrix scaffold. Cadaveric lungs are decellularized by detergent perfusion, and histologic examination confirms the absence of cellular components but the preservation of matrix proteins. The resulting lung scaffolds are recellularized in a bioreactor that provides biomimetic conditions, including vascular perfusion and liquid ventilation. Cell seeding, engraftment, and tissue maturation are achieved in whole-organ culture. Bioartificial lungs are transplantable, similarly to donor lungs, because the scaffolds preserve the vascular and airway architecture. In rat and porcine transplantation models, successful anastomoses of the vasculature and the airway were achieved, and gas exchange was evident after reperfusion. However, long-term function has not been achieved because of the immaturity of the vascular bed and distal lung epithelia. The goal of this strategy is to create patient-specific transplantable lungs using induced pluripotent stem cell (iPSC)-derived cells. The repopulation of decellularized scaffolds to create transplantable organs is one of possible future clinical applications of iPSCs.
Assuntos
Órgãos Bioartificiais , Matriz Extracelular , Transplante de Pulmão/métodos , Pulmão/fisiologia , Células-Tronco Pluripotentes , Regeneração , Engenharia Tecidual/métodos , Alicerces Teciduais , Animais , Humanos , Transplante de Pulmão/tendências , Modelos Animais , Perfusão , Ratos , SuínosRESUMO
PURPOSE: The ImmuKnow (IK) assay is a comprehensive immune function test that involves measuring adenosine triphosphate produced by the cluster of differentiation 4+ T lymphocytes in peripheral blood. The aim of this study was to analyze the time trends of IK values and assess the relationship between IK values and infections in lung transplants. METHODS: We prospectively collected 178 blood samples from 22 deceased-donor lung transplant (DDLT) recipients and 17 living-donor lobar lung transplant (LDLLT) recipients. A surveillance IK assay was performed postoperatively, then after 1 week and 1, 3, 6, and 12 months. RESULTS: Time trends of IK values in stable recipients peaked 1 week after DDLT (477 ± 247 ATP ng/ml), and 1 month after LDLLT (433 ± 134 ng/ml), followed by a gradual decline over 1 year. The mean IK values in infections were significantly lower than those in the stable state (119 vs 312 ATP ng/ml, p = 0.0002). CONCLUSIONS: IK values increased sharply after lung transplantation and then decreased gradually over time in the first year, suggesting a natural history of immune function. IK values were also significantly reduced during infections. These results may provide new insights into the utility of immune monitoring after lung transplantation.
Assuntos
Trifosfato de Adenosina/sangue , Linfócitos T CD4-Positivos/imunologia , Testes Imunológicos/métodos , Infecções/diagnóstico , Transplante de Pulmão , Monitorização Fisiológica/métodos , Complicações Pós-Operatórias/diagnóstico , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/cirurgia , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Humanos , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
PURPOSE: Although repeat pulmonary metastasectomy for sarcoma is not uncommon and associated with a favorable survival in select patients, there is a paucity of data on the demographics and tumor characteristics of patients with repeat pulmonary metastasis following complete resection of pulmonary metastases from osteogenic or soft tissue sarcoma. METHODS: A retrospective chart review was performed to identify patients with isolated repeat pulmonary metastasis after complete resection of pulmonary metastases from sarcoma at Kyoto University Hospital between January 1990 and December 2014. Isolated pulmonary metastasis was defined as limited to presumable pulmonary metastasis according to the follow-up radiologic workup. RESULTS: Thirty-five patients were identified to have repeat pulmonary metastasis. Thirty patients underwent attempted repeat pulmonary metastasectomy (including 21 undergoing documented complete resection and 7 undergoing documented incomplete or aborted resections). Five patients received non-surgical management. The median follow-up period was 16 months (range 1-234) from repeat pulmonary metastasis. The five-year overall survival of the whole patient cohort and those undergoing repeat pulmonary metastasectomy were 37.6 and 41.1 %, respectively, from repeat pulmonary metastasis. CONCLUSIONS: A majority of patients with repeat pulmonary metastasis from sarcoma undergo repeat metastasectomy, which is associated with favorable survival outcomes. However, a greater accumulation of data on non-surgically managed patients is needed as such information is currently limited available.
