RESUMO
The aim of the study is to develop a method for detection of pathological respiratory sound, caused by bronchial asthma, with the aid of machine learning techniques. Materials and Methods: To build and train neural networks, we used the records of respiratory sounds of bronchial asthma patients at different stages of the disease (n=951) aged from several months to 47 years old and healthy volunteers (n=167). The sounds were recorded with calm breathing at four points: at the oral cavity, above the trachea, on the chest (second intercostal space on the right side), and at a point on the back. Results: The method developed for computer-aided detection of respiratory sounds allows to diagnose sounds typical for bronchial asthma in 89.4% of cases with 89.3% sensitivity and 86.0% specificity regardless of sex and age of the patients, stage of the disease, and the point of sound recording.
Assuntos
Asma , Sons Respiratórios , Humanos , Sons Respiratórios/diagnóstico , Asma/diagnóstico , Computadores , Redes Neurais de Computação , TraqueiaRESUMO
Recently, multiple studies have reported declining phenological sensitivities (∆ days per â) with higher temperatures. Such observations have been used to suggest climate change is reshaping biological processes, with major implications for forecasts of future change. Here, we show that these results may simply be the outcome of using linear models to estimate nonlinear temperature responses, specifically for events that occur after a cumulative thermal threshold is met-a common model for many biological events. Corrections for the nonlinearity of temperature responses consistently remove the apparent decline. Our results show that rising temperatures combined with linear estimates based on calendar time produce the observations of declining sensitivity-without any shift in the underlying biology. Current methods may thus undermine efforts to identify when and how warming will reshape biological processes.
Assuntos
Mudança Climática , TemperaturaRESUMO
Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8+ T cells are considered a barrier to immunosuppression-mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8+ T lymphocytes. Here we demonstrate that costimulation blockade-mediated tolerance after lung transplantation is dependent on programmed cell death 1 (PD-1) expression on CD8+ T cells. In the absence of PD-1 expression, CD8+ T cells form prolonged interactions with graft-infiltrating CD11c+ cells; their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely. These findings extend the notion that requirements for tolerance induction after lung transplantation differ from other organs. Thus, immunosuppressive strategies for lung transplant recipients need to be tailored based on the unique immunological properties of this organ.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Pulmão , Receptor de Morte Celular Programada 1/metabolismo , Aloenxertos , Animais , Rejeição de Enxerto/patologia , Terapia de Imunossupressão , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology. Intravenous immunoglobulin (IVIG) is an effective treatment and decreases the risk of cardiac complications to less than 5%. In spite of its effectiveness, some children do not respond to this therapy and still develop coronary aneurysms (CAA). The optimal treatment for IVIG non-responsive patients remains controversial although corticoids have been suggested to be an effective treatment in some patients. For those patients still resistant to IVIG and corticoids, interleukin-1 receptor antagonists (IL-1RA) such anakinra could be an alternative. CASE PRESENTATION: We present a 3 year-old Caucasian patient with KD without cardiac complications but with important resistance to treatment. After becoming resistant to IVIG and corticoids, anakinra proved to be an effective treatment. CONCLUSIONS: To our knowledge, this is the first report of the utility of IL-1RA in refractory KD without coronary impairment. The patient fulfilled the classical criteria for KD and, after becoming resistant to first and second line treatments, anakinra proved to be an effective treatment. Further studies are required to determine if this is an effective treatment option for other cases of resistant Kawasaki disease.
Assuntos
Anti-Inflamatórios/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Síndrome de Linfonodos Mucocutâneos/diagnósticoRESUMO
Ischemia-reperfusion injury-mediated primary graft dysfunction substantially hampers short- and long-term outcomes after lung transplantation. This condition continues to be diagnosed based on oxygen exchange parameters as well as radiological appearance, and therapeutic strategies are mostly supportive in nature. Identifying patients who may benefit from targeted therapy would therefore be highly desirable. Here, we show that C-C chemokine receptor type 2 (CCR2) expression in murine lung transplant recipients promotes monocyte infiltration into pulmonary grafts and mediates graft dysfunction. We have developed new positron emission tomography imaging agents using a CCR2 binding peptide, ECLi1, that can be used to monitor inflammatory responses after organ transplantation. Both 64 Cu-radiolabeled ECL1i peptide radiotracer (64 Cu-DOTA-ECL1i) and ECL1i-conjugated gold nanoclusters doped with 64 Cu (64 CuAuNCs-ECL1i) showed specific detection of CCR2, which is upregulated during ischemia-reperfusion injury after lung transplantation. Due to its fast pharmacokinetics, 64 Cu-DOTA-ECL1i functioned efficiently for rapid and serial imaging of CCR2. The multivalent 64 CuAuNCs-ECL1i with extended pharmacokinetics is favored for long-term CCR2 detection and potential targeted theranostics. This imaging may be applicable for diagnostic and therapeutic purposes for many immune-mediated diseases.
