RESUMO
We report experimental results on the competitive passage of elongated self-propelled vehicles rushing through a constriction. For the chosen experimental conditions, we observe the emergence of intermittencies similar to those reported previously for active matter passing through narrow doors. Noteworthy, we find that, when the number of individuals crowding in front of the bottleneck increases, there is a transition from an unclogged to a clogged state characterized by a lack of convergence of the mean clog duration as the measuring time increases. It is demonstrated that this transition-which was reported previously only for externally vibrated systems such as colloids or granulars-appears also for self-propelled agents. This suggests that the transition should also occur for the flow through constrictions of living agents (e.g., humans and sheep), an issue that has been elusive so far in experiments due to safety risks.
Assuntos
Aglomeração , Modelos Teóricos , Movimento (Física) , VibraçãoRESUMO
The pathogenesis of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation (LT) is poorly understood. We hypothesized that development of antibodies to HLA (DSA) is associated with dysregulation of microRNA (miRNA) that predisposes BOS. Towards this, miRNA profiling of mononuclear cells from 10 stable LT (DSA(-) BOS(-) ), 10 LT with DSA(+) BOS(-) (DSA group) and 10 LT with DSA(+) BOS(+) (BOS group) were performed. Prediction by mirPath indicated that differential miRNAs in DSA(+) BOS(-) compared to stable are significantly up-regulated (relative fold >2, p < 0.05) for TGF-ß and B cell receptor signal pathways. A total of seventy-four miRNAs were up-regulated and six miRNAs were down regulated in LT with DSA(+) BOS(+) when compared to stable (relative fold >2, p < 0.05). There was also significant enrichment of cell cycle and gap junction pathways. An inverse correlation between expression of two key miRNAs and their target genes were observed: miR-369-5p and miR-548d were down regulated in DSA(+) LT while their gene targets in TGF-ß signal pathways were up-regulated. In addition, miR-628-5p and miR-134 were down regulated and their target genes (B cell development) were up-regulated. Therefore, we conclude that alloimmunity induced changes in miRNAs affecting the TGF-ß and B cell receptor signal pathways play important roles in BOS development.
Assuntos
Bronquiolite Obliterante/cirurgia , Rejeição de Enxerto/etiologia , Antígenos HLA/imunologia , Isoanticorpos/imunologia , Transplante de Pulmão , MicroRNAs/genética , Aloenxertos , Bronquiolite Obliterante/complicações , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Antígenos HLA/genética , Humanos , Isoanticorpos/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Doadores de Tecidos , Fator de Crescimento Transformador beta/genética , TransplantadosRESUMO
In this paper, we conduct experimental investigations on the behavior of confined self-propelled particles within a circular arena, employing small commercial robots capable of locomotion, communication, and information processing. These robots execute circular trajectories, which can be clockwise or counterclockwise, based on two internal states. Using a majority-based stochastic decision algorithm, each robot can reverse its direction based on the states of two neighboring robots. By manipulating a control parameter governing the interaction, the system exhibits a transition from a state where all robots rotate randomly to one where they rotate uniformly in the same direction. Moreover, this transition significantly impacts the trajectories of the robots. To extend our findings to larger systems, we introduce a mathematical model enabling characterization of the order transition type and the resulting trajectories. Our results reveal a second-order transition from active Brownian to chiral motion.
RESUMO
Bronchiolitis obliterans syndrome (BOS), the clinical correlate of chronic rejection after lung transplantation, is the leading obstacle to better long-term outcomes. We previously instituted a clinical protocol to screen for donor-specific human leukocyte antigen (HLA) antibodies (DSA) and a preemptive antibody-directed therapy protocol consisting of rituximab and/or intravenous immune globulin. In this study, we retrospectively analyzed serum samples from lung transplant recipients (n = 108) for antibodies to self-antigens (K-α 1 tubulin and collagen V) before and after antibody-directed therapy and correlated the results with the subsequent development of BOS. Seventy-two of the 108 recipients developed antibodies to self-antigens. There was a correlation between the development of antibodies to self-antigens and DSA. Sixteen of the 54 patients who had antibodies to self-antigens and were treated with antibody-directed therapy cleared the antibodies, and they were significantly less likely to develop BOS than those who had persistent antibodies. Furthermore, those who cleared DSA after treatment but had persistent antibodies to self-antigens were significantly more likely to develop BOS than those who cleared these antibodies. We conclude that antibodies to self-antigens are an important risk factor for the development of BOS.