Assuntos
Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia/terapia , Pneumonectomia , Sarcoma/secundário , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Extremidades , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Reoperação , Estudos Retrospectivos , Sarcoma/mortalidade , Sarcoma/cirurgia , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Living-donor lobar lung transplantation (LDLLT) remains a life-saving option for pediatric patients with respiratory failure. However, the long-term survival and post-transplant quality of adult lobar grafts transplanted into children are unknown. Therefore, this study aimed to evaluate the outcomes of pediatric LDLLT and post-transplant graft growth. METHODS: We retrospectively reviewed the prospectively collected clinical data of 25 living-donor lung transplantations performed in 24 pediatric recipients aged ≤17 years. The annual pulmonary function test data and computed tomography scans of 12 recipients, followed up for >5 years without significant complications, were used to evaluate growth in height, graft function, and radiological changes. The Kaplan-Meier method and simple linear regression were performed for analysis. RESULTS: Bilateral lower lobe transplantation was performed in 12 patients, unilateral lower lobe transplantation in 12, and bilateral middle lobe transplantation in 1. The median volumetric size matching at transplantation was 142% (range, 54%-457%). The 5- and 10-year overall survival rates were 87.7% and 75.1༠, respectively. Chronic lung allograft dysfunction occurred in 2 patients. During a median follow-up of 6 years, the median increases in height and vital capacity were 14.4% (range, 0.80%-43.5%) and 58.5% (range, 6.7%-322%), respectively. Graft weight was positively correlated with graft volume (r2=0.622, p<0.001) after the graft volume exceeded the original lobar volume in the donor. CONCLUSIONS: This study shows that pediatric LDLLT offers satisfactory long-term survival, with the growth of mature adult lobes transplanted into growing children.
Assuntos
Doadores Vivos , Transplante de Pulmão , Adulto , Humanos , Criança , Estudos Retrospectivos , Pulmão , Transplante de Pulmão/métodos , Capacidade Vital , Resultado do TratamentoRESUMO
The combination of bevacizumab and standard chemotherapy prolongs progression-free survival and improves response rates in advanced nonsquamous non-small-cell lung cancer(NSCLC). We evaluated the efficacy and safety of bevacizumab based chemotherapy in 31 cases of NSCLC. Adverse events occurred in all patients. Grade≥3 hematotoxicities were seen in 27 patients(87. 0%). Grade≥3 non-hematotoxicities were seen in 13 patients(41. 9%). Bevacizumab-related adverse events included epistaxis(74. 2%), hypertension(22. 6%), and proteinuria(22. 6%). Hemoptysis was reported in 9 patients( 29. 0%), but there was no pulmonary hemorrhage or severe hemoptysis. The treatment results of the 18 patients were evaluated as followes: partial response(PR)10, stable disease(SD)7, and progressive disease(PD)1 patient. The response rate(CR+PR)and disease control rate(CR+PR+SD)were 55. 6%and 94. 4%, respectively. The response rates were 66. 7%, 50. 0%, and 57. 1% for 1st-line(6 patients), 2nd-line and later(12 patients), and postoperative recurrence(7 patients all after 2nd-line)patients, respectively. Bevacizumab-based chemotherapy is an efficacious and safe treatment for advanced nonsquamous NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Non-invasive analysis using computed tomography (CT) data may be a promising candidate to evaluate neo-alveolarization in adult lungs following lung resection. This study evaluates and compares the validity of CT analysis with histologic morphometry for compensatory lung growth in a large animal model. We calculated the radiologic tissue volume and the radiologic lung weight from CT data taken at 1, 3, and 6 months post-surgery on 15 male beagle dogs that had a right thoractotomy, bilobectomy, or pneumonectomy (n = 5 in each group). Results were analyzed using one-way ANOVA and were subsequently compared to histologic findings of tissue samples at 6 months post-surgery using Pearson's correlation. An increase in radiologic tissue volume and radiologic lung weight was identified, which was positively correlated with histologic lung parenchymal amounts (correlation coefficient = 0.955 and 0.934, respectively, p < 0.001). Histology of lung specimens at 6 months post-surgery revealed an increase in the tissue amount in both Bilobectomy and Peumonectomy groups, which was consistent with compensatory lung growth. Radiologic tissue volume and radiologic lung weight reflected compensatory lung growth following lung resection. Radiologic assessment using CT data can be a promising clinical modality to evaluate postoperative lung growth.
