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Renal fibrosis is the common final pathway of progressive renal diseases, in which the macrophages play an important role. ELISA was used to detect CD5 antigen-like (CD5L) in serum samples from end-stage renal disease (ESRD), as well as in mice serum with unilateral ureteral occlusion (UUO). Recombinant CD5L was injected into UUO mice to assess renal injury, fibrosis, and macrophage infiltration. The expression of CD5L was significantly upregulated in the serum of patients with ESRD and UUO mice. Histological analysis showed that rCD5L-treated UUO mice had more severe renal injury and fibrosis. Furthermore, rCD5L promoted the phenotypic transfer of monocytes from Ly6Chigh to LyC6low. RCD5L promoted TGF-ß signaling pathway activation by promoting Smad2/3 phosphorylation. We used Co-IP to identify HSPA5 interact with CD5L on cell membrane could inhibit the formation of the Cripto/HSPA5 complex, and promote the activation of the TGF-ß signaling pathway. The CD5L antibody could reduce the degree of renal fibrosis in UUO mice.
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The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2-/- mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2-/- BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-ß1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.
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Apoptose , Macrófagos , Glicoproteínas de Membrana , Camundongos Endogâmicos C57BL , Receptores Imunológicos , Fatores de Transcrição STAT , Transdução de Sinais , Animais , Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Rim/patologia , Rim/metabolismo , Camundongos Knockout , Masculino , Fibrose , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/genética , Obstrução Ureteral/patologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/complicações , Polaridade Celular , Serina-Treonina Quinases TOR/metabolismo , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/genéticaRESUMO
OBJECTIVES: The mouse kidney transplantation model presents challenges in terms of surgical difficulty and low success rate, making it difficult to master. This study aims to provide a crucial model for transplantation immunology research by modifying and developing novel techniques for mouse kidney transplantation. METHODS: A total of 57 pairs of mice were used to establish and compare the modified and innovative surgical techniques for mouse kidney transplantation. Three different surgical models were established, including the abdominal suture technique for orthotopic kidney transplantation, the abdominal cuff technique for orthotopic kidney transplantation, and the cervical cuff technique for ectopic kidney transplantation. BALB/c or C57BL/6 male mice, aged 8 to 12 weeks and weighed 20 to 25 g with specified pathogen free-grade were served as the donor mice or the recipient mice. The surgical technique characteristics, key surgical times, complications, and pathological examination in the early postoperative period were summarized and compared. RESULTS: Three different surgical models of mouse kidney transplantation were successfully established. The comparison of warm ischemic time for the 3 groups of mice showed no statistical significance (P=0.510 4). The abdominal suture group had the shortest total operation time of the donor compared with the abdominal cuff group and the cervical cuff group [(18.3±3.6) min vs (26.2±4.7) min and (22.8±2.5) min; both P<0.000 1]. There was a significant difference in cold ischemia time among the 3 groups (all P<0.000 1), with (60.8±4.1) min in the cervical cuff group, (43.3±5.0) min in the abdominal suture group, and (88.8±6.7) min in the abdominal cuff group. Due to different anastomosis methods, the cervical cuff group had the shortest time [(17.6±2.7) min], whereas the abdominal cuff group had the longest time [(38.8±5.4) min]. The total operation time for the recipients showed significant differences (P<0.000 1), with the abdominal suture group having the shortest time [(44.0±6.9) min], followed by the cervical cuff group [(64.1±5.2) min], and the abdominal cuff group [(80.0±6.0) min] being the longest. In the 32 mice of the abdominal suture group, there were 6 with intraoperative bleeding, including 1 arterial intimal injury bleeding and 5 with bleeding after vessel opening. Six mice had ureteral complications, including ureteral bladder anastomotic stenosis, necrosis, and renal pelvis dilation. Two mice had postoperative abdominal infections. In the abdominal cuff group, there was no intraoperative bleeding, but 6 mice showed mild arterial stenosis and 5 showed venous stenosis, 4 arterial injury, 4 arterial thrombosis, and 2 ureteral complications. No postoperative infections occurred in the mice. In the cervical cuff group, no intraoperative bleeding, arterial intimal injury, arterial/venous stenosis, or thrombosis were found in 13 mice. Five mice had ureteral complications, including ureteral necrosis and infection, which were the main complications in the cervical cuff group. The renal function in mice of the 3 groups remained stable 7 days after surgery. Hematoxylin and eosin staining and periodic acid-Schiff staining showed no significant differences in terms of acute rejection among the 3 surgical methods (all P>0.05). CONCLUSIONS: All 3 surgical methods are able to successfully establish mouse kidney transplantation models, with no significant differences observed in the short-term graft survival and acute rejection. The modified abdominal suture technique and abdominal cuff technique have their respective advantages in research applications. The novel cervical cuff technique for ectopic kidney transplantation model is relatively simple to be prepared and causes less trauma to the mice, providing more options for studies involving xenotransplantation, secondary transplantation, and local lymphatic drainage. However, the difficulty in harvesting the donor kidney and the high incidence of ureteral infections need further validation in long-term survival. This study holds important reference value for choosing the type of mouse kidney transplantation model for different research needs.
