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1.
Nat Immunol ; 19(6): 571-582, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29760532

RESUMO

The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.


Assuntos
Apoptose/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Animais , Humanos , Camundongos , Transdução de Sinais/imunologia , Receptor Toll-Like 9/imunologia
2.
J Immunol ; 200(2): 512-522, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29237779

RESUMO

Glomerulonephritis is one of the most serious manifestations of systemic lupus erythematous (SLE). Because SLE is ≥10 times more common in women, a role for estrogens in disease pathogenesis has long been suspected. Estrogen receptor α (ERα) is highly expressed in renal tissue. We asked whether ERα expression contributes to the development of immune-mediated nephropathies like in lupus nephritis. We tested the overall effects of estrogen receptors on the immune response by immunization with OVA and induction of chronic graft-versus-host disease in female ERα-knockout mice. We used nephrotoxic serum nephritis as a model of immune-mediated nephropathy. We investigated the influence of ERα on molecular pathways during nephritis by microarray analysis of glomerular extract gene expression. We performed RNA sequencing of lupus patient whole blood to determine common pathways in murine and human nephritis. Absence of ERα protects female mice from developing nephritis, despite the presence of immune complexes and the production of proinflammatory cytokines in the kidneys and normal humoral responses to immunization. Time-course microarray analysis of glomeruli during nephrotoxic serum nephritis revealed significant upregulation of genes related to PPAR-mediated lipid metabolism and downregulation of genes in the retinol metabolism in wild-type females compared with ERα-knockout females. Similarly, RNA sequencing of lupus patient blood revealed similar expression patterns of these same pathways. During nephritis, the altered activity of metabolic pathways, such as retinol metabolism, occurs downstream of ERα activation and is essential for the progression to end-stage renal failure.


Assuntos
Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Glomerulonefrite/imunologia , Glomerulonefrite/metabolismo , Transdução de Sinais , Animais , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Autoanticorpos/imunologia , Biologia Computacional , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Receptor alfa de Estrogênio/genética , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Glomerulonefrite/patologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Metabolismo dos Lipídeos , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Camundongos , Camundongos Knockout , Fatores Sexuais
3.
Kidney Int ; 95(6): 1359-1372, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30905471

RESUMO

In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GECs) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel(ENaC), which is expressed by GEC, upon binding to the channel's α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E2 and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Glomerulonefrite/tratamento farmacológico , Glomérulos Renais/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Proteinúria/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Dinoprostona/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Glomerulonefrite/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Injeções Intraperitoneais , Glomérulos Renais/citologia , Glomérulos Renais/patologia , Camundongos , Óxido Nítrico/metabolismo , Técnicas de Patch-Clamp , Cultura Primária de Células , Proteinúria/sangue , Proteinúria/imunologia , Proteinúria/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Kidney Int ; 94(2): 280-291, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29731111

RESUMO

To investigate the role of protein kinase C-α (PKC-α) in glomerulonephritis, the capacity of PKC-α inhibition to reverse the course of established nephrotoxic nephritis (NTN) was evaluated. Nephritis was induced by a single injection of nephrotoxic serum and after its onset, a PKC-α inhibitor was administered either systemically or by targeted glomerular delivery. By day seven, all mice with NTN had severe nephritis, whereas mice that received PKC-α inhibitors in either form had minimal evidence of disease. To further understand the underlying mechanism, label-free shotgun proteomic analysis of the kidney cortexes were performed, using quantitative mass spectrometry. Ingenuity pathway analysis revealed 157 differentially expressed proteins and mitochondrial dysfunction as the most modulated pathway. Functional protein groups most affected by NTN were mitochondrial proteins associated with respiratory processes. These proteins were down-regulated in the mice with NTN, while their expression was restored with PKC-α inhibition. This suggests a role for proteins that regulate oxidative phosphorylation in recovery. In cultured glomerular endothelial cells, nephrotoxic serum caused a decrease in mitochondrial respiration and membrane potential, mitochondrial morphologic changes and an increase in glycolytic lactic acid production; all normalized by PKC-α inhibition. Thus, PKC-α has a critical role in NTN progression, and the results implicate mitochondrial processes through restoring oxidative phosphorylation, as an essential mechanism underlying recovery. Importantly, our study provides additional support for targeted therapy to glomeruli to reverse the course of progressive disease.