Assuntos
Regeneração Hepática/fisiologia , Pulmão/diagnóstico por imagem , Pulmão/cirurgia , Pneumonectomia/métodos , Toracotomia/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Cães , Pulmão/fisiologia , Medidas de Volume Pulmonar/métodos , Masculino , Modelos AnimaisRESUMO
Lung transplantation is the only treatment for end-stage lung disease; however, donor organ shortage and intense immunosuppression limit its broad clinical impact. Bioengineering of lungs with patient-derived cells could overcome these problems. We created bioartificial lungs by seeding human-derived cells onto porcine lung matrices and performed orthotopic transplantation to assess feasibility and in vivo function. Porcine decellularized lung scaffolds were seeded with human airway epithelial cells and human umbilical vein endothelial cells. Following in vitro culture, the bioartificial lungs were orthotopically transplanted into porcine recipients with planned 1-day survival (nâ¯=â¯3). Lungs were assessed with histology and in vivo function. Orthotopic transplantation of cadaveric lungs was performed as control. Engraftment of endothelial and epithelial cells in the grafts were histologically demonstrated. Technically successful orthotopic anastomoses of the vasculatures and airway were achieved in all animals. Perfusion and ventilation of the lung grafts were confirmed intraoperatively. The gas exchange function was evident immediately after transplantation; PO2 gradient between pulmonary artery and vein were 178 ± 153 mm Hg in the bioartificial lung group and 183 ± 117 mm Hg in the control group. At time of evaluation 24 hours after reperfusion, the pulmonary arteries were found to be occluded with thrombus in all bioartificial lungs. Engineering and orthotopic transplantation of bioartificial lungs with human cells were technically feasible in a porcine model. Early gas exchange function was evident. Further progress in optimizing recellularization and maturation of the grafts will be necessary for sustained perfusability and function.
Assuntos
Transplante de Pulmão , Alicerces Teciduais , Animais , Células Endoteliais , Estudos de Viabilidade , Humanos , Pulmão/cirurgia , Suínos , Resultado do TratamentoRESUMO
BACKGROUND: Whether compensatory lung growth occurs in adult humans is controversial. The aim of this study was to confirm compensatory lung growth by analyzing ipsilateral residual lung after lower lobectomy in living lung transplant donors with quantitative and qualitative computed tomography assessments. METHODS: Chest computed tomography and pulmonary function tests were performed in 31 eligible donors before and 1 year after donor lobectomy. Ipsilateral residual lung volume was measured with three-dimensional computed tomography volumetry. The computed tomography-estimated volumes of low, middle, and high attenuations in the lung were calculated. Assessment of the D value, a coefficient of the cumulative size distribution of low-density area clusters, was performed to evaluate the structural quality of the residual lung. RESULTS: Postoperative pulmonary function test values were significantly larger than preoperative estimated values. Although postoperative total volume, low attenuation volume, middle attenuation volume, and high attenuation volume of the ipsilateral residual lung were significantly larger than the preoperative volumes, with 50.2%, 50.0%, 41.5%, and 43.1% increase in the median values, respectively (all p < 0.0001), the differences in D values before and after donor lobectomy were not significant (p = 0.848). The total volume of ipsilateral residual lung was increased by more than 600 mL (50%). CONCLUSIONS: The volume of ipsilateral residual lung increased, but its structural quality did not change before and after donor lobectomy. The existence of compensatory lung growth in adult humans was suggested by quantitative and qualitative computed tomography assessments.