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Transplante de Rim , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Animais , Camundongos , Transplante de Rim/métodos , Transplante de Rim/efeitos adversos , Masculino , Modelos AnimaisRESUMO
BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of MAPK and mammalian target of Rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro, blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg-1·day-1) and Rapamycin (0.1 mg·kg-1·day-1) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS: Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
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The murine heterotopic cardiac transplantation model has been widely used to study antigen-specific immune responses or new immunosuppressive agents, which have a strong correlation with peripheral lymph nodes. Thus, a new organ transplantation model that is applicable to related studies is needed. Here, we describe a groin-site murine heart transplantation model using a cuff technique, in which the donor aorta and pulmonary artery are anastomosed to the truncated femoral vessels of the recipient. The mean survival time (MST) of the grafts in BALB/c-to-C57BL/6 allo-transplant group was 7.2 ± 0.3 days, and 1.9 ± 0.2 days in BALB/c-to-Sprague-Dawley (SD) rat xeno-transplant group. H&E results show that donor hearts from both groups demonstrate typical pathological features at the endpoint. Evans Blue tracing revealed that the popliteal lymph nodes of the grafted side hindlimb are larger than those of the contralateral side. Moreover, IHC staining for CD3, CD20 shows that the germinal center and cortex region of the grafted side of popliteal lymph nodes is apparently increased than that of the contralateral side. To sum up, this model may serve as an ideal model to study the role of peripheral lymph nodes in organ transplant rejection. In addition, extra-peritoneal grafting makes a step forward in animal welfare under the 3Rs' principle (Replacement, Reduction, Refinement).
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Transplante de Coração , Ratos , Camundongos , Animais , Humanos , Transplante de Coração/métodos , Virilha , Ratos Sprague-Dawley , Transplante Heterólogo , Doadores de Tecidos , Linfonodos , Camundongos Endogâmicos C57BL , Rejeição de EnxertoRESUMO
BACKGROUND: Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model. METHODS: Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. RESULTS: HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days (P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4+ and CD8+ T cells in the spleen (P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes (CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF)-ß pathway-related genes and Treg signature genes (CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4+ Foxp3+ cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. CONCLUSIONS: HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.
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The abnormal enrichment of cadmium (Cd) in soil caused by rock weathering and mining activities is an issue in southern China. Although the soil Cd content in these regions is extremely high, the bioavailability of Cd in the soils differs significantly. The carbonate area (CBA) and tin-mining area (TIA) in Hezhou City were investigated to determine the primary features of soil Cd mobility in these regions and improve environmental management. Lateral and vertical spatial distributions revealed different accumulation and migration mechanisms of soil Cd in the CBA and TIA. Further analyses revealed that mining activities and geological weathering resulted in different soil geochemical parameters, thus yielding significantly lower levels of Cd in rice grains in the CBA than in the TIA. The random forest (RF) model predicted the bioaccumulation factor (BAF) (R2 = 0.69) better than the support vector machine (SVM) model (R2 = 0.68). Subsequently, a novel land management scheme was proposed based on soil Cd and the prediction of Cd in rice to optimize the spatial resources of agricultural land and ensure the safety of rice for consumption. This study provides a novel approach for land management in Cd-contaminated areas.
