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1.
Urology ; 137: 146-151, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31887351

RESUMO

OBJECTIVE: To explore a series of classic bladder exstrophy (CBE) cases referred to the authors' institution where primary closure with penile disassembly epispadias repair was complicated by penile injury. The penile disassembly technique is frequently combined with bladder closure in patients with CBE undergoing the complete primary repair of exstrophy (CPRE). Penile disassembly has been posited as a risk for penile injury by ischemic mechanisms. METHODS: A prospectively-maintained institutional database of 1337 exstrophy-epispadias complex patients was reviewed for CPRE cases referred to the authors' institution, and those with injury to the penis were identified. The location, extent of injury, and subsequent management is reported. RESULTS: One hundred and thirteen male CBE patients were referred after prior CPRE. Twenty-six (20%) were identified with penile loss and reviewed. Eighty-one percent were closed in the neonatal period, and 54% had a pelvic osteotomy. Median follow-up time was 9.9 years (range 0.6-21.3). Of 26 patients with penile loss, 77% had unilateral loss and in 23% had bilateral loss involving the glans and/or one or both corpora cavernosa. Three patients were successfully managed with myocutaneous neophalloplasty. CONCLUSION: Complete penile disassembly during bladder exstrophy closure may lead to penile injury. This major complication questions the continued application of complete penile disassembly in the reconstruction of bladder exstrophy.


Assuntos
Extrofia Vesical/cirurgia , Epispadia/cirurgia , Complicações Intraoperatórias , Doenças do Pênis , Pênis , Procedimentos Cirúrgicos Urológicos , Atrofia , Criança , Humanos , Recém-Nascido , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/cirurgia , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Doenças do Pênis/diagnóstico , Doenças do Pênis/etiologia , Doenças do Pênis/cirurgia , Pênis/irrigação sanguínea , Pênis/lesões , Pênis/patologia , Pênis/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Reoperação/métodos , Fatores de Risco , Procedimentos Cirúrgicos Urológicos/efeitos adversos , Procedimentos Cirúrgicos Urológicos/métodos , Adulto Jovem
2.
J Urol ; 203(1): 200-205, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437120

RESUMO

PURPOSE: We investigated surgical approaches to urinary incontinence and long-term continence outcomes after successful bladder reconstruction in a heterogeneous patient population with classic bladder exstrophy. We hypothesized that while most patients will achieve urinary continence after surgery, only a select group will void volitionally per urethra. MATERIALS AND METHODS: An institutional database of 1,323 patients with exstrophy-epispadias complex was reviewed for patients with classic bladder exstrophy who underwent successful bladder closure and a subsequent continence procedure between 1975 and 2017. Procedures included bladder neck reconstruction, bladder neck reconstruction with augmentation cystoplasty or continent catheterizable stoma, and bladder neck closure with continent catheterizable stoma. Cloacal exstrophy, epispadias and variant exstrophy cases were excluded from analysis. Continence at last followup was defined as a dry interval of 3 or more hours without nighttime leakage. Those patients with more than 3 months of followup were assessed. RESULTS: Overall 432 patients underwent successful bladder closure (primary 71.5%, repeat 28.5%) and a urinary continence procedure. At last followup 162 (37%) underwent bladder neck reconstruction, 76 (18%) underwent bladder neck reconstruction with augmentation cystoplasty or continent catheterizable stoma, 173 (40%) underwent bladder neck closure with continent catheterizable stoma and 18 underwent other procedures. Median followup from the first continence procedure was 7.2 years (IQR 2.3-13.7). Continence was assessed in 350 patients. After isolated bladder neck reconstruction 91 of 142 patients were continent (64%, 95% CI 56-72). After bladder neck closure with continent catheterizable stoma 124 of 133 patients evaluated were continent (93%, 95% CI 87-97). CONCLUSIONS: Most patients with classic bladder exstrophy require multiple reconstructive procedures to achieve continence. Only about 25% of patients are expected to void normally per urethra without reliance on catheterization or urinary diversion.