Assuntos
Autoanticorpos/imunologia , Colágeno Tipo V/imunologia , Rejeição de Enxerto , Transplante de Pulmão , Tubulina (Proteína)/imunologia , Adulto , Autoantígenos/imunologia , Bronquiolite Obliterante/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The molecular mechanisms leading to the development of chronic lung allograft dysfunction following de novo development of antibodies to mismatched donor MHC remain undefined. We demonstrated that intrabronchial administration of antibodies to MHC class I resulted in induction of both innate and adaptive cellular immune responses characterized by a predominance of Th17 specific to lung associated self-antigens Kα1-tubulin and Collagen-V leading to the development of obliterative airway lesions (OAD), correlate of chronic rejection following human lung transplantation. To determine the role of regulatory T cells (Treg) in the pathogenesis of OAD, we administered anti-MHC class I to mice, in which Treg were depleted by conditional ablation of FoxP3+cells. Under this condition, we observed a threefold increase in pulmonary cellular infiltration, luminal occlusion and fibrous deposition when compared anti-MHC class I Ab administered mice maintaining FoxP3. OAD lesions were accompanied with enhanced accumulation of neutrophils along with self-antigen-specific Th17 and humoral responses. However, IL-17-blockade or adoptive transfer of Treg abrogated OAD. We conclude that Treg exerts a suppressive effect on anti-MHC induced IL-8-mediated neutrophil infiltration and innate immune responses that leads to inhibition of Th17 immune responses to lung associated self-antigens which is critical for development of OAD.
Assuntos
Autoanticorpos/imunologia , Bronquiolite Obliterante/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Imunidade Celular , Imunidade Inata , Interleucina-17/imunologia , CamundongosRESUMO
In this paper, the dynamics of a self-propelled stochastic particle under the influence of an axisymmetric light field is experimentally studied. The particle under consideration has the main characteristic of carrying a light sensor in an eccentric location. For the chosen experimental conditions, the emerging trajectories are orbital, and, more interestingly, they suggest the existence of bistability. A mathematical model incorporating the key experimental components is introduced. By means of numerical simulations and theoretical analysis, it is found that, in addition to the orbiting behavior, the sensor location could produce trapped or diffusive behaviors. Furthermore, the study reveals that stochastic perturbation and the eccentric location of the sensor are responsible for inducing bistability in the orbital trajectories, supporting experimental observations.
RESUMO
Graft rejection remains a formidable problem contributing to poor outcomes after lung transplantation. Blocking chemokine pathways have yielded promising results in some organ transplant systems. Previous clinical studies have demonstrated upregulation of CCR2 ligands following lung transplantation. Moreover, lung injury is attenuated in CCR2-deficient mice in several inflammatory models. In this study, we examined the role of CCR2 in monocyte recruitment and alloimmune responses in a mouse model of vascularized orthotopic lung transplantation. The CCR2 ligand MCP-1 is upregulated in serum and allografts following lung transplantation. CCR2 is critical for the mobilization of monocytes from the bone marrow into the bloodstream and for the accumulation of CD11c(+) cells within lung allografts. A portion of graft-infiltrating recipient CD11c(+) cells expresses both recipient and donor MHC molecules. Two-photon imaging demonstrates that recipient CD11c(+) cells are associated with recipient T cells within the graft. While recipient CCR2 deficiency does not prevent acute lung rejection and is associated with increased graft infiltration by T cells, it significantly reduces CD4(+) T(h)1 indirect and direct allorecognition. Thus, CCR2 may be a potential target to attenuate alloimmune responses after lung transplantation.