Assuntos
Glomerulonefrite/tratamento farmacológico , Proteína Quinase C-alfa/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Anticorpos Monoclonais/imunologia , Autoantígenos/imunologia , Colágeno Tipo IV/imunologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Hibridomas , Soros Imunes/administração & dosagem , Soros Imunes/imunologia , Fragmentos de Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Proteína Quinase C-alfa/imunologia , Proteína Quinase C-alfa/metabolismo , Inibidores de Proteínas Quinases/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
5.
Proc Natl Acad Sci U S A ; 112(34): 10774-9, 2015 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-26261340

RESUMO

Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-ß production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.


Assuntos
Apoptose/fisiologia , Autoimunidade/fisiologia , Tolerância Imunológica/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Aminoácidos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/fisiologia , Inflamação , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Piperidinas/farmacologia , Proteínas Serina-Treonina Quinases/deficiência , Quinazolinonas/farmacologia , Transdução de Sinais
6.
Int Immunol ; 28(4): 197-208, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26567290

RESUMO

Leptin, one of the typical adipokines, is reported to promote Th17 cell responses and to enhance production of proinflammatory cytokines. To clarify the role of leptin in the regulation of the IL-23/IL-17 axis and the development of kidney disease, we used a murine model of nephrotoxic serum (NTS) nephritis (NTN). Sheep NTS was administered in wild-type C57BL/6J mice and food-restricted, leptin-deficient C57BL/6J-ob/ob(FR-ob/ob) mice after preimmunization with sheep IgG. The profile of mRNA expression relevant to T helper lymphocytes in the kidneys was analyzed by quantitative real-time PCR (qRT-PCR). Cultured murine glomerular podocytes and peritoneal exudate macrophages (PEMs) were used to investigate the direct effect of leptin on IL-23 or MCP-1 production by qRT-PCR. Kidney injury and macrophage infiltration were significantly attenuated in FR-ob/obmice 7 days after NTS injection. The Th17-dependent secondary immune response against deposited NTS in the glomeruli was totally impaired in FR-ob/obmice because of deteriorated IL-17 and proinflammatory cytokine production including IL-23 and MCP-1 in the kidney. IL-23 was produced in glomerular podocytes in NTN mice and cultured murine glomerular podocytes produced IL-23 under leptin stimulation. MCP-1 production in PEMs was also promoted by leptin. Induction of MCP-1 expression was observed in PEMs regardless of Ob-Rb, and the leptin signal was transduced without STAT3 phosphorylation in PEMs. Leptin deficiency impairs the secondary immune response against NTS and down-regulates IL-23 production and Th17 responses in the NTN kidney, which is accompanied by decreased MCP-1 production and macrophage infiltration in the NTN kidney.


Assuntos
Interleucina-23/biossíntese , Leptina/deficiência , Nefrite/etiologia , Nefrite/metabolismo , Podócitos/metabolismo , Animais , Biópsia , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunofenotipagem , Interleucina-23/genética , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nefrite/patologia , Índice de Gravidade de Doença , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
7.
J Immunol ; 194(12): 5713-24, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25980011

RESUMO

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.


Assuntos
Aminoácidos/metabolismo , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/metabolismo , Autoanticorpos/imunologia , Autofagia/imunologia , Animais , Doença Antimembrana Basal Glomerular/genética , Doença Antimembrana Basal Glomerular/patologia , Citocinas/biossíntese , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Camundongos Knockout , Podócitos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Estresse Fisiológico
9.
Am J Physiol Renal Physiol ; 309(8): F680-4, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26290372

RESUMO

Current therapies to limit kidney disease progression lack specificity and often have systemic toxicity. To approach this problem, we postulated that a human monoclonal antibody (F1.1), directed against the noncollagenous-1 domain (NC1) of α3(IV) collagen that localizes in glomeruli, could serve as a vehicle for targeted drug delivery. Given enhanced exposure of the NC1 domain of α3(IV) during glomerular diseases, with limited epitope expression in other organs, α3(IV)NC1 provides an ideal target for delivery of disease-modifying agents. As a potential disease-modifying agent, we initially took advantage of recent observations that PGE2 promoted recovery after established injury during the course of nephrotoxic nephritis. To address the general applicability of the approach, the efficacy of glomerular delivery of dexamethasone was also examined. To achieve glomerular targeted therapy, PGE2 and dexamethasone were coupled to F1.1. After confirmation of the composition and activity of the conjugates, both glomerular localization and the capacity of the conjugates to modify disease were evaluated. After injection into mice with established nephritis, resolution of disease was enhanced with both agents, with normalization of histology and improved blood urea nitrogen levels in conjugate-treated mice compared with untreated mice. The results provide a novel means of targeting glomeruli during nephritis, irrespective of cause, by providing efficient drug delivery, with the potential of limiting systemic effects.


