RESUMO
Survival from traumatic injury requires a coordinated and controlled inflammatory and immune response. Mitochondrial and metabolic responses to stress have been shown to play a role in these inflammatory and immune responses. We hypothesized that increases in mitochondrial biogenesis via a sirtuin 1 agonist would decrease tissue injury and partially ameliorate the immunosuppression seen following trauma. C57Bl/6 mice were subjected to a multiple trauma model. Mice were pretreated with either 100 mg/kg per day of the sirtuin 1 agonist, Srt1720, via oral gavage for 2 days prior to trauma and extended until the day the animals were killed, or they were pretreated with peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) siRNA via hydrodynamic tail vein injection 48 h prior to trauma. Markers for mitochondrial function and biogenesis were measured in addition to splenocyte proliferative capacity and bacterial clearance. Srt1720 was noted to improve mitochondrial biogenesis, mitochondrial function, and complex IV activity following traumatic injury (P < 0.05), whereas knockdown of PGC1α resulted in exacerbation of mitochondrial dysfunction (P < 0.05). These changes in mitochondrial function were associated with altered severity of hepatic injury with significant reductions in serum alanine aminotransferase levels seen in mice treated with srt1720. Splenocyte proliferative capacity and intraperitoneal bacterial clearance were evaluated as markers for overall immune function following trauma-hemorrhage. Treatment with Srt1720 minimized the trauma-induced decreases in splenocyte proliferation (P < 0.05), whereas treatment with PGC1α siRNA led to diminished bacterial clearance. The PGC1α signaling pathway is an important regulator of mitochondrial function and biogenesis, which can potentially be harnessed to protect against hepatic injury and minimize the immunosuppression that is seen following trauma-hemorrhage.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/química , Choque Traumático/imunologia , Choque Traumático/terapia , Sirtuína 1/química , Alanina Transaminase/metabolismo , Animais , Proliferação de Células , Escherichia coli , Hidrodinâmica , Sistema Imunitário , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Peritônio/microbiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Baço/citologia , Fatores de Transcrição/químicaRESUMO
Clostridium difficile is increasing in both incidence and severity. Although metronidazole and vancomycin remain the gold standard for medical management, and surgical colectomy the gold standard for surgical management, new treatment alternatives, including the creation of a diverting loop ileostomy along with colonic lavage and vancomycin enemas, are being investigated that may lead to changes in the current treatment algorithms. The most exciting development in the treatment options for C difficile infection, however, is likely to be novel immunologic agents, which hold the potential to reduce the incidence, mortality, and costs associated with C difficile.
Assuntos
Clostridioides difficile , Enterocolite Pseudomembranosa , Antibacterianos/uso terapêutico , Clostridioides difficile/isolamento & purificação , Colectomia , Terapia Combinada , Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/etiologia , Enterocolite Pseudomembranosa/terapia , Humanos , Ileostomia , Recidiva , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Total knee arthroplasty (TKA) has become the predominant treatment modality for severe degenerative joint disease. With recent advancements in surgical and anesthetic technique, patients with severe comorbidities are able to have this procedure; they would have been precluded from TKA only a matter of years ago. Although many studies have investigated risk factors and the causes of perioperative morbidity and mortality in the arthroplasty patient, few have linked risk factors with specific outcomes. We present a case report that illustrates the link between the use of angiotensin-converting enzyme inhibitors and the development of postoperative acute kidney injury. While this relationship has been extensively studied in cardiac and gastric bypass patient populations, it has never been examined in the setting of joint replacement.
RESUMO
1. In the present study, we tested hypothesis that upregulation of hypoxia-inducible factor-1 (HIF-1) would improve the actions of positive inotropic agents in cardiac myocytes after simulated ischaemia-reperfusion (I/R). 2. Hypoxia-inducible factor-1α was upregulated with deferoxamine (150 mg/kg per day for 2 days). Rabbit cardiac myocytes were subjected to simulated ischaemia (15 min, 95% N(2)-5% CO2) and reperfusion (re-oxygenation) and compared with control myocytes. Cell contraction and calcium transients were measured at baseline and after forskolin (10(-7) and 10(-6) mol/L) or ouabain (10(-5) and 10(-4) mol/L). 3. Under control conditions, high-dose forskolin and ouabain increased percentage shortening by 20 and 18%, respectively. Deferoxamine-treated control myocytes responded similarly. In stunned myocytes, forskolin and ouabain did not significantly increase shortening (increases of 8% and 9%, respectively). Deferoxamine restored the effects of forskolin (+26%) and ouabain (+28%) in stunning. The results for maximum shortening and relaxation rates were similar. The increased calcium transients caused by forskolin and ouabain were also depressed in stunned myocytes, but were maintained by HIF-1 upregulation. 4. These results suggest that simulated I/R impaired the functional and calcium transient effects of positive inotropic agents. Upregulation of HIF-1 protects cardiac myocyte function after I/R by maintaining calcium release.
Assuntos
Cardiotônicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Contração Miocárdica/efeitos dos fármacos , Miocárdio Atordoado/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Animais , Antifúngicos/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Ciclopirox , Colforsina/farmacologia , Desferroxamina/farmacologia , Relação Dose-Resposta a Droga , Quelantes de Ferro/farmacologia , Miocárdio Atordoado/fisiopatologia , Miócitos Cardíacos/metabolismo , Ouabaína/farmacologia , Piridonas/farmacologia , Coelhos , Traumatismo por Reperfusão/fisiopatologia , Fatores de Tempo , Regulação para CimaRESUMO
Ischemia-reperfusion reduces the negative functional effects of cyclic GMP in cardiac myocytes. In this study, we tested the hypothesis that upregulation of hypoxic inducible factor-1 (HIF-1) would improve the actions of cyclic GMP signaling following simulated ischemia-reperfusion. HIF-1 alpha was increased with deferoxamine (150 mg/kg for 2 days). Rabbit cardiac myocytes were subjected to simulated ischemia [15 min 95% N(2)-5% CO(2)] and reperfusion [reoxygenation] to produce myocyte stunning. Cell function was measured utilizing a video-edge detector. Shortening was examined at baseline and after brain natriuretic peptide (BNP, 10(-8), 10(-7)M) or S-nitroso-N-acetyl-penicillamine (SNAP, 10(-6), 10(-5)M) followed by KT5823 (cyclic GMP protein kinase inhibitor, 10(-6)M). Kinase activity was measured via a protein phosphorylation assay. Under control conditions, BNP (-30%) and SNAP (-41%) reduced percent shortening, while KT5823 partially restored function (+18%). Deferoxamine treated control myocytes responded similarly. In stunned myocytes, BNP (-21%) and SNAP (-25%) reduced shortening less and KT5823 did not increase function (+2%). Deferoxamine increased the effects of BNP (-38%) and SNAP (-41%) in stunning and restored the effects of KT5823 (+12%). The cyclic GMP protein kinase increased phosphorylation of several proteins in control HIF-1 +/- cells. Phosphorylation was reduced in stunned cells and was restored in deferoxamine treated stunned cells. This study demonstrated that simulated ischemia-reperfusion reduced the negative functional effects of increasing cyclic GMP and this was related to reduced effects of the cyclic GMP protein kinase. Increased HIF-1 alpha protects the functional effects of cyclic GMP thorough maintenance of cyclic GMP protein kinase activity after ischemic-reperfusion.