Assuntos
Transplante de Pulmão/métodos , Monócitos , Animais , Quimiocinas , Rejeição de Enxerto/imunologia , Inflamação , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/fisiologia , Pneumonia/metabolismo , Linfócitos T/metabolismo , Transplante HomólogoRESUMO
We study experimentally the properties of the flow of mechanical vibration-driven vehicles confined in two chambers connected through a narrow opening. We report that the density of particles around the opening presents critical behavior and scaling properties. By mapping this density to the financial market price, we document that the main stylized facts observed in financial systems have their counterparts in the mechanical system. The experimental model accurately reproduces financial properties such as scaling of the price fluctuation, volatility clustering, and multiscaling.
RESUMO
In lung grafts, ischemia-reperfusion signals rapidly induce the recruitment and differentiation of host monocytes into macrophages and dendritic cells. The nature of ischemia-reperfusion signals are antigen independent, but have been hypothesized to initiate Toll-like receptor (TLR) and interleukin (IL)-1R-mediated signaling pathways that are thought to potentiate alloimmune responses. We wondered whether MyD88, an adaptor molecule critical for both TLR and IL-1R-mediated inflammatory responses, regulated monocyte differentiation in a mouse model of vascularized orthotopic lung transplantation. Orthotopic left lung transplants were performed in the following syngeneic combinations: CD45.1(+) B6 --> CD45.2(+) MyD88(-/-) and CD45.1(+) B6 --> CD45.2(+) B6. One day later, recipient-derived dendritic cells and macrophage numbers were assessed in the bronchiolar lavage by FACS analysis. Compared with the bronchiolar lavage of wildtype recipients, MyD88(-/-) recipients had lower numbers of dendritic cells in lung graft airways that were of recipient origin. Lower numbers of newly differentiated lung graft dendritic cells was coincident with the appearance of higher numbers of undifferentiated monocytes in the lung airways of MyD88(-/-) recipients as compared with wild-type recipients. Moreover, adoptive transfer experiments demonstrated that MyD88(-/-) monocytes were poorer at differentiating into lung dendritic cells as compared with wild-type monocytes. Taken together, these data show that MyD88 regulates graft-infiltrating monocyte differentiation and suggests a mechanism by which TLR/IL-1R-signaling pathways control adaptive responses in lung allografts through controlling monocyte fate.
Assuntos
Transplante de Pulmão/fisiologia , Monócitos/fisiologia , Fator 88 de Diferenciação Mieloide/fisiologia , Animais , Diferenciação Celular , Células Dendríticas/imunologia , Antígenos Comuns de Leucócito/imunologia , Transplante de Pulmão/imunologia , Macrófagos/citologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/citologia , Transdução de Sinais/imunologia , Transplante Homólogo/imunologia , Transplante Homólogo/fisiologiaRESUMO
Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb --> B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c --> B6 lung transplants had severe acute rejection 7 days after transplantation and CD8(+) T cells outnumbered CD4(+) T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8(+) and CD4(+) T cells in these grafts. Approximately one third of graft-infiltrating CD4(+) T cells expressed Foxp3. CD4(+) T cells isolated from these grafts induced apoptosis of alloreactive CD8(+) T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8(+) T cells outnumbered CD4(+) T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4(+) T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8(+) T cells expressed intereferon-gamma. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients.
Assuntos
Transplante de Pulmão/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transplante Homólogo/fisiologia , Abatacepte , Animais , Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica , Rejeição de Enxerto/imunologia , Imunoconjugados/imunologia , Transplante de Pulmão/imunologia , Transplante de Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Primary graft dysfunction (PGD) is a common early complication after lung transplantation. We conducted a retrospective cohort study of 334 recipients to evaluate the impact of PGD graded at 24, 48 and 72 h on the risk of bronchiolitis obliterans syndrome (BOS) development (stage 1) and progression (stages 2 and 3). We constructed multivariable Cox proportional hazards models to determine the risk of BOS attributable to PGD in the context of other potential risk factors including acute rejection, lymphocytic bronchitis and respiratory viral infections. All grades of PGD at all time points were significant risk factors for BOS development and progression independent of acute rejection, lymphocytic bronchitis and respiratory viral infections. Specifically, PGD grade 1 at T24 was associated with a relative risk of BOS stage 1 of 1.93, grade 2 with a relative risk of 2.29 and grade 3 with a relative risk of 3.31. Furthermore, this direct relationship between the severity of PGD and the risk of BOS persisted at all time points. We conclude that all grades of PGD at all time points are independent risk factors for BOS development and progression. Future strategies that might attenuate the severity of PGD may mitigate the risk of BOS.