Assuntos
Transplante de Pulmão/métodos , Imagem Molecular/métodos , Receptores CCR2/fisiologia , Traumatismo por Reperfusão/diagnóstico por imagem , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Fragmentos de Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Transdução de SinaisRESUMO
Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper-17 (Th17)-mediated immunity against lung self-antigens (SAgs), K-α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell-activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti-H2K(b) was administered intrabronchially into Batf (-/-) and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf (-/-) mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction. There was lack of Abs to SAgs, reduction of Sag-specific interleukin (IL)-17 T cells, IL-6, IL-23, IL-17, IL-1ß, fibroblast growth factor-6, and CXCL12 and decreased Janus kinase 2, signal transducer and activator of transcription 3 (STAT3), and retinoid-related orphan receptor γT. Further, micro-RNA (miR)-301a, a regulator of Th17, was reduced in Batf (-/-) mice in contrast to upregulation of miR-301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) in anti-MHC-induced OAD animals. We also demonstrate an increase in miR-301a in the bronchoalveolar lavage cells from lung transplant recipients with Abs to human leukocyte antigen. This was accompanied by reduction in PIAS3 mRNA. Therefore, we conclude that BATF plays a critical role in the immune responses to SAgs and pathogenesis of anti-MHC-induced rejection. Targeting BATF should be considered for preventing chronic rejection after human lung transplantation.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Bronquiolite Obliterante/prevenção & controle , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Celular/imunologia , Fibrose Pulmonar/prevenção & controle , Animais , Autoanticorpos/sangue , Autoantígenos/imunologia , Autoimunidade/imunologia , Western Blotting , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Transplante de Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
De novo induction of organized lymphoid aggregates at nonlymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, autoantigens or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3(+) cells are present in long-term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of "tolerogenic" TLOs may prove advantageous. In this review, we discuss our current understanding of how TLOs are induced and how they regulate immune responses with a particular focus on alloimmunity.
Assuntos
Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Tecido Linfoide/imunologia , Transplante de Órgãos , Aloenxertos , Animais , HumanosRESUMO
Immune responses against lung-associated self-antigens (self-Ags) are hypothesized to play a role in the development of chronic lung graft rejection. We determined whether immune responses to lung self-Ags, K-alpha-1-tubulin (Kα1T) and Collagen V (Col-V) in the absence of alloimmunity, could promote airway inflammation and fibrosis. Following syngeneic murine orthotopic lung transplantation (LTx) we administered antibodies (Abs) to either Kα1T or Col-V or in combination to both of these self-Ags. As compared to recipients of isotype control Abs, Kα1T Abs and/or Col-V Abs-treated recipients had marked lung graft cellular infiltration and bronchiolar fibrosis. This inflammation was also associated the accumulation of Kα1T and Col-V-specific interferon-γ+ and IL-17+ T cells. Notably, the administration of Abs to Kα1T led to cellular and humoral immune responses to Col-V prior to development of fibrosis, and vice versa, indicating that epitope spreading can occur rapidly in an alloantigen independent manner. Collectively, these data support a model of chronic LTx rejection where the progressive loss of self-tolerance through epitope spreading promotes airway fibrosis. Strategies that target autoreactive Abs may be useful to inhibit chronic rejection of lung grafts.
Assuntos
Bronquite/prevenção & controle , Transplante de Pulmão , Animais , Autoanticorpos/imunologia , Bronquite/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologiaRESUMO
Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [(18)F]fluorodeoxyglucose ([(18)F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [(18)F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [(18)F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8(+) T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen-presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Fluordesoxiglucose F18 , Rejeição de Enxerto/diagnóstico por imagem , Transplante de Pulmão , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Processamento de Imagem Assistida por Computador , Terapia de Imunossupressão , Imunossupressores/farmacologia , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante Homólogo , Transplante IsogênicoRESUMO
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
Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance, we developed a method to retransplant mouse lungs. Retransplantation into T-cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 h of transplantation are reversible. In contrast to hearts, a 72-h period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3(+) cells accumulate and recipient T cells interact with CD11c(+) dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.
Assuntos
Células Dendríticas/imunologia , Transplante de Pulmão/imunologia , Tecido Linfoide/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Antígeno CD11c/metabolismo , Células Dendríticas/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Depleção Linfocítica , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Modelos Animais , Reoperação , Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
Immune responses to human leucocyte antigen (HLA) and self-antigen collagen V (Col-V) have been proposed in the pathogenesis of chronic rejection (bronchiolitis obliterans syndrome, BOS) following human lung transplantation (LTx). In this study, we defined the role for the shift in immunodominant epitopes of Col-V in inducing T helper phenotype switch leading to immunity to Col-V and BOS. Sera and lavage from BOS(+) LTx recipients with antibodies to Col-V were analysed. Two years prior to BOS, patients developed antibodies to both Col-V,α1(V) and α2(V) chains. However, at clinical diagnosis of BOS, antibodies became restricted to α1(V). Further, lung biopsy from BOS(+) patients bound to antibodies to α1(V), indicating that these epitopes are exposed. Fourteen Col-V peptides [pep1-14, pep1-4 specific to α1(V), pep5-8 to α1,2(V) and pep9-14 to α2(V)] which bind to HLA-DR4 and -DR7, demonstrated that prior to BOS, pep 6, 7, 9, 11 and 14 were immunodominant and induced interleukin (IL)-10. However, at BOS, the response switched to pep1, 4 and 5 and induced interferon (IFN)-γ and IL-17 responses, but not IL-10. The T helper (Th) phenotype switch is accompanied by decreased frequency of regulatory T cells (T(regs) ) in the lavage. LTx recipients with antibodies to α1(V) also demonstrated increased matrix metalloproteinase (MMP) activation with decreased MMP inhibitor, tissue inhibitor of metalloproteinase (TIMP), suggesting that MMP activation may play a role in the exposure of new Col-V antigenic epitopes. We conclude that a shift in immunodominance of self-antigenic determinants of Col-V results in induction of IFN-γ and IL-17 with loss of tolerance leading to autoimmunity to Col-V, which leads to chronic lung allograft rejection.