Assuntos
Extrofia Vesical/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Incontinência Urinária/cirurgia , Procedimentos Cirúrgicos Urológicos/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino
3.
J Pediatr Surg ; 54(9): 1761-1765, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31003729

RESUMO

INTRODUCTION: A successful abdominal wall and bladder closure is critical in the management of cloacal exstrophy (CE). This study examines closure outcomes and practices over the last 4 decades at the authors' institution. Beginning in 1995, the authors' institution standardized CE closure and management with the Dual-Staged Pathway (DSP). The DSP consists of a staged bladder closure, a staged or concurrent osteotomy, and postoperative immobilization with external fixation. The authors hypothesize that the DSP has provided better outcomes in CE closures. METHODS: A prospective database of 1332 Exstrophy-Epispadias Complex (EEC) patients was reviewed for CE patients closed between 1975 and 2015. The DSP consists of a staged osteotomy and a staged bladder closure in CE patients with a diastasis greater than 4 cm. To evaluate the DSP, outcomes of closure at the authors' institution were compared between two equal, twenty-year periods before and after its implementation. Data on timing of closure, postoperative management, surgical complications, and outcomes were collected. RESULTS: There are 142 CE patients in the database. In this study, 49 CE patients with 50 closures met inclusion criteria. The overall success rate of closures from 1975 to 1994 was 88% (14 of 16), while the success rate of the DSP was 100% (n = 34), p = 0.098. Twenty-two (65%) primary and 12 (35%) secondary closures were performed using the DSP. Overall complication rates of the DSP remained similar to previous closures, (29% vs 19%, p = 0.508). Since incorporation of the DSP, patients referred for closure have generally had a larger preclosure diastasis (7.2 cm vs 5.1 cm, p = 0.011). CONCLUSION: The standardized DSP closure has proven successful in 34 primary and reoperative cloacal closures in the past 20 years. With this approach, the authors feel that the DSP offers greater patient safety and better outcomes. LEVEL OF EVIDENCE: Level III, retrospective comparative study.


Assuntos
Extrofia Vesical/cirurgia , Procedimentos Cirúrgicos Urológicos/métodos , Humanos , Estudos Retrospectivos
4.
Urol Case Rep ; 23: 101-102, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30740310

RESUMO

Circumcision is often the earliest surgery performed in a young male's life. Though complications in this procedure are rare, prolong postoperative bleeding may be the first sign of undiagnosed hemophilia. Hemophilia is a rare X-linked bleeding disorder and if not treated prophylactically or promptly during surgical intervention can be fatal. In this case presentation we describe the diagnosis of hemophilia in a child presenting with postoperative bleeding from circumcision. We review the literature regarding the history of this disease with early surgery and highlight the current treatments.

5.
Urology ; 125: 184-190, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30576745

RESUMO

OBJECTIVE: To investigate the diagnosis, surgical management, and outcomes in patients with variant EEC. Variant presentations of the exstrophy-epispadias complex (EEC) span a wide range of abnormalities. The rarity and diversity of EEC variants can lead to challenges in the diagnosis and subsequent management of this population. METHODS: The authors reviewed an institutional database of 1336 EEC patients from 1975 to 2018 for variant presentations of EEC. Variant presentations included those with skin covered bladder exstrophy (BE), duplicate bladders, superior vesical fistula, and epispadias with major bladder prolapse. Surgical management and outcomes were assessed. RESULTS: In total, 44 EEC variants were identified. Nineteen (43%) presented with a skin-covered BE variant. Five patients presented with duplicate BE, while 6 presented with superior vesical fistula. Fourteen patients (32%) presented with epispadias with major bladder prolapse. Overall, 36 (82%) EEC variants underwent primary bladder closure, at a median of 135 days after birth (range 1-2010), with 21 (58%) undergoing pelvic osteotomy. Primary closures were successful in 89% of cases. Continence procedures were performed in 17 patients. This includes 5 patients who underwent bladder augmentation. However even without a continence procedure, continence with volitional voiding was found in 8 patients. CONCLUSION: The most common EEC variant is the skin-covered form of BE. In order to expedite appropriate management, accurate diagnosis upon initial presentation is crucial. Still, successful surgical reconstruction often results in continence that is similar to, or better than, nonvariant EEC presentations.