Assuntos
Doadores Vivos , Pulmão/crescimento & desenvolvimento , Pneumonectomia , Adulto , Feminino , Humanos , Pulmão/diagnóstico por imagem , Transplante de Pulmão , Medidas de Volume Pulmonar , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Rho-kinase, an intracellular serine/threonine kinase, is a key regulator of cytoskeletal dynamics. Recent studies have demonstrated that Rho-kinase is involved in the ischemia-reperfusion injury (IRI) pathogenesis of many organs; however, its involvement with lung IRI remains unclear. This study assessed the association of Rho-kinase with lung IRI and evaluated the protective effect of inhaled Rho-kinase inhibitors in lung IRI. METHODS: The study included isolated rat lung perfusion models, divided into three groups: sham, Rho-kinase inhibitor, and warm ischemia (n = 6 each). The lungs were exposed to 60 minutes of warm ischemia by perfusion cessation. At the onset of ischemia, nebulized fasudil, a novel Rho-kinase inhibitor, and saline were inhaled in the Rho-kinase inhibitor and warm ischemia groups, respectively. Perfusion was restarted after the ischemic period, and physiologic data were collected for 90 minutes. Lungs in the sham group were continuously perfused without ischemia or drug administrations. Protein expression in tissue specimens related to the Rho-kinase pathway was evaluated by Western blotting. RESULTS: Warm ischemia and subsequent reperfusion enhanced Rho-kinase activity, and this was suppressed by fasudil inhalation. Fasudil inhalation significantly attenuated IRI pathophysiology, including pulmonary vascular contraction, dynamic compliance, lung edema, and oxygenation. Molecular analysis showed that Rho-kinase suppressed myosin phosphatase and endothelial nitric oxide synthase activities, suggesting these are downstream targets of Rho-kinase during lung IRI pathogenesis. CONCLUSIONS: The present study suggests that Rho-kinase activation is involved in lung IRI pathogenesis and that inhaled Rho-kinase inhibitors may attenuate this pathogenesis.
Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Pulmão/patologia , Pulmão/cirurgia , Óxido Nítrico Sintase Tipo III/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Administração por Inalação , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Perfusão , Circulação Pulmonar/fisiologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Valores de Referência , Sensibilidade e Especificidade , Resistência Vascular/efeitos dos fármacos , Quinases Associadas a rho/efeitos dos fármacosRESUMO
BACKGROUND: We hypothesized that an injured lung graft from donation after cardiac death donors could be reconditioned before transplantation using an ex vivo lung perfusion (EVLP) system and ventilation with high-dose short-acting ß2-adrenergic receptor agonists. METHODS: Cardiac arrest was induced in a canine model by intravenous potassium chloride injection. Lungs were randomly assigned to two groups after 150 minutes of warm ischemia: inhalation of 1,400 µg of procaterol (BETA group, n = 5) or control group receiving solvent (CON group, n = 5) during EVLP. Left lungs were transplanted after 120 minutes of EVLP. Functional variables, tissue adenosine 5'-triphosphate levels, and tissue cyclic adenosine monophosphate levels were measured 240 minutes after transplantation. RESULTS: Physiologic pulmonary function was similar at the end of EVLP in both groups. However, significantly better graft oxygenation, dynamic pulmonary compliance, and reduced pulmonary vascular resistance were observed in the BETA group than in the CON group 240 minutes after transplantation. No severe adverse effects were observed after lung transplantation in the BETA group. Lung tissue adenosine 5'-triphosphate levels and cyclic adenosine monophosphate levels were significantly higher in the BETA group than in the CON group at the end of EVLP and at 240 minutes after transplantation. CONCLUSIONS: High-dose nebulized procaterol during EVLP ameliorated lung graft dysfunction at the early posttransplantation period without severe adverse effects. These data suggest that lung reconditioning with procaterol ventilation during EVLP improves lung graft function after transplantation.