Assuntos
Doença Antimembrana Basal Glomerular/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Autoantígenos/imunologia , Colágeno Tipo IV/imunologia , Dexametasona/análogos & derivados , Dinoprostona/análogos & derivados , Imunoconjugados/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Nefrite/tratamento farmacológico , Animais , Doença Antimembrana Basal Glomerular/induzido quimicamente , Anti-Inflamatórios/uso terapêutico , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Dexametasona/uso terapêutico , Dinoprostona/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Hepatócitos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/imunologia , Podócitos/efeitos dos fármacos , Ovinos
10.
J Am Soc Nephrol ; 25(11): 2483-98, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24790181

RESUMO

Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against α-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of α-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-α-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-α-enolase/low anti-annexin AI IgG2 and patients with low anti-α-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-α-enolase IgG2 recognized specific epitopes of α-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human α-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against α-enolase and annexin AI predominate in the glomerulus and can be detected in serum.


Assuntos
Anexina A1/imunologia , Biomarcadores Tumorais/imunologia , Proteínas de Ligação a DNA/imunologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Fosfopiruvato Hidratase/imunologia , Proteínas Supressoras de Tumor/imunologia , Adolescente , Adulto , Animais , Anexina A1/isolamento & purificação , Autoanticorpos/sangue , Autoanticorpos/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/isolamento & purificação , Biópsia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/isolamento & purificação , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Camundongos SCID , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/isolamento & purificação , Proteômica , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/isolamento & purificação , Adulto Jovem
11.
Health Care Manage Rev ; 40(4): 324-36, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25120195

RESUMO

BACKGROUND: The problem of interest in this study is the challenge of consistent implementation of evidence-based infection prevention practices at the unit level, a challenge broadly characterized as "change implementation failure." The theoretical literature suggests that periodic top-down communications promoting tacit knowledge exchanges across professional subgroups may be effective for enabling change in health care organizations. However, gaps remain in understanding the mechanisms by which top-down communications enable practice change at the unit level. Our study sought to both validate the theoretical literature and address this gap. PURPOSE: Correspondingly, this study posed two research questions. (1) What is the impact of periodic "top-down" communications on practice change at the unit level? (2) What are the "unit-level" communication dynamics enabling practice changes? Whereas this article focuses on addressing the first question, the second question has been addressed in an earlier Health Care Management Review article (Rangachari et al., 2013). METHODS: A prospective study was conducted in two intensive care units at an academic health center. Both units had low baseline adherence to central line bundle (CLB) and higher-than-expected catheter-related bloodstream infections (CRBSIs). Periodic top-down communication interventions were conducted over 52 weeks to promote CLB adherence in both units. Simultaneously, the study examined (a) unit-level communication dynamics related to CLB through weekly "communication logs," completed by unit physicians, nurses, and managers, and (b) unit outcomes, that is, CLB adherence and CRBSI rates. FINDINGS: Both units showed increased adherence to CLB and significant, sustained declines in CRBSIs. Results showed that the interventions cumulatively had a significant negative (desired) impact on "catheter days," that is, central catheter use. PRACTICE IMPLICATIONS: Results help validate the theoretical literature and identify evidence-based management strategies for practice change at the unit level. They suggest that periodic top-down communications have the potential to modify interprofessional knowledge exchanges and enable practice change at the unit level, leading to significantly improved outcomes and reduced costs.


Assuntos
Infecções Relacionadas a Cateter/prevenção & controle , Comunicação , Controle de Infecções/organização & administração , Centros Médicos Acadêmicos , Prática Clínica Baseada em Evidências , Humanos , Unidades de Terapia Intensiva , Inovação Organizacional , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Prospectivos
12.
Health Care Manage Rev ; 40(1): 65-78, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24153028