Assuntos
Bronquiolite Obliterante/terapia , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/métodos , Disfunção Primária do Enxerto/terapia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury. Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A non-neointimal pattern of remodeling after mild monocrotaline-induced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-beta gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.
Assuntos
Hemodinâmica , Pulmão/irrigação sanguínea , Músculo Liso Vascular/fisiologia , Artéria Pulmonar/lesões , Artéria Pulmonar/fisiologia , Adulto , Anastomose Cirúrgica , Animais , Pressão Sanguínea/efeitos dos fármacos , Endarterectomia/efeitos adversos , Expressão Gênica , Humanos , Hibridização In Situ , Masculino , Microscopia Eletrônica , Monocrotalina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/lesões , Pró-Colágeno/biossíntese , Artéria Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional , Artéria Subclávia/efeitos dos fármacos , Artéria Subclávia/fisiologia , Fator de Crescimento Transformador beta/biossíntese , Tropoelastina/análiseRESUMO
The incidence of esophageal adenocarcinoma has increased dramatically over the past 20 years. The causes for this change in incidence and the genetic defects that underlie tumorigenesis are unknown. We performed loss of heterozygosity (LOH) studies in esophageal adenocarcinomas in an effort to map the location of tumor suppressor genes involved in the initiation or progression of this cancer. A genome-wide search for LOH was undertaken using microsatellite repeat polymorphisms and a panel of 27 tumor and matched normal DNAs. This is the first report of an allelotype analysis of esophageal adenocarcinomas. We observed frequent loss of sequences on the short arm of chromosome 17 in the region of the TP53 gene. We also identified a region on 4q lost in more than half of the tumors investigated. The high rate of LOH for 4q sequences speaks to the involvement of an as yet unidentified tumor suppressor gene in esophageal adenocarcinoma tumorigenesis.
Assuntos
Adenocarcinoma/genética , Alelos , Cromossomos Humanos Par 4/genética , Neoplasias Esofágicas/genética , Repetições de Microssatélites , Deleção de Sequência , Cromossomos Humanos Par 4/ultraestrutura , DNA de Neoplasias/genética , Genes Supressores de Tumor , HumanosRESUMO
Surgery alone is inadequate therapy for limited small-cell lung cancer (SCLC), resulting in less than 5% long-term survival. Since 1976, we treated patients undergoing surgery for SCLC with adjuvant chemotherapy in an attempt to prolong survival and increase cure. Seventy-seven patients who underwent surgery as their primary treatment were identified, and of these 63 (46 male and 17 female) received chemotherapy. Fifteen patients had a pneumonectomy, 46 a lobectomy, and two had wedge resections. Six patients had positive microscopic resection margins. Pathologic staging showed tumor, node, metastasis (TNM) involvement as follows: T1N0, eight; T2N0, ten; T1N1, six; T2N1, 18; T1N2, five; T2N2, nine; T3N0, three; T3N1, one; and T3N2, three. All patients received cyclophosphamide, Adriamycin (doxorubicion; Adria Laboratories, Mississauga, Ontario), and vincristine; four also received etoposide (VP-16) and cisplatin, one VP-16, and four methotrexate, procarbazine, and lomustine (CCNU). Forty-nine patients received prophylactic cranial irradiation, and 35 received radiotherapy to the mediastinum and primary site. The overall median survival of the 63 patients is 83 weeks, and the projected 5-year survival is 31%. Patients with T1 or T2 tumors without nodal involvement had a median survival of 191 weeks, and projected 5-year survival of 48%. Stage II (T1N1, T2N1) and stage III (any T3 or T1-2N2) patients had median survivals of 72 weeks and 65 weeks, and projected 5-year survivals of 24.5% and 24%, respectively. Thirty-three patients have relapsed and died of disease. Only two patients had an isolated relapse at the primary site. Seven other patients have died without recurrent disease. Adjuvant chemotherapy after surgery results in prolonged survival and cure for a significant number of patients with stage I SCLC, although nodal involvement at any level is associated with shorter survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/cirurgia , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Mediastinoscopia , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