Assuntos
Transplante de Pulmão/métodos , Preservação de Órgãos/métodos , Procaterol/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Isquemia Quente/métodos , Administração por Inalação , Animais , Biópsia por Agulha , Broncodilatadores/administração & dosagem , Modelos Animais de Doenças , Cães , Rejeição de Enxerto , Sobrevivência de Enxerto/efeitos dos fármacos , Parada Cardíaca , Imuno-Histoquímica , Pulmão/patologia , Transplante de Pulmão/efeitos adversos , Perfusão , Distribuição Aleatória , Medição de Risco , Doadores de TecidosRESUMO
Objectives: Anti-oxidant effects of hydrogen have been reported in studies examining ischaemia-reperfusion injury (IRI). In this study, we evaluated the therapeutic efficacy of immersing lungs in hydrogen-rich saline on lung IRI. Methods: Lewis rats were divided into three groups: (i) sham, (ii) normal saline and (iii) hydrogen-rich saline. In the first experiment, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline for 1 h. Then, we measured the hydrogen concentration in the left lung using a sensor gas chromatograph ( N = 3 per group). In the second experiment, lung IRI was induced by occlusion of the left pulmonary hilum for 1 h, followed by reperfusion for 3 h. During the ischaemic period, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline. After reperfusion, we assessed lung function, histological changes and cytokine production ( N = 5-7 per group). Results: Immersing lungs in hydrogen-rich saline resulted in an elevated hydrogen concentration in the lung (6.9 ± 2.9 µmol/1 g lung). After IRI, pulmonary function (pulmonary compliance and oxygenation levels) was significantly higher in the hydrogen-rich saline group than in the normal saline group ( P < 0.05). Similarly, pro-inflammatory cytokine levels (interleukin-1ß and interleukin-6) in the left lung were significantly lower in the hydrogen-rich saline group than in the normal saline group ( P < 0.05). Conclusions: Immersing lungs in hydrogen-rich saline delivered hydrogen into the lung and consequently attenuated lung IRI. Hydrogen-rich solution appears to be a promising approach to managing lung IRI.
Assuntos
Antioxidantes/farmacocinética , Hidrogênio/farmacocinética , Pulmão/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/farmacologia , Citocinas/biossíntese , Hidrogênio/farmacologia , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Complacência Pulmonar/efeitos dos fármacos , Preservação de Órgãos , Soluções para Preservação de Órgãos/química , Soluções para Preservação de Órgãos/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Cloreto de Sódio , SolubilidadeRESUMO
OBJECTIVES: Cytomegalovirus (CMV) infection remains a major cause of morbidity after lung transplantation. Some studies have reported prognostic factors for the postoperative development of CMV infection in cadaveric lung transplantation (CLT), but no research has been performed in living-donor lobar lung transplantation (LDLLT). Therefore, we analysed the possible risk factors of post-transplant CMV infection and the differences between LDLLT and CLT. METHODS: The development of CMV disease and viraemia in 110 patients undergoing lung transplantation at Kyoto University Hospital in 2008-2015 were retrospectively assessed. The prognostic factors in the development of CMV infection and the differences between LDLLT and CLT were analysed. RESULTS: Among 110 patients, 58 LDLLTs and 52 CLTs were performed. The 3-year freedom rates from CMV disease and viraemia were 92.0% and 58.5%, respectively. There was no difference in the development of CMV infection between LDLLT and CLT (disease: 94.6% vs 91.0%, P = 0.58 and viraemia: 59.3% vs 57.2%, P = 0.76). In preoperative anti-CMV immunoglobulin status, R-D+ recipients (recipient: negative, donor: positive) and R-D- recipients (recipient: negative, donor: negative) tended to have higher and lower cumulative incidences, respectively, of CMV infection (disease: P = 0.34 and viraemia: P = 0.24) than that with R+ recipients (recipient: seropositive). Significantly lower cumulative incidence of CMV viraemia was observed in patients receiving 12-month prophylactic medication (70.6% vs 36.8%, P < 0.001). Twenty-eight patients (25.5%) had early cessation of anti-CMV prophylaxis due to toxicity; however, the extended prophylaxis duration did not increase the incidence of early cessation (P = 0.88). These trends were seen in both LDLLT and CLT. CONCLUSIONS: We found that there was no difference in the development of CMV infection between LDLLT and CLT. Twelve-month prophylaxis protocol provides beneficial effect without increased toxicity also in LDLLT.