RESUMO

BACKGROUND: Many hospitals are unable to consistently implement evidence-based practices. For example, implementation of the central line bundle (CLB), known to prevent catheter-related bloodstream infections (CRBSIs), is often challenging. This problem is broadly characterized as "change implementation failure." PURPOSE: The theoretical literature on organizational change has suggested that periodic top-down communications promoting tacit knowledge exchanges across professional subgroups may be effective for enabling learning and change in health care organizations. However, gaps remain in understanding the mechanisms by which top-down communications enable practice change at the unit level. Addressing these gaps could help identify evidence-based management strategies for successful practice change at the unit level. Our study sought to address this gap. METHODS: A prospective study was conducted in two intensive care units within an academic health center. Both units had low baseline adherence to CLB and higher-than-expected CRBSIs. Periodic top-down quality improvement communications were conducted over a 52-week period to promote CLB implementation in both units. Simultaneously, the study examined (a) the content and frequency of communication related to CLB through weekly "communication logs" completed by unit physicians, nurses, and managers and (b) unit outcomes, that is, CLB adherence rates through weekly chart reviews. FINDINGS: Both units experienced substantially improved outcomes, including increased adherence to CLB and statistically significant (sustained) declines in both CRBSIs and catheter days (i.e., central line use). Concurrently, both units indicated a statistically significant increase in "proactive" communications-that is, communications intended to reduce infection risk-between physicians and nurses over time. Further analysis revealed that, during the early phase of the study, "champions" emerged within each unit to initiate process improvements. PRACTICE IMPLICATIONS: The study helps identify evidence-based management strategies for successful practice change at the unit level. For example, it underscores the importance of (a) screening each unit for change champions and (b) enabling champions to emerge from within the unit to foster change implementation.


Assuntos
Unidades de Terapia Intensiva/organização & administração , Gestão do Conhecimento , Inovação Organizacional , Infecções Relacionadas a Cateter/prevenção & controle , Comunicação , Prática Clínica Baseada em Evidências/organização & administração , Humanos , Estudos Prospectivos
13.
Ann Rheum Dis ; 73(10): 1888-97, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23897774

RESUMO

OBJECTIVE: Accumulation of mitochondria underlies T-cell dysfunction in systemic lupus erythematosus (SLE). Mitochondrial turnover involves endosomal traffic regulated by HRES-1/Rab4, a small GTPase that is overexpressed in lupus T cells. Therefore, we investigated whether (1) HRES-1/Rab4 impacts mitochondrial homeostasis and (2) Rab geranylgeranyl transferase inhibitor 3-PEHPC blocks mitochondrial accumulation in T cells, autoimmunity and disease development in lupus-prone mice. METHODS: Mitochondria were evaluated in peripheral blood lymphocytes (PBL) of 38 SLE patients and 21 healthy controls and mouse models by flow cytometry, microscopy and western blot. MRL/lpr mice were treated with 125 µg/kg 3-PEHPC or 1 mg/kg rapamycin for 10 weeks, from 4 weeks of age. Disease was monitored by antinuclear antibody (ANA) production, proteinuria, and renal histology. RESULTS: Overexpression of HRES-1/Rab4 increased the mitochondrial mass of PBL (1.4-fold; p=0.019) and Jurkat cells (2-fold; p=0.000016) and depleted the mitophagy initiator protein Drp1 both in human (-49%; p=0.01) and mouse lymphocytes (-41%; p=0.03). Drp1 protein levels were profoundly diminished in PBL of SLE patients (-86±3%; p=0.012). T cells of 4-week-old MRL/lpr mice exhibited 4.7-fold over-expression of Rab4A (p=0.0002), the murine homologue of HRES-1/Rab4, and depletion of Drp1 that preceded the accumulation of mitochondria, ANA production and nephritis. 3-PEHPC increased Drp1 (p=0.03) and reduced mitochondrial mass in T cells (p=0.02) and diminished ANA production (p=0.021), proteinuria (p=0.00004), and nephritis scores of lupus-prone mice (p<0.001). CONCLUSIONS: These data reveal a pathogenic role for HRES-1/Rab4-mediated Drp1 depletion and identify endocytic control of mitophagy as a treatment target in SLE.


Assuntos
GTP Fosfo-Hidrolases/sangue , Lúpus Eritematoso Sistêmico/sangue , Proteínas Associadas aos Microtúbulos/sangue , Mitocôndrias/metabolismo , Proteínas Mitocondriais/sangue , Proteínas rab4 de Ligação ao GTP/fisiologia , Animais , Autofagia/fisiologia , Estudos de Casos e Controles , Células Cultivadas , Difosfonatos/uso terapêutico , Dinaminas/sangue , Dinaminas/fisiologia , Feminino , GTP Fosfo-Hidrolases/fisiologia , Homeostase/fisiologia , Humanos , Células Jurkat , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lisossomos/metabolismo , Camundongos Endogâmicos MRL lpr , Proteínas Associadas aos Microtúbulos/fisiologia , Proteínas Mitocondriais/fisiologia , Mitofagia/imunologia , Terapia de Alvo Molecular/métodos , Piridinas/uso terapêutico , Linfócitos T/metabolismo
14.
J Immunol ; 189(11): 5434-41, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23109726

RESUMO

CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.