Assuntos
Extrofia Vesical/diagnóstico , Extrofia Vesical/cirurgia , Epispadia/diagnóstico , Epispadia/cirurgia , Extrofia Vesical/classificação , Pré-Escolar , Epispadia/classificação , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fatores de Tempo , Resultado do Tratamento
6.
J Urol ; 200(6): 1354-1361, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29906437

RESUMO

PURPOSE: We used magnetic resonance imaging to define the innate pelvic neurovascular course and prostatic anatomy in infants with classic bladder exstrophy before the pelvis was altered by surgery. MATERIALS AND METHODS: Pelvic magnetic resonance imaging was performed in male infants with classic bladder exstrophy and compared to a group of age matched controls. Data collected included prostatic dimensions as well as course of the prostatic artery, periprostatic vessels and pudendal neurovasculature. RESULTS: The prostate was larger in the transverse (p <0.001) and anteroposterior (p <0.001) dimensions in patients with classic bladder exstrophy compared to those with normal prostates but was smaller in the craniocaudal dimension (p <0.001). This finding resulted in a larger calculated prostate volume in patients with classic bladder exstrophy compared to controls (p = 0.015). The pelvic vasculature and prostatic artery followed a similar course in patients with classic bladder exstrophy and controls. Relative to each other, the lateral to medial course of the prostatic arteries in males with classic bladder exstrophy was less pronounced than in normal males. A similar externally rotated pattern was seen when both sides of the pudendal vasculature were compared in males with classic bladder exstrophy. CONCLUSIONS: The prostate in infants with classic bladder exstrophy has a consistent configuration and dimensions that differ from those in normal infants. When both sides are compared, the periprostatic vasculature and penile sensory neurovascular bundles are externally rotated in infants with classic bladder exstrophy. However, these components course along the same landmarks as in normal patients.


Assuntos
Extrofia Vesical/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Pênis/diagnóstico por imagem , Próstata/diagnóstico por imagem , Pontos de Referência Anatômicos , Extrofia Vesical/cirurgia , Estudos de Casos e Controles , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Masculino , Pelve/irrigação sanguínea , Pelve/diagnóstico por imagem , Pênis/irrigação sanguínea , Período Pré-Operatório , Estudos Prospectivos , Próstata/irrigação sanguínea
7.
J Urol ; 200(4): 882-889, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29723567

RESUMO

PURPOSE: Understanding the distinct female anatomy in classic bladder exstrophy is crucial for optimal reconstructive and functional outcomes. We present novel quantitative anatomical data in females with classic bladder exstrophy before primary closure. MATERIALS AND METHODS: 3-Dimensional reconstruction was performed in patients undergoing pelvic magnetic resonance imaging, and pelvic anatomy was characterized, including measurements of the vagina, cervix and erectile bodies. RESULTS: We examined magnetic resonance imaging of 5 females (mean age 5.5 months) with classic bladder exstrophy and 4 age matched controls (mean age 5.8 months). Mean distance between the anal verge and vaginal introitus was greater in patients with classic bladder exstrophy (2.43 cm) than in controls (1.62 cm). Mean total vaginal length in patients with classic bladder exstrophy was half that of controls (1.64 cm vs 3.39 cm). All 4 controls had posterior facing cervical ora, while 4 of 5 females with exstrophy had anterior facing cervical ora located in the anterior vaginal wall. Lateral deviation of the cervical ora was also seen in all 5 patients with classic bladder exstrophy but in only 1 control. Clitoral body length was comparable in both groups (26.2 mm and 28.0 mm). However, the anterior cavernosa-to-posterior (pelvic rami associated) cavernosa ratio was much greater in patients with classic bladder exstrophy (6.4) compared to controls (2.5). CONCLUSIONS: This study uncovers the uniquely novel finding that contrary to their male counterparts, females with classic bladder exstrophy have the majority of the clitoral body anterior to the pelvic attachment. This discovery has surgical and embryological implications.