PURPOSE: The 5-year survival rates with surgical resection for preoperatively identified stage IIIA N2 non-small-cell lung cancer (NSCLC) are less than 10%. A pilot study of mitomycin, vindesine, and cisplatin (MVP) induction chemotherapy was undertaken in an attempt to improve the curative potential of surgery in this group of patients. PATIENTS AND METHODS: Thirty-nine patients with mediastinoscopy stage IIIA N2 NSCLC received two cycles of MVP. Responding patients underwent thoracotomy for resection and two further courses of MVP. RESULTS: The overall response rate was 64% (25 of 39) with three complete and 22 partial responses. Twenty-two patients were resected, which included a radical mediastinal node dissection. Eighteen resections were complete and four were incomplete. Pathologically, three patients (7.7%) had no tumor remaining. Toxicity included two postoperative deaths secondary to a bronchopleural (BP) fistula, mitomycin pulmonary toxicity in two patients, and septic deaths in four patients. Twenty-eight patients have died; 20 have recurrent or progressive disease. Eight of the 18 patients completely resected have recurred, with a median time to recurrence of 20.6 months. Sites of recurrence include two locoregional, five distant (two in brain), and one in both. Median survival of all 39 patients is 18.6 months, with a 3-year survival of 26%. The median survival for those patients completely resected was 29.7 months with a 3-year survival of 40%. CONCLUSIONS: We conclude (1) that MVP is an effective but toxic chemotherapeutic regimen for limited NSCLC; (2) the median survival seems to be prolonged; and (3) the role of induction chemotherapy followed by surgery in stage IIIA N2 NSCLC requires a phase III randomized trial to compare it with other treatment modalities.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Avaliação de Medicamentos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mitomicinas/administração & dosagem , Estadiamento de Neoplasias , Projetos Piloto , Indução de Remissão , Análise de Sobrevida , Vindesina/administração & dosagemRESUMO
OBJECTIVE: Complement activation has been shown to play a significant role in ischemia-reperfusion injury after lung transplantation. TP-10 (soluble complement receptor 1 inhibitor) inhibits the activation of complement by inactivating C3a and C5a convertases. This was a clinical trial of TP-10 to reduce ischemia-reperfusion injury in lung transplantation. METHODS: In a randomized, double-blinded, multicenter, placebo-controlled trial, 59 patients from four lung transplant programs received TP-10 (10 mg/kg, n = 28) or placebo (n = 31) before reperfusion. This dose achieved 90% complement inhibition for 24 hours, and activity had returned toward normal by 72 hours. RESULTS: At 24 hours, 14 of 28 patients in the TP-10 group (50%) were extubated, whereas only 6 of 31 patients in the placebo group (19%) were (P = .01). The total times on the ventilator and in the intensive care unit both tended to be shorter in the TP-10 group, but these differences did not achieve statistical significance. Among patients requiring cardiopulmonary bypass (n = 5 in placebo group and n = 7 in TP-10 group), the mean duration of mechanical ventilation was reduced by 11 days in the TP-10 group (10.6 +/- 5.0 days vs 21.5 +/- 5.9 days in placebo group, P = .2). Operative deaths, incidences of infection and rejection, and length of hospital stay were not significantly different between the two groups. CONCLUSIONS: Short-term complement inhibition with TP-10 led to early extubation in a significantly higher proportion of lung transplant recipients. The effect of TP-10 was greater among patients undergoing cardiopulmonary bypass, with a large reduction in ventilator days. Complement inhibition thus significantly decreases the duration of mechanical ventilation and could be useful in improving the outcome of lung transplant recipients.