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Oryza , Solo , Bioacumulação , Cádmio , Agricultura , Disponibilidade BiológicaRESUMO
OBJECTIVES: Immunoglobulin A nephropathy (IgAN) is one of the most common types of kidney disease, and kidney transplantation is the most effective treatment for end-stage renal disease. This study aims to analyze the clinical curative effect of renal transplantation for adults with IgAN and to discuss the efficacy and safety of kidney transplantation for IgAN at the perioperative period and medium- and long-term follow-up. METHODS: This retrospective study included the clinical and follow-up data of 81 adult patients with IgAN who underwent kidney transplantation at the Second Xiangya Hospital, Central South University from January 2018 to January 2022. Of the 81 patients whose age at (34.1±9.9) years old, 47 (58.0%) were male. The body mass index was (20.8±3.2) kg/m2, and the human leukocyte antigen (HLA) mismatch number was 3.5±1.2. The estimated glomerular filtration rate (eGFR) and daily 24-hour urine output for the recipients on the 1st, 5th, and 7th day after kidney transplantation and when they were discharged were analyzed. The recovery of the transplanted kidney and occurrence of complications were comprehensively evaluated. The eGFR, urinary protein, and occult blood were evaluated at the 6th, 12th, 24th, 36th, and 48th month and at the last follow-up. RESULTS: The follow-up time was (25.7±15.8) months. No primary non-function occurred in any patient during the perioperative period time. Fifty-one (63.0%) patients had immediate graft function recovery, and 16 (19.8%) patients had slow graft function recovery. Delayed recovery of graft function was observed in 14 (17.3%) patients. A total of 19 perioperative complications occurred, including 9 patients with acute rejection, 5 patients with urinary fistula, 1 thrombosis in both lower limbs, and 4 lymphatic fistula. The eGFR at 6th, 12th, 24th, 36th, and 48th month of follow-up were (65.3±22.9), (67.6±23.0), (64.3±21.8), (65.9±24.7), and (68.7±31.2) mL/(min·1.73 m2), respectively. The eGFR remained high during the medium- and long-term follow-ups. At the longest follow-up of 56 months, eGFR fluctuation was still mild, and the positive rate of urine protein and occult blood was low. IgAN recurred in 4 transplanted kidneys, accounting for 4.94% of the total patients, without severe renal insufficiency. Three patients had kidney dysfunction due to severe pneumonia, rejection, and stone in the transplanted kidney. The overall survival rate of the transplanted kidney was higher than 95%, and the survival rate of all patients was 100% till Januray 2022. CONCLUSIONS: Renal transplantation for adults with IgAN had a remarkable short-term effect. The recipients can be beneficial significantly to favorable midium- and long-term outcomes. IgAN recurrence is infrequent and rarely causes severe renal function damage.
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Glomerulonefrite por IGA , Falência Renal Crônica , Transplante de Rim , Adulto , Humanos , Masculino , Adulto Jovem , Feminino , Glomerulonefrite por IGA/cirurgia , Estudos Retrospectivos , Rim , Falência Renal Crônica/cirurgiaRESUMO
Disulfide bond A oxidoreductase-like protein (DsbA-L) drives acute kidney injury (AKI) by directly upregulating the expression of voltage-dependent anion-selective channels in proximal tubular cells. However, the role of DsbA-L in immune cells remains unclear. In this study, we used an LPS-induced AKI mouse model to assess the hypothesis that DsbA-L deletion attenuates LPS-induced AKI and explore the potential mechanism of DsbA-L action. After 24 hours of LPS exposure, the DsbA-L knockout group exhibited lower serum creatinine levels compared to the WT group. Furthermore, peripheral levels of the inflammatory cytokine IL-6 were decreased. Transcriptomic data analysis revealed a significant down-regulation in the IL-17 and tumor necrosis factor pathways in DsbA-L knockout mice following LPS induction. Metabolomic analysis suggested that arginine metabolism was significantly different between the WT and DsbA-L knockout groups after LPS treatment. Notably, the M1 polarization of macrophages in the kidneys of DsbA-L knockout AKI mice was significantly reduced. Expression of the transcription factors NF-κB and AP-1 was downregulated after DsbA-L knockout. Our results suggest that DsbA-L regulates LPS-mediated oxidative stress, promotes M1 polarization of macrophages, and induces expression of inflammatory factors via the NF-κB/AP-1 pathway.