Assuntos
Extrofia Vesical/diagnóstico por imagem , Extrofia Vesical/cirurgia , Genitália Feminina/diagnóstico por imagem , Imageamento Tridimensional , Imagem por Ressonância Magnética/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Estudos de Casos e Controles , Feminino , Genitália Feminina/anatomia & histologia , Humanos , Lactente , Amostragem , Sensibilidade e Especificidade
8.
BMC Microbiol ; 17(1): 127, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28545489

RESUMO

BACKGROUND: Urinary tract infections (UTI) are among the most common and costly infections in both hospitalized and ambulatory patients. Uropathogenic E. coli (UPEC) represent the majority of UTI isolates and are a diverse group of bacteria that utilize a variety of virulence factors to establish infection of the genitourinary tract. The virulence factor cytotoxic necrotizing factor-1 (CNF1) is frequently expressed in clinical UPEC isolates. To date, there have been conflicting reports on the role of CNF1 in the pathogenesis of E. coli urinary tract infections. RESULTS: We examined the importance of CNF1 in a murine ascending kidney infection/ pyelonephritis model by performing comparative studies between a clinical UPEC isolate strain and a CNF1-deletion mutant. We found no alterations in bacterial burden with the loss of CNF1, whereas loss of the virulence factor fimH decreased bacterial burdens. In addition, we found no evidence that CNF1 contributed to the recruitment of inflammatory infiltrates in the kidney or bladder in vivo. CONCLUSIONS: While further examination of CNF-1 may reveal a role in UTI pathogenesis, our data casts doubt on the role of CNF-1 in the pathogenesis of UPEC UTI. As with other infections, different models and approaches are needed to elucidate the contribution of CNF1 to E. coli UTI.


Assuntos
Toxinas Bacterianas/metabolismo , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/metabolismo , Pielonefrite/microbiologia , Escherichia coli Uropatogênica/patogenicidade , Fatores de Virulência , Adesinas de Escherichia coli/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/genética , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Proteínas de Escherichia coli/genética , Feminino , Proteínas de Fímbrias/metabolismo , Humanos , Rim/microbiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Deleção de Sequência , Bexiga Urinária/microbiologia , Sistema Urinário/microbiologia , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/genética
9.
Urol Case Rep ; 13: 42-44, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28443240

RESUMO

Urinary continence can be achieved in up to 90% of patients with bladder exstrophy. However, select patients remain incontinent despite modern reconstruction. Repeat operations for continence combined with the congenital pelvic abnormalities of exstrophy put patients at risk for urinary fistula formation. We report the use of a rectus muscle flap in the repair of two concomitant vesicocutaneous and urethrocutaneous fistulae in a patient with classic bladder exstrophy.

10.
Curr Urol Rep ; 18(3): 21, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28233227

RESUMO

PURPOSE OF REVIEW: Ureteral duplication and ectopic upper pole ureters are commonly associated with renal pathology, including vesicoureteral reflux, obstruction, infection, and renal function loss. There remains no consensus on the most appropriate management of these complex patients. In this review, we sought to compare existing data on upper pole heminephrectomy with ipsilateral ureteroureterostomy. RECENT FINDINGS: Application of magnetic resonance imaging and minimally invasive techniques have led to changes in the diagnosis and treatment of ectopic upper pole ureters. Recent studies have highlighted the safety of laparoscopic and robot-assisted upper pole heminephrectomy and ureteroureterostomy. Minimally invasive approaches to ectopic upper pole ureters appear safe and effective, with complication rates remaining low. Minimally invasive upper pole heminephrectomy carries a higher risk of lower pole function loss. Both upper pole heminephrectomy and ureteroureterostomy carry a small risk of additional surgery on the bladder and remnant ureter.