Assuntos
Transplante de Pulmão , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Ponte Cardiopulmonar , Proteínas Inativadoras do Complemento/antagonistas & inibidores , Proteínas Inativadoras do Complemento/uso terapêutico , Proteínas do Sistema Complemento/efeitos dos fármacos , Proteínas do Sistema Complemento/metabolismo , Método Duplo-Cego , Feminino , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/prevenção & controle , Humanos , Tempo de Internação , Pneumopatias/mortalidade , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , América do Norte , Consumo de Oxigênio/efeitos dos fármacos , Complicações Pós-Operatórias/mortalidade , Receptores de Complemento/antagonistas & inibidores , Receptores de Complemento/uso terapêutico , Traumatismo por Reperfusão/mortalidade , Respiração Artificial , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/mortalidade , Infecção da Ferida Cirúrgica/prevenção & controle , Análise de Sobrevida , Resultado do TratamentoRESUMO
Major advancements in the field of lung transplantation have occurred over the past thirty-five years. Despite these advancements, limitations in our ability to obtain sufficient numbers of organs and in our comprehension of the problems associated with the procedure persist. The purpose of this article is to review the current understanding of both the surgical procedure and its most unfortunate complication, bronchiolitis obliterans. Even now, after over three decades of experience, this complication remains the most significant cause of morbidity and mortality following lung transplantation. This article is not meant to be an exhaustive review, and certainly there are important topics not covered herein. We have focused the discussion on ongoing studies, which attempt to understand bronchiolitis obliterans at both the clinical as well as the immunopathological level.
Assuntos
Bronquiolite Obliterante/etiologia , Transplante de Pulmão/efeitos adversos , Animais , Bronquiolite Obliterante/imunologia , Modelos Animais de Doenças , Antígenos de Histocompatibilidade/imunologia , Humanos , Pneumopatias Obstrutivas/etiologia , Pneumopatias Obstrutivas/imunologia , Transplante de Pulmão/imunologia , CamundongosRESUMO
We studied the effect of a vasodilator (prostaglandin E1) as well as flush (F) and storage (S) temperatures (4 degrees C or 10 degrees C) on lung preservation in an isolated rabbit lung perfusion model. Low-potassium dextran (LPD) or Euro-Collins (E-C) solution was used as flush solution. Six groups of six animals were studied: group 1 (LPD, 4 degrees C F-S), group 2 (LPD with PGE1, 4 degrees C F-S), group 3 (E-C with PGE1, 4 degrees C F-S), group 4 (LPD, 10 degrees C F-S), group 5 (LPD with PGE1, 10 degrees C F-S), group 6 (E-C with PGE1, 10 degrees C F-S). After 18-hr preservation, left lungs alone were ventilated, and reperfused with fresh venous blood. PaO2, PaCO2, pulmonary artery pressure (PAP), tracheal pressure (Pt) during reperfusion, and wet/dry weight (W/D) ratios were measured. PaO2 after LPD with or without PGE1 was significantly higher than after E-C with PGE1 at 4 degrees C (95.8 +/- 11.5 mmHg in group 1 or 102.7 +/- 8.6 in group 2 vs. 41.8 +/- 10.5 in group 3, P less than 0.01) and at 10 degrees C (119.3 +/- 2.3 in group 4 or 131.1 +/- 6.2 in group 5 vs. 54.6 +/- 5.2 in group 6, P less than 0.01). PaCO2, PAP, Pt, and W/D ratios in the LPD groups were lower than in the E-C groups. LPD/PGE1 and LPD alone produced similar pulmonary preservation. PaO2 of lungs flushed with LPD and preserved at 10 degrees C was higher than that of lungs stored at 4 degrees C. We conclude that LPD solution is superior to E-C solution in this ex vivo rabbit lung preservation model, even when PGE1 is used. A moderate dose of PGE1 did not improve the performance of LPD as a flush solution. Pulmonary preservation with LPD at 10 degrees C is superior to preservation at 4 degrees C.