Assuntos
Autoanticorpos/biossíntese , Autoimunidade , Antígenos CD59/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Anemia Hemolítica/genética , Anemia Hemolítica/imunologia , Animais , Anticorpos/farmacologia , Antígenos CD59/genética , Complemento C3/deficiência , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/antagonistas & inibidores , Complemento C5/genética , Complemento C5/imunologia , Dermatite/genética , Dermatite/imunologia , Dermatite/patologia , Feminino , Expressão Gênica , Hemoglobinúria/genética , Hemoglobinúria/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Proteinúria/genética , Proteinúria/imunologia , Proteinúria/patologia , Fatores Sexuais , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-25722732

RESUMO

Nephritis as a result of autoimmunity is a common morbidity associated with Systemic Lupus Erythematosus (SLE). There is substantial clinical and industry interest in medicinal intervention in the SLE nephritic process; however, clinical trials to specifically treat lupus nephritis have not resulted in complete and sustained remission in all patients. Multiple mouse models have been used to investigate the pathologic interactions between autoimmune reactivity and SLE pathology. While several models bear a remarkable similarity to SLE-driven nephritis, there are limitations for each that can make the task of choosing the appropriate model for a particular aspect of SLE pathology challenging. This is not surprising given the variable and diverse nature of human disease. In many respects, features among murine strains mimic some (but never all) of the autoimmune and pathologic features of lupus patients. Although the diversity often limits universal conclusions relevant to pathogenesis, they provide insights into the complex process that result in phenotypic manifestations of nephritis. Thus nephritis represents a microcosm of systemic disease, with variable lesions and clinical features. In this review, we discuss some of the most commonly used models of lupus nephritis (LN) and immune-mediated glomerular damage examining their relative strengths and weaknesses, which may provide insight in the human condition.

16.
Front Med (Lausanne) ; 11: 1381123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38813376

RESUMO

Meningitis caused by Acinetobacter species is a rare complication of neurosurgical procedures, although it is associated with high morbidity and mortality. Carbapenem-resistant Acinetobacter is particularly difficult to treat, considering the limited selection and tolerability of effective antimicrobials. Sulbactam-durlobactam was approved by the FDA in 2023 for treatment of hospital-acquired and ventilator-associated pneumonia due to susceptible strains of Acinetobacter, including carbapenem-resistant Acinetobacter baumannii. Here, we present a case of carbapenem-resistant Acinetobacter baumannii neurosurgical infection and meningitis successfully treated with sulbactam-durlobactam combination therapy.

17.
Am J Physiol Renal Physiol ; 304(5): F463-70, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23283994

RESUMO

We postulated that prostaglandin E2 (PGE2), which exhibits regulatory functions to control immune-mediated inflammation, fibrosis, oxidative stress, and tissue/cellular regeneration, has the potential to improve the course of nephritis. Therefore, the therapeutic potential of prostanoid on established nephritis in mice was evaluated focusing on its role on renal cellular recovery, with emphasis on its cytoprotecting and growth-promoting effects. Acute nephritis was induced in mice by single injection of nephrotoxic serum (NTS), followed by PGE2 administration with severity of nephritis evaluated over time. Mice injected with PGE2 recovered promptly with normalization of blood urea nitrogen and urine protein levels and histology. Recovery was observed with dosing of prostanoid at day 1, as well as day 4. With the use of selective EP1-4 receptor agonists, EP3 receptor has been identified as important in mediating beneficial effects of PGE2 in our system. PGE2 normalized glomerular cell losses during nephrotoxic serum-induced nephritis, restored synaptopodin distribution and F-actin filaments arrangement in glomeruli. In cell culture, PGE2 reduced nephrotoxim serum (NTS)-induced apoptosis of glomerular cells and promoted cell reproliferation after NTS-mediated injury. In conclusion, PGE2 treatment promotes resolution of glomerular inflammation. Consistent with this observation, the regenerative and cytoprotective effects of prostanoid on glomerular cells in culture were observed, suggesting that PGE2 may be beneficial in the treatment of glomerulonephritis.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Nefrite/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Dinoprostona/farmacologia , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Camundongos , Nefrite/induzido quimicamente , Nefrite/metabolismo , Nefrite/patologia , Índice de Gravidade de Doença , Sinaptofisina/metabolismo
18.
Kidney Int ; 84(2): 403-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23515049