Assuntos
Obstrução Ureteral/cirurgia , Procedimentos Cirúrgicos Urológicos , Humanos , Nefrectomia , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia , Refluxo Vesicoureteral/etiologia
11.
J Surg Res ; 203(2): 313-8, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27363638

RESUMO

BACKGROUND: Technetium-99m dimercaptosuccinic acid (DMSA) scans are often used in the evaluation of pediatric patients with febrile urinary tract infections (UTIs). Given the prevalence of febrile UTIs, we sought to quantify the cost, radiation exposure, and clinical utility of DMSA scans when compared with dedicated pediatric renal ultrasounds (RUSs). MATERIALS AND METHODS: An institutional review board approved retrospective study of children under the age of 18 years evaluated at our institution for febrile UTIs between the years 2004-2013 was conducted. The patients had to meet all of the following inclusion criteria: a diagnosis of vesicoureteral reflux, a fever >38°C, a positive urine culture, and evaluation with a DMSA scan and RUS. A chart review was used to construct a cost analysis of technical and professional fees, radiographic results, and radiation dose equivalents. RESULTS: Overall, 104 children met the inclusion criteria. A total of 122 RUS and 135 DMSA scans were performed. The technical costs of a DMSA scan incurred a 35% cost premium as compared to an RUS. The average effective radiation dose of a single DMSA scan was 2.84 mSv. New radiographic findings were only identified on 7% of those patients who underwent greater than 1 DMSA scan. CONCLUSIONS: The utility of the unique information acquired from a DMSA scan as compared to a RUS in the evaluation of febrile UTI must be evaluated on an individual case-by-case basis given the increased direct costs and radiation exposure to the patient.


Assuntos
Análise Custo-Benefício/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Exposição à Radiação/estatística & dados numéricos , Infecções Urinárias/diagnóstico por imagem , Infecções Urinárias/economia , Adolescente , Criança , Pré-Escolar , Feminino , Febre/etiologia , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Maryland , Cintilografia/economia , Compostos Radiofarmacêuticos/economia , Estudos Retrospectivos , Ácido Dimercaptossuccínico Tecnécio Tc 99m/economia , Ultrassonografia/economia , Infecções Urinárias/complicações
12.
J Pediatr Urol ; 12(5): 289.e1-289.e5, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27086261

RESUMO

PURPOSE: The authors have reviewed the use of muscle pedicle flaps for the treatment of failed bladder neck closure in exstrophy spectrum patients. METHODS: A retrospective review of all exstrophy spectrum patients who underwent continence procedures with the use of muscle pedicle flaps at our institution during the last 15 years was performed. Patient characteristics, surgical history, and outcomes, including complications, continence, morbidity, and infection, were assessed. The authors utilized muscle pedicle flaps in eight exstrophy patients, including four patients with classic bladder exstrophy and four patients with cloacal exstrophy. Seven of eight patients had failed at least one prior bladder neck closure, and they had undergone a median of three prior urologic procedures. To achieve continence, five rectus muscle flaps and three gracilis muscle flaps were utilized in combination with bladder neck closure. RESULTS: There were no major intraoperative or postoperative complications. All patients were initially continent, and after a median follow-up of 18.7 months seven of eight patients were continent. One patient required continent urinary stoma revision and one patient developed perineal incontinence after perineal trauma. No patients required revision of, or additional, continence procedures at the bladder neck. DISCUSSION: The use of pedicle muscle flaps appears to be a safe and feasible option for exstrophy spectrum patients with failed bladder neck closure. Although achieving continence can be difficult in this population, use of muscle flaps and bladder neck closure is a viable and effective option in this challenging subset of patients.