Assuntos
Alprostadil/farmacologia , Transplante de Pulmão/fisiologia , Pulmão , Preservação de Órgãos/métodos , Animais , Temperatura Baixa , Dextranos/farmacologia , Soluções Hipertônicas/farmacologia , Pulmão/fisiologia , Transplante de Pulmão/métodos , Oxigênio/fisiologia , Pressão Parcial , Potássio/farmacologia , Artéria Pulmonar/fisiologia , Coelhos , TemperaturaRESUMO
Limited availability of donor organs is a major factor restricting the clinical application of lung transplantation. Improvements in preservation techniques are essential for prolonging storage time and improving lung function following transplantation. The present investigation used primary cultures of adult rat alveolar type II cells as a model for evaluating lung-preservation solutions. Type II cells were plated onto tissue-culture plastic at a density 5 x 10(5) cells/cm2 and maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (D10) for 40 hr. Cells were then exposed to Euro-Collins solution or a low-potassium-dextran solution (LPD). At designated time points, measurements of lactate-dehydrogenase (LDH) release, protein content, and incorporation of 3H-thymidine into cellular DNA were made. During 12 hr of "storage" at 37 degrees C, cells maintained in LPD released less LDH (14.3 +/- 1.2% of cellular total, mean +/- SEM, n = 5) than their counterparts stored in EC (20.6 +/- 1.6%, P less than 0.05). During the 36 hr following a 6-hr exposure to preservative solutions, LPD-treated cells incorporated more thymidine per mg of protein (2566 +/- 419.8 cpm/micrograms protein, mean +/- SEM, n = 6) compared with cells maintained continuously in D10 (1431 +/- 351, P less than 0.05). By contrast, cells exposed to EC incorporated less thymidine (82.2 +/- 62.8 cpm/micrograms protein) than either cells maintained in LPD or D10 (P less than 0.01 for each comparison). These results suggest that LPD solution is less cytotoxic than EC and that LPD enables higher levels of metabolic activity in recovering epithelial cells. In vitro cultures of type II epithelial cells are a useful model system for the study of lung preservation and posttransplantation lung injury.
Assuntos
Dextranos , Soluções Hipertônicas , Pulmão/citologia , Preservação de Órgãos/métodos , Potássio , Fosfatase Alcalina , Animais , Células Cultivadas , Células Epiteliais , Epitélio/efeitos dos fármacos , Concentração de Íons de Hidrogênio , L-Lactato Desidrogenase/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Ratos , Ratos Endogâmicos , SoluçõesRESUMO
BACKGROUND: Immunosuppressive therapy has limited activity against the mesenchymal cell proliferation of obliterative bronchiolitis. Clotrimazole (CLT) has been shown to inhibit proliferation in normal and cancer cell lines. Here we investigate whether CLT inhibits the proliferation of lung mesenchymal cells. METHODS: Proliferation of human lung fibroblasts (MRC-5) in the presence of CLT was determined by [3H]thymidine incorporation. Messenger ribonucleic acid (mRNA) expression of platelet-derived growth factor (PDGF)-B and transforming growth factor (TGF)-beta after treatment with CLT was measured by reverse transcriptase-polymerase chain reaction. RESULTS: Treatment of MRC-5 cells with CLT resulted in a significant reduction in proliferation as assessed by DNA incorporation and cell counts compared with dimethylsulfoxide alone. There was no cytotoxic effect associated with CLT treatment. Reverse transcriptase-polymerase chain reaction demonstrated a marked decrease in PDGF-B and TGF-beta mRNA levels in cells treated with CLT compared with those treated with dimethylsulfoxide. CONCLUSION: CLT inhibits proliferation of human lung fibroblasts. This inhibitory effect is associated with decreased levels of PDGF-B and TGF-beta mRNA expression and may have value in the prevention and treatment of obliterative bronchiolitis.