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Injúria Renal Aguda , NF-kappa B , Animais , Camundongos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Rim/patologia , Lipopolissacarídeos/farmacologia , Macrófagos , NF-kappa B/metabolismo , Fator de Transcrição AP-1RESUMO
Background: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. Methods: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. Results: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. Conclusions: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.
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Anemia de Fanconi , Síndrome de Fanconi , Transplante de Rim , Insuficiência Renal , Escoliose , Aloenxertos , Antivirais/efeitos adversos , Creatinina , Anemia de Fanconi/patologia , Síndrome de Fanconi/induzido quimicamente , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/terapia , Humanos , Transplante de Rim/efeitos adversos , Túbulos Renais Proximais/patologia , Estudos Retrospectivos , Escoliose/induzido quimicamente , Escoliose/patologia , Tacrolimo/efeitos adversosRESUMO
Background: Kidney transplantation from donors who weigh ≤5 kg is performed at only a few transplant centers owing to the high complication and low graft survival rates associated with this approach. Methods: We retrospectively compared the results of kidney transplantation at our center between January 2015 and December 2019 based on the following pediatric donor criteria: donor body weight ≤5 kg (n=32), 5 kg< donor weight ≤20 kg (n=143), and donor weight >20 kg (n=110). We also perform subgroup analysis of kidney transplantation outcomes from ≤5 kg donors, using conventional (dual separate and classic en-bloc KTx)/novel (en-bloc KTx with outflow tract) surgical methods and allocating to adult/pediatric recipients. Results: The death-censored graft survival rates from extremely low body weight ≤5kg at 1 month, and 1, 3, and 5 years were 90.6%, 80.9%, 77.5%, and 73.9%, respectively, which were significantly lower than that from larger body weight pediatric donors. However, the 3-, and 5-year post-transplantation eGFRs were not significantly different between the pediatric and adult recipient group. The thrombosis (18.8%) and urinary leakage (18.8%) rates were significantly higher in the donor weight ≤5 kg group. Compared with 5 kg< donor weight ≤20 kg group, donor weight ≤5kg group was at elevated risk of graft loss due to thrombosis (OR: 13.4) and acute rejection (OR: 6.7). No significant difference on the outcomes of extremely low body weight donor kidney transplantation was observed between adults and pediatric recipients. Urinary leakage rate is significantly lower in the novel operation (8.7%) than in the conventional operation group (44.4%). Conclusions: Although the outcomes of donor body weight ≤5kg kidney transplantation is inferior to that from donors with large body weight, it can be improved through technical improvement. Donors with body weight ≤5 kg can be considered as an useful source to expand the donor pool.
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Peso Corporal , Seleção do Doador , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/etiologia , Doadores de Tecidos , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.
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Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Interleucina-33/imunologia , Macrófagos/imunologia , Alarminas/imunologia , Aloenxertos , Animais , Criança , Modelos Animais de Doenças , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/imunologia , Humanos , Interleucina-33/administração & dosagem , Interleucina-33/deficiência , Interleucina-33/genética , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Miocárdio/imunologia , Miocárdio/patologia , Regulação para CimaRESUMO
Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.
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Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Memória Imunológica , Macrófagos/imunologia , Monócitos/imunologia , Receptores Imunológicos/fisiologia , Animais , Deleção de Genes , Rejeição de Enxerto/genética , Transplante de Coração , Transplante de Rim , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Receptores Imunológicos/genéticaRESUMO
The Liulin Spring is one of the ten most famous karst springs in the Shanxi province. The abundant karst groundwater resources support the economic and social development in the Luliang Prefecture. Therefore, the study of evolution and control factors of karst groundwater is of great significance to the sustainable utilization of water resources in the watershed. For revealing the evolution and control factors of karst groundwater in the Liulin Spring area, the main ion components of 29 karst groundwater samples from spring supply area, runoff area, discharge area, and deep buried area were analyzed. The results showed that the temperature and Na+, Ca2+, Mg2+, Cl-, HCO3-, and SO42- concentrations increased continuously along the runoff route, from the recharge area to the runoff area, to the discharge area, and then to the deep burial area. K+, Na+, and Cl- mainly come from salt rock dissolution, and Ca2+, Mg2+, HCO3-, and SO42- mainly come from the dissolution of calcite, dolomite, and gypsum. Because they are controlled by the continuous dissolution of salt rock and gypsum, the concentration of Na+, Cl-, and SO42- in groundwater has increased greatly, with the maximum value being 50 times, 80 times, and 32 times of the minimum value, respectively. Under the influence of dedolomitization, the concentration of Ca2+ and HCO3- in groundwater does not change significantly, the maximum is 2-3 times of the minimum. In the recharge area and runoff area, Na+ and Cl- amounts are lower, and Ca2+ and HCO3- are the main cations and anions in the groundwater. However, in the discharge area and deep buried area, Cl- and Na+ exceed HCO3-, Ca2+, and Mg2+ and become the main anions and cations in the groundwater. The hydrochemical type changes from HCO3-Ca·Mg in the supply area to HCO3·SO4-Ca·Mg in the runoff area, to HCO3·SO4-Ca·Na·Mg in the recharge area, and finally to Cl·HCO3-Na·Ca, Cl·HCO3-Na, and Cl-Na·Ca in the deep burial area.