Assuntos
Anticorpos Antivirais/análise , Infecções por Citomegalovirus/epidemiologia , Citomegalovirus/imunologia , Doadores Vivos , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Viremia/epidemiologia , Adulto , Antivirais/uso terapêutico , Cadáver , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/virologia , Estudos Retrospectivos , Fatores de Risco , Viremia/prevenção & controle , Viremia/virologiaRESUMO
BACKGROUND: Antibody-mediated rejection may lead to chronic lung allograft dysfunction, but antibody-mediated rejection may develop in the absence of detectable donor-specific antibody (DSA) in recipient serum. This study investigated whether humoral immune responses develop not only systemically but locally within rejected lung allografts, resulting in local production of DSA. METHODS: Lewis rats received orthotopic left lung transplantation from Lewis (syngeneic control) or Brown-Norway (major histocompatibility complex-mismatched allogeneic) donor rats. Rats that underwent allogeneic lung transplantation were subsequently administered cyclosporine until day 14 (short immunosuppression) or day 35 (long immunosuppression). The lung grafts and spleens of recipient animals were tissue cultured for 4 days, and the titer of antibody against donor major histocompatibility complex molecules was assayed by flow cytometry. Explanted lung grafts were also evaluated pathologically. RESULTS: By day 98, DSA titers in supernatants of lung graft (P = 0.0074) and spleen (P = 0.0167) cultures, but not serum, from the short immunosuppression group were significantly higher than titers in syngeneic controls. Cultures and sera from the long immunosuppression group showed no production of DSA. Microscopically, the lung grafts from the short immunosuppression group showed severe bronchiole obliteration and parenchymal fibrosis, along with lymphoid aggregates containing T and B cells, accompanying plasma cells. These findings suggestive of local humoral immune response were not observed by days 28 and 63. CONCLUSIONS: DSA can be locally produced in chronically rejected lung allografts, along with intragraft immunocompetent cells. Clinical testing of DSA in serum samples alone may underestimate lung allograft dysfunction.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Isoanticorpos/metabolismo , Transplante de Pulmão , Pulmão/imunologia , Animais , Biomarcadores/metabolismo , Citometria de Fluxo , Rejeição de Enxerto/diagnóstico , Masculino , Ratos , Ratos Endogâmicos Lew , Baço/imunologiaRESUMO
We report a rare case of protrusion of an invasive thymoma with intraluminal growth through the thymic vein into the superior vena cava (SVC) without direct invasion of the vessel walls. The tumor and left brachiocephalic vein were resected, and the tumor in the SVC was removed with temporal bypass of the right brachiocephalic vein and right auricle. Histopathological finding showed that the thymoma had protruded via a thymic vein. During resection of a thymoma, a detailed examination of thymic vein is necessary to ensure that no tumor tissue remains in the vessels.
Assuntos
Timoma/patologia , Neoplasias do Timo/patologia , Veia Cava Superior/patologia , Biópsia , Veias Braquiocefálicas/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Timectomia , Timoma/cirurgia , Neoplasias do Timo/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Veia Cava Superior/cirurgiaRESUMO
BACKGROUND: Vascular endothelial-cadherin (VEC), composing the adherens junction of endothelial cells, has been shown to regulate vascular permeability. The aim of this study was to investigate VEC expression during cold ischemia (CI) and reperfusion and whether a dibutyryl cyclic adenosine 3',5'-monophosphate (db-cAMP) and nitroglycerin (NTG) additive to preservation solution can maintain VEC. METHODS: Rat left lung transplantation after CI was performed, and reperfusion was done for 2 hours. The experimental groups were Control (n = 5), CI3 (n = 5), CI6 (n = 6), and CI6+AMP/NTG (n = 6) with minimum ischemic period, 3 hours and 6 hours of CI, respectively, and 6 hours of CI with db-cAMP and NTG additive to preservation solution, respectively. Lung mechanics, lung wet-to-dry weight ratio (W/D), and the histologic findings of the graft were evaluated. The expression of VEC was evaluated by Western blot analysis of the lung tissue lysates. RESULTS: The CI3 group showed a decrease in dynamic compliance with perivascular edema. Dynamic compliance, graft oxygenation, and W/D were substantially deteriorated, and intraalveolar edema with neutrophil infiltration was recognized in the CI6 group. They were improved in the CI6+AMP/NTG group. VEC expression was maintained during CI. After reperfusion, it reduced substantially in the CI6 group and was maintained in the CI6+AMP/NTG group. CONCLUSIONS: VEC expression was maintained during CI; however, it reduced early after reperfusion after 6 hours of CI, correlating with severe intraalveolar edema. db-cAMP/NTG additive to the preservation solution contributed to the maintenance of VEC expression after reperfusion.