Assuntos
Extrofia Vesical/cirurgia , Retalhos Cirúrgicos , Criança , Humanos , Masculino , Reto do Abdome/transplante , Estudos Retrospectivos , Procedimentos Cirúrgicos Urológicos/métodos
13.
Urology ; 89: 129-31, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26724411

RESUMO

Bladder exstrophy is a rare major birth defect which requires specialized surgical care. Associated genitourinary tract anomalies are extremely rare in this population, yet significantly impact surgical planning and outcomes. In this case, a full-term newborn girl with a prenatal diagnosis of classic bladder exstrophy was found to have a complete duplicated left collecting system with an ectopic ureter inserted to urethral plate. The patient underwent modern staged repair of exstrophy with bilateral anterior innominate osteotomies and concomitant ureteral reimplantation-the first reported case of ureteral reimplantation at the time of initial closure in a newborn.


Assuntos
Anormalidades Múltiplas , Extrofia Vesical/complicações , Túbulos Renais Coletores/anormalidades , Ureter/anormalidades , Anormalidades Múltiplas/cirurgia , Extrofia Vesical/cirurgia , Feminino , Humanos , Recém-Nascido , Túbulos Renais Coletores/cirurgia , Ureter/cirurgia
14.
Ther Adv Urol ; 7(6): 378-87, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26622322

RESUMO

Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH). Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The 'androgen hypothesis' asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.

15.
Arterioscler Thromb Vasc Biol ; 31(1): 81-5, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20947824

RESUMO

OBJECTIVE: Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P), which activates G protein-coupled receptors to regulate vascular and immune cells. The role of S1P receptors in atherosclerosis has not been examined. METHODS AND RESULTS: We tested the hypothesis that S1P receptor-2 (S1PR2) regulates atherosclerosis. Apoe(-/-) S1pr2(-/-) mice showed greatly attenuated atherosclerosis compared with the Apoe(-/-) mice. Bone marrow transplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 is expressed in bone marrow-derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. Reduced macrophage-like foam cells were found in the atherosclerotic plaques of Apoe(-/-)S1pr2(-/-) mice, suggesting that S1PR2 retains macrophages in atherosclerotic plaques. Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow-derived macrophages were not altered by the S1pr2 genotype. In contrast, endotoxin-induced inflammatory cytokine (interleukin [IL]-1ß, IL-18) levels in the serum of S1PR2 knockout mice were significantly reduced. Furthermore, treatment of wild-type mice with S1PR2 antagonist JTE-013 suppressed IL-1ß and IL-18 levels in plasma. CONCLUSIONS: These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Transplante de Medula Óssea , Modelos Animais de Doenças , Endotoxinas , Inflamação/etiologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Lipídeos/sangue , Lipoproteínas/sangue , Lipoproteínas LDL/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Lisoesfingolipídeo/genética
16.
J Immunol ; 184(3): 1475-83, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20042570

RESUMO

Macrophage recruitment to sites of inflammation is an essential step in host defense. However, the mechanisms preventing excessive accumulation of macrophages remain relatively unknown. The lysophospholipid sphingosine 1-phosphate (S1P) promotes T and B cell egress from lymphoid organs by acting on S1P receptor 1 (S1P(1)R). More recently, S1P(5)R was shown to regulate NK cell mobilization during inflammation, raising the possibility that S1P regulates the trafficking of other leukocyte lineages. In this study, we show that S1P(2)R inhibits macrophage migration in vitro and that S1P(2)R-deficient mice have enhanced macrophage recruitment during thioglycollate peritonitis. We identify the signaling mechanisms used by S1P(2)R in macrophages, involving the second messenger cAMP and inhibition of Akt phosphorylation. In addition, we show that the phosphoinositide phosphatase and tensin homolog deleted on chromosome 10, which has been suggested to mediate S1P(2)R effects in other cell types, does not mediate S1P(2)R inhibition in macrophages. Our results suggest that S1P serves as a negative regulator of macrophage recruitment by inhibiting migration in these cells and identify an additional facet to the regulation of leukocyte trafficking by S1P.