RESUMO

Progressive kidney disease is a significant clinical problem. However, despite research aimed toward developing improved predictors of disease, the major tool to assess kidney ultrastructure damage is the kidney biopsy. Here we tested the capability of a labeled human monoclonal antibody (F1.1), directed against the NC1 domain of α3(IV) collagen, to detect pathologic kidney alterations in vivo using mouse models of nephrotoxic serum-induced nephritis and puromycin aminoglycoside nephrosis. The F1.1 antibody-fluorophore conjugate signal rapidly localized specifically to injured glomeruli in both the severe and mild kidney disease models while minimally labeling healthy kidney. This differential labeling is likely due to cryptic NC1-domain exposure as enzymatic or chemical treatment of healthy human or mouse kidney sections significantly increased F1.1 binding to the glomeruli. Finally, kidney tissue from patients with renal disease show significant glomerular staining by F1.1 indicating that exposure of the NC1 domain occurs in clinically relevant circumstances. Thus, NC1 domain exposure may represent an in situ biomarker for assessment of kidney injury. Our study suggests that F1.1 and similar antibodies may represent a new class of non-invasive renal imaging reagents.


Assuntos
Anticorpos Monoclonais , Autoantígenos/análise , Colágeno Tipo IV/análise , Glomérulos Renais/química , Nefrite/diagnóstico , Nefrose/diagnóstico , Adolescente , Adulto , Idoso , Animais , Autoantígenos/imunologia , Biomarcadores/análise , Criança , Colágeno Tipo IV/imunologia , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Humanos , Imuno-Histoquímica , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Nefrite/induzido quimicamente , Nefrite/imunologia , Nefrite/metabolismo , Nefrose/induzido quimicamente , Nefrose/imunologia , Nefrose/metabolismo , Valor Preditivo dos Testes , Estrutura Terciária de Proteína , Puromicina , Índice de Gravidade de Doença , Fatores de Tempo , Adulto Jovem
19.
Arthritis Rheum ; 64(10): 3399-408, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22674120

RESUMO

OBJECTIVE: To analyze the mechanism for the therapeutic effects of tumor necrosis factor α (TNFα) inhibition in a murine model of systemic lupus erythematosus. METHODS: We used the (NZB × NZW)F(1) (NZB/NZW) mouse model of interferon-α-induced lupus nephritis and treated mice with TNF receptor type II (TNFRII) Ig after TNFα expression was detected in the kidneys. Autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), and autoantibody- forming cells were determined using an enzyme-linked immunospot assay. Activation of splenocytes was analyzed by flow cytometry. Kidneys were harvested and analyzed using flow cytometry, immunohistochemistry, ELISA, Western blotting, and real-time polymerase chain reaction. RESULTS: TNFRII Ig treatment stabilized nephritis and markedly prolonged survival. Autoantibody production and systemic immune activation were not inhibited, but the renal response to glomerular immune complex deposition was attenuated. This was associated with decreases in renal production of chemokines, renal endothelial cell activation, interstitial F4/80(high) macrophage accumulation, tubular damage, and oxidative stress. In contrast, perivascular lymphoid aggregates containing B cells, T cells, and dendritic cells accumulated unabated. CONCLUSION: Our data suggest that TNFα is a critical cytokine that amplifies the response of the nephron to immune complex deposition, but that it has less influence on the response of the systemic vasculature to inflammation.


Assuntos
Complexo Antígeno-Anticorpo/efeitos dos fármacos , Rim/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Modelos Animais de Doenças , Interferon-alfa , Rim/imunologia , Rim/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo
20.
J Immunol ; 187(3): 1506-13, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21705616

RESUMO

The critical role of IFN-α in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-α in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL-6, and TNF-α, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-α-accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-α challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of short-lived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-α renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus.


Assuntos
Cruzamentos Genéticos , Imunidade Inata/imunologia , Interferon-alfa/efeitos adversos , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Abatacepte , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Autoanticorpos/biossíntese , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/biossíntese , Fator Ativador de Células B/sangue , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Imunidade Inata/genética , Imunoconjugados/uso terapêutico , Interferon-alfa/administração & dosagem , Óperon Lac/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos NZB , Proteínas Recombinantes de Fusão/uso terapêutico , Recidiva
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