Assuntos
Lesão Pulmonar Aguda/patologia , Antígenos CD/análise , Caderinas/análise , Transplante de Pulmão/efeitos adversos , Preservação de Órgãos/métodos , Traumatismo por Reperfusão/patologia , Lesão Pulmonar Aguda/etiologia , Animais , Biópsia por Agulha , Western Blotting , Modelos Animais de Doenças , Rejeição de Enxerto , Sobrevivência de Enxerto , Imuno-Histoquímica , Transplante de Pulmão/métodos , Soluções para Preservação de Órgãos/farmacologia , Distribuição Aleatória , Ratos , Valores de Referência , Reperfusão/métodos , Traumatismo por Reperfusão/prevenção & controleRESUMO
BACKGROUND: Recent lung transplantation studies have shown that peri-operative hyperglycemia is an important factor affecting recipient survival; however, its underlying mechanisms are not well understood. We hypothesized that acute hyperglycemia exacerbates lung ischemia-reperfusion injury (IRI) through up-regulation of Toll-like receptor 4 (TLR4) signaling pathways. METHODS: C57BL/6Ncr mice were divided into 3 treatment groups: sham; IRI; and IRI under acute hyperglycemic conditions (IRI+HG). Mice in the IRI and IRI+HG groups were exposed to IRI via clamping the left hilum for 1 hour, followed by reperfusion for 2 hours. Acute hyperglycemia was established by glucose injection. The severity of lung injury and TLR4 signaling pathway activity were assessed. Further, we performed a pharmacologic blockade of TLR4 signaling to determine the effect of TLR4 signaling inhibition on lung injury. RESULTS: Compared with normoglycemic mice, hyperglycemic mice had 2-fold higher blood glucose levels (p < 0.001). Pulmonary compliance was significantly lower, and airway resistance was significantly higher, in the IRI+HG group than in the IRI group (p < 0.05). Levels of inflammatory cytokines in bronchoalveolar lavage fluid were significantly higher in the IRI+HG group than in the IRI group. Correspondingly, TLR4 signaling pathways were up-regulated in the IRI+HG group. Moreover, pharmacologic inhibition of TLR4 signaling significantly decreased lung injury markers under hyperglycemic conditions. CONCLUSIONS: Acute hyperglycemia exacerbated lung IRI and was associated with up-regulation of TLR4 signaling pathways. Pharmacologic inhibition of TLR4 signaling ameliorated lung IRI with acute hyperglycemia. Targeting TLR4 appears to be a promising approach to managing coexisting pathologies in lung transplant recipients.
Assuntos
Traumatismo por Reperfusão , Animais , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Receptor 4 Toll-LikeRESUMO
BACKGROUND: Ischemia/reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage and inflammation contribute to its development. Imatinib has been reported to regulate vascular permeability by maintaining endothelial junctions and showing antiinflammatory effects through inhibition of the Abl kinases. We hypothesized that imatinib could have a protective effect against IRI. METHODS: Male Lewis rats were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes followed by reperfusion for 120 minutes. Imatinib mesylate (50 mg/kg) and a solvent were administered intraperitoneally 20 minutes before ischemia in the imatinib group and the vehicle group, respectively (n = 7 in each group). After reperfusion, lung function, lung wet to dry weight (W/D) ratio, and histologic findings were obtained. The expression of vascular endothelial cadherin (VEC), the phosphorylation level of CrkL (pCrkL) (an exclusive target of Abl kinases), and the cytokine level were evaluated using lung tissue lysate. The imatinib concentrations of plasma and lungs after reperfusion were measured in this hilar clamp model (n = 7). RESULTS: In the imatinib group, lung function was improved with a lower W/D ratio. Perivascular edema and neutrophil infiltration were ameliorated. The imatinib group demonstrated maintained expression of VEC, inhibition of pCrkL, and a significantly higher level of interleukin (IL)-10. The imatinib concentration in both lungs showed a strong correlation with plasma concentration. CONCLUSIONS: In a rat IRI model, imatinib attenuated lung injury by an antipermeability and antiinflammatory effect. The delivery and function of imatinib in the lung was also confirmed in this model.