Assuntos
Inibição de Migração Celular/imunologia , Regulação para Baixo/imunologia , Mediadores da Inflamação/fisiologia , Macrófagos/imunologia , Macrófagos/patologia , Peritonite/imunologia , Peritonite/patologia , Receptores de Lisoesfingolipídeo/fisiologia , Animais , Inibição de Migração Celular/genética , Células Cultivadas , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , AMP Cíclico/biossíntese , Regulação para Baixo/genética , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Peritonite/metabolismo , Fosforilação/genética , Fosforilação/imunologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Lisoesfingolipídeo/biossíntese , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Lisoesfingolipídeo/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Tioglicolatos/toxicidade , Regulação para Cima/genética , Regulação para Cima/imunologia
17.
J Clin Invest ; 119(12): 3530-43, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19884656

RESUMO

The RNA-binding protein HuR (also known as ELAV1) binds to the 3'-untranslated region of mRNAs and regulates transcript stability and translation. However, the in vivo functions of HuR are not well understood. Here, we report that murine HuR is essential for life; postnatal global deletion of Elavl1 induced atrophy of hematopoietic organs, extensive loss of intestinal villi, obstructive enterocolitis, and lethality within 10 days. Upon Elavl1 deletion, progenitor cells in the BM, thymus, and intestine underwent apoptosis, whereas quiescent stem cells and differentiated cells were unaffected. The survival defect of hematopoietic progenitor cells was cell intrinsic, as transplant of Elavl1-/- BM led to compromised hematopoietic reconstitution but did not cause lethality. Expression of p53 and its downstream effectors critical for cell death were induced in progenitor cells as HuR levels declined. In mouse embryonic fibroblasts, HuR bound to and stabilized the mRNA for Mdm2, a critical negative regulator of p53. Furthermore, cell survival was restored by expression of Mdm2 in Elavl1-/- cells, suggesting that HuR keeps p53 levels in check in progenitor cells and thereby promotes cell survival. This regulation of cell stress response by HuR in progenitor cells, which we believe to be novel, could potentially be exploited in cytotoxic anticancer therapies as well as stem cell transplant therapy.


Assuntos
Antígenos de Superfície/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Antígenos de Superfície/genética , Apoptose , Diferenciação Celular , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Feminino , Trato Gastrointestinal/citologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Deleção de Genes , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Tolerância a Radiação , Tamoxifeno/toxicidade , Quimeras de Transplante , Proteína Supressora de Tumor p53/metabolismo
18.
Biochim Biophys Acta ; 1781(9): 477-82, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18674637

RESUMO

Sphingosine 1-phosphate (S1P), a product of sphingomyelin metabolism, is enriched in the circulatory system whereas it is estimated to be much lower in interstitial fluids of tissues. This concentration gradient, termed the vascular S1P gradient appears to form as a result of substrate availability and the action of metabolic enzymes. S1P levels in blood and lymph are estimated to be in the muM range. In the immune system, the S1P gradient is needed as a spatial cue for lymphocyte and hematopoietic cell trafficking. During inflammatory reactions in which enhanced vascular permeability occurs, a burst of S1P becomes available to its receptors in the extravascular compartment, which likely contributes to the tissue reactions. Thus, the presence of the vascular S1P gradient is thought to contribute to physiological and pathological conditions. From an evolutionary perspective, S1P receptors may have co-evolved with the advent of a closed vascular system and the trafficking paradigms for hematopoietic cells to navigate in and out of the vascular system.