Assuntos
Autoantígenos/imunologia , Bronquiolite Obliterante/imunologia , Colágeno Tipo I/imunologia , Colágeno Tipo V/imunologia , Rejeição de Enxerto/imunologia , Epitopos Imunodominantes/imunologia , Transplante de Pulmão/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Sequência de Aminoácidos , Bronquiolite Obliterante/etiologia , Metilação de DNA , Ativação Enzimática , Feminino , Seguimentos , Fatores de Transcrição Forkhead/genética , Humanos , Imunofenotipagem , Imunossupressores/uso terapêutico , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-17/biossíntese , Interleucina-17/genética , Isoantígenos/imunologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Tolerância ao Transplante/imunologiaRESUMO
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
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
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
Outcomes after lung transplantation are markedly inferior to those after other solid organ transplants. A better understanding of cellular and molecular mechanisms contributing to lung graft injury will be critical to improve outcomes. Advances in this field have been hampered by the lack of a mouse model of lung transplantation. Here, we report a mouse model of vascularized aerated single lung transplantation utilizing cuff techniques. We show that syngeneic grafts have normal histological appearance with minimal infiltration of T lymphocytes. Allogeneic grafts show acute cellular rejection with infiltration of T lymphocytes and recipient-type antigen presenting cells. Our data show that we have developed a physiological model of lung transplantation in the mouse, which provides ample opportunity for the study of nonimmune and immune mechanisms that contribute to lung allograft injury.
Assuntos
Transplante de Pulmão/métodos , Circulação Pulmonar/fisiologia , Animais , Transplante de Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Artéria Pulmonar/patologia , Veias Pulmonares/patologia , Transplante Isogênico/patologia , Transplante Isogênico/fisiologiaRESUMO
Ischemia reperfusion (I/R) injury following lung transplantation is exacerbated by the destruction of the endothelial cell barrier leading to pulmonary edema and dysregulated activated lymphocyte migration. Sphingosine 1-phosphate (S1P), a G-coupled protein receptor (GPCR) agonist, has been previously shown to promote endothelial cell tight junction formation and prevent monocyte chemotaxis. We asked if S1P treatment could improve pulmonary function and attenuate I/R injury following syngeneic rat lung transplantation. In comparison to vehicle-treated recipients, S1P administered before reperfusion significantly improved recipient oxygenation following transplantation. Improved graft function was associated with reduced inflammatory signaling pathway activation along with attenuated intragraft levels of MIP-2, TNF-alpha and IL-1beta. Moreover, S1P-treated recipients had significantly less apoptotic endothelial cells, pulmonary edema and graft accumulation of neutrophils than did vehicle-treated recipients. Thus our data show that S1P improves lung tissue homeostasis following reperfusion by enhancing endothelial barrier function and blunting monocytic graft infiltration and inflammation.
Assuntos
Edema/prevenção & controle , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/fisiologia , Lisofosfolipídeos/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Esfingosina/análogos & derivados , Animais , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Caspase 3/análise , Quimiocina CXCL2 , Marcação In Situ das Extremidades Cortadas , Inflamação , Interleucina-1beta/análise , Modelos Animais , Monocinas/análise , Peroxidase/metabolismo , Ratos , Ratos Endogâmicos F344 , Esfingosina/uso terapêutico , Fator de Necrose Tumoral alfa/análiseRESUMO
The Bangladesh Arsenic Mitigation and Water Supply Program (BAMWSP) has compiled field-kit measurements of the arsenic content of groundwater for nearly five million wells. By comparing the spatial distribution of arsenic inferred from these field-kit measurements with geo-referenced laboratory data in a portion of Araihazar upazila, it is shown here that the BAMWSP data could be used for targeting safe aquifers for the installation of community wells in many villages of Bangladesh. Recent experiences with mobile-phone technology to access and update the BAMWSP data in the field are also described. It is shown that the technology, without guaranteeing success, could optimize interventions by guiding the choice of the drilling method that is likely to reach a safe aquifer and identifying those villages where exploratory drilling is needed.