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BACKGROUND: The effects of ß blockers on the primary prevention of anthracycline-induced cardiotoxicity were controversial. METHODS: We searched PubMed, Embase and Cochrane Library for randomized controlled trials of the comparison of ß blockers versus placebo in patients undergoing anthracycline chemotherapy. This meta-analysis was performed by using random-effect models. RESULTS: Nine hundred forty participants from 11 trials were included in this meta-analysis. ß blockers led to a significant reduction in symptomatic heart failure (risk ratio [RR] 0.29, 95% CI 0.10 to 0.85). Compared with placebo, ß blockers were associated with improved left ventricular ejection fraction (mean difference [MD] 4.46, 95% CI 1.77 to 7.15) and s' (MD 0.78, 95% CI 0.01 to 1.55) in parallel with reduced left ventricular diameter (left ventricular end systolic diameter, MD -3.19, 95% CI -6.17 to - 0.21; left ventricular end diastolic diameter, MD -2.28, 95% CI 4.50 to - 0.05). ß blockers also improved strain and strain rate when compared with placebo. There were no significant differences in diastolic function variables between ß blockers and placebo except e' (MD 2.33, 95% CI 0.16 to 4.51). In addition, ß blockers compared with placebo reduced the risk of cardiac troponin I elevation > 0.04 ng/ml (RR 0.60, 95% CI 0.42 to 0.85). There was no marked difference in adverse events (RR 0.94, 95% CI 0.56 to 1.59) between ß blockers and placebo. CONCLUSIONS: In cancer patients with anthracycline therapy, prophylactic ß blockers were associated with reduced risk of heart failure, decreased left ventricular diameter, improved left ventricular systolic function, and alleviative cardiomyocyte injury.
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Antagonistas Adrenérgicos beta/uso terapêutico , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Humanos , Neoplasias/tratamento farmacológico , Prevenção Primária , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Currently, the robot-assisted laparoscopic donor nephrectomy (RDN) technique is used for live donor nephrectomy. Does it provide sufficient safety and benefits for living donors? We conducted a meta-analysis to assess the safety and efficacy of RDN compared with the laparoscopic donor nephrectomy (LDN). MATERIAL AND METHODS: Eligible studies were retrieved and screened from electronic databases from 1999 onward: PubMed, Cochrane Library, and Web of Science. Relevant parameters were explored using Review Manager V5.3 and included operative time, warm ischemia time, estimated blood loss, and length of hospital stay. RESULTS: Compared with RDN, LDN had shorter operative time (min; weighted mean difference (WMD): -0.53; 95% CI: [-0.85, 0.20]; P = 0.001) and warm ischemia time (second; WMD: -55.01; 95% CI: [-71.56, 38.45]; P < 0.00001) and less estimated blood loss (mL; WMD: -28.30, 95% CI: [-46.37, 10.24], P = 0.002). The pooled analysis of postoperative pain showed lower visual analog scale (VAS) scores for RDN compared with LDN (WMD:1.28, P < 0.00001). We also observed that length of hospital stay, postoperative serum creatinine (SCr) in donors, postoperative estimated glomerular filtration rate (eGFR) of recipients and postoperative complications for donors were not significantly different between groups. CONCLUSION: As long as RDN is practiced proficiently, it is believed that RDN is a feasible alternative to LDN.