Assuntos
Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Transporte Biológico , Vasos Sanguíneos/metabolismo , Humanos , Receptores de Lisoesfingolipídeo/metabolismo , Serotonina/metabolismo , Esfingosina/metabolismo
19.
Circ Res ; 102(6): 669-76, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18258856

RESUMO

Sphingosine 1-phosphate (S1P), an abundant lipid mediator in plasma, regulates vascular and immune cells by activating S1P receptors. In this report, we investigated the mechanisms by which high plasma S1P levels are maintained in mice. We found that plasma S1P turns over rapidly with a half-life of approximately 15 minutes, suggesting the existence of a high-capacity biosynthetic source(s). Transplantation of bone marrow from wild-type to Sphk1(-/-)Sphk2(+/-) mice restored plasma S1P levels, suggesting that hematopoietic cells are capable of secreting S1P into plasma. However, plasma S1P levels were not appreciably altered in mice that were thrombocytopenic, anemic, or leukopenic. Surprisingly, reconstitution of Sphk1(-/-)Sphk2(+/-) bone marrow cells into wild-type hosts failed to reduce plasma S1P, suggesting the existence of an additional, nonhematopoietic source for plasma S1P. Adenoviral expression of Sphk1 in the liver of Sphk1(-/-) mice restored plasma S1P levels. In vitro, vascular endothelial cells, but not hepatocytes, secreted S1P in a constitutive manner. Interestingly, laminar shear stress downregulated the expression of S1P lyase (Sgpl) and S1P phosphatase-1 (Sgpp1) while concomitantly stimulating S1P release from endothelial cells in vitro. Modulation of expression of endothelial S1P lyase with small interfering RNA and adenoviral expression altered S1P secretion, suggesting an important role played by this enzyme. These data suggest that the vascular endothelium, in addition to the hematopoietic system, is a major contributor of plasma S1P.


Assuntos
Células da Medula Óssea/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Lisofosfolipídeos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Esfingosina/análogos & derivados , Adenoviridae/genética , Aldeído Liases/genética , Aldeído Liases/metabolismo , Anemia/sangue , Anemia/induzido quimicamente , Animais , Anticorpos Monoclonais , Células da Medula Óssea/enzimologia , Células da Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Endotélio Vascular/enzimologia , Vetores Genéticos , Meia-Vida , Humanos , Leucopenia/sangue , Fígado/enzimologia , Fígado/metabolismo , Lisofosfolipídeos/sangue , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenil-Hidrazinas , Monoéster Fosfórico Hidrolases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Esfingosina/sangue , Esfingosina/metabolismo , Estresse Mecânico , Trombocitopenia/sangue , Trombocitopenia/imunologia , Fatores de Tempo , Transdução Genética , Irradiação Corporal Total
20.
FEBS Lett ; 580(19): 4607-12, 2006 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-16876794

RESUMO

Sphingosine-1-phosophate, generated from the phosphorylation of sphingosine by sphingosine kinase enzymes, is suggested to function as an intracellular second messenger for inflammatory mediators, including formyl peptide, C5a, and Fc. More recently, a role for sphingosine kinases during inflammation has also been proposed. Here we show that sphingosine kinase 1 knockout mice exhibit normal inflammatory cell recruitment during thioglycollate-induced peritonitis and that sphingosine kinase 1-null neutrophils respond normally to formyl peptide. In the collagen-induced arthritis model of rheumatoid arthritis, sphingosine kinase 1 knockout mice developed arthritis with normal incidence and severity. Our findings show that sphingosine kinase 1 is dispensable for inflammatory responses and support the need for more extensive studies of sphingosine kinases in inflammation.


Assuntos
Inflamação/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Doença Aguda , Animais , Sequência de Bases , Doença Crônica , Primers do DNA , Masculino , Camundongos , Camundongos Knockout , N-Formilmetionina Leucil-Fenilalanina/metabolismo , NADPH Oxidases/metabolismo , Neutrófilos/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Transdução de Sinais
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