Assuntos
Mesilato de Imatinib/administração & dosagem , Lesão Pulmonar/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Animais , Western Blotting , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Injeções Intraperitoneais , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/fisiopatologia , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Ratos , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
OBJECTIVES: The purpose of this study was to use Hounsfield unit (HU) thresholds of computed tomography (CT) images to predict pathological lymph node metastasis and tumour invasiveness of cT1N0M0 lung adenocarcinoma on 3D evaluations. METHODS: Preoperative CT images of 211 lesions of surgically resected cT1N0M0 lung adenocarcinoma were retrospectively examined. The tumour size was calculated in 1D, 2D and 3D views. Tumours with -300 HU and over were defined as 'solid tumours', and those between -800 and -301 HU were defined as 'ground glass opacity tumours'. Tumours with -800 HU and over were assumed to be the whole tumour entity. The proportion of 'solid tumour' within the whole tumour entity was also calculated as the 'solid tumour ratio'. These were compared with pathological information. RESULTS: Solid tumour size and ratio were positively correlated with microscopic invasion to pleura, vessels and lymphatics in all dimensional evaluations. Pathological lymph node metastases were also well predicted by solid tumour size and ratio in all dimensional evaluations. The P-values for the receiver operating characteristic (ROC) curves of 1D, 1D ×2, 2D and 3D evaluations were: solid tumour size P = 0.013, 0.014 and 0.032; and solid tumour ratio 0.016, 0.0032 and <0.0001. In comparisons of 1D, 2D and 3D evaluations, 'solid tumour size' of the area under the curve (AUC) of ROC to detect pathological lymph node metastases was not significant. However, strikingly, the 3D solid tumour ratio was found to be significantly more accurate for the prediction of pathological lymph node metastases than the 1D and 2D solid tumour ratios on ROC evaluation (AUC: 1D 0.736, 2D 0.803 and 3D 0.882; P-values for the AUC comparisons were P = 0.013 for 3D versus 1D and P = 0.022 for 3D versus 2D). The correlations of subtypes of adenocarcinoma and the 3D solid tumour ratio were also investigated. Subtypes of adenocarcinoma were well correlated with the 3D solid tumour ratio. CONCLUSIONS: Preoperative 3D CT using threshold values of -800 and -300 HU was useful for predicting pathological lymph node metastases and tumour invasiveness of cT1N0M0 lung adenocarcinoma.
Assuntos
Adenocarcinoma/diagnóstico , Tomografia Computadorizada de Feixe Cônico/métodos , Neoplasias Pulmonares/diagnóstico , Estadiamento de Neoplasias , Adenocarcinoma/secundário , Adenocarcinoma de Pulmão , Idoso , Feminino , Humanos , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: Attenuation of ischemia reperfusion injury (IRI) is important in lung transplantation. Our group previously reported that ß2-adrenoreceptor agonist inhalation during the period before procurement successfully attenuated IRI in donated lungs after cardiac death. We therefore hypothesized that ß2-adrenoreceptor agonist inhalation during ex vivo lung perfusion (EVLP) after procurement might also have a protective effect. METHODS: Cardiac-dead beagles were left at room temperature for 210 minutes, and all lungs were subsequently procured and subjected to EVLP for 240 minutes. The beagles were allocated to 2 groups: the ß2 group (receiving an aerosolized ß2-adrenoreceptor agonist 20 minutes after initiation of EVLP; n = 7) and the control group (receiving an aerosolized control solvent at the same time point; n = 6). Physiologic data, including lung function, were evaluated during EVLP. RESULTS: The ß2 group showed significantly lower peak airway pressure and pulmonary artery pressure than the control group. Dynamic pulmonary compliance was higher, pulmonary vascular resistance (PVR) was lower, and the wet-to-dry lung weight ratio was lower in the ß2 group than in the control group. Cyclic adenosine monophosphate (cAMP) and total adenosine nucleotide (TAN) levels in lung tissue after EVLP were higher in the ß2 group than in the control group. The ß2 group also showed more cystic fibrosis transmembrane conductance regulator (CFTR) gene expression. CONCLUSIONS: After procurement, ß2-adrenoreceptor agonist inhalation during EVLP attenuates lung injury in a canine model of organ donation after cardiac death.