Abstract:
OBJECTIVE:The mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway is an essential component of innate immunity necessary for mediating proinflammatory responses in the setting of sepsis. We previously demonstrated that the mitogen-activated protein kinase 1/2 inhibitor trametinib prevents endotoxin-induced renal injury in mice. We therefore assessed efficacy of trametinib in a more clinically relevant experimental model of sepsis. DESIGN:Controlled in vivo laboratory study. SETTING:University animal research laboratory. SUBJECTS:Male C57BL/6 mice. INTERVENTIONS:Mice were subjected to cecal ligation and puncture to induce sepsis or underwent sham operation as controls. Six hours after cecal ligation and puncture, mice were randomized to four experimental groups as follows: 1) sham control; 2) sham control + trametinib (1 mg/kg, IP); 3) cecal ligation and puncture; and 4) cecal ligation and puncture + trametinib. All animals received buprenorphine (0.05 mg/kg, SC) and imipenem/cilastatin (14 mg/kg, SC) in 1.5 mL of warm saline (40 mL/kg) at the 6-hour time point. Mice were euthanized at 18 hours after induction of cecal ligation and puncture. MEASUREMENTS AND MAIN RESULTS:Trametinib inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling 6 hours after cecal ligation and puncture attenuated increases in circulating proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, and granulocyte macrophage colony-stimulating factor) and hypothermia at 18 hours. Trametinib also attenuated multiple organ injury as determined by serum creatinine, alanine aminotransferase, lactate dehydrogenase, and creatine kinase. At the organ level, trametinib completely restored peritubular capillary perfusion in the kidney. Restoration of microvascular perfusion was associated with reduced messenger RNA expression of well-characterized markers of proximal tubule injury. mitogen-activated protein kinase/extracellular signal-regulated kinase blockade attenuated cecal ligation and puncture-mediated up-regulation of cytokines (tumor necrosis factor-α, interleukin-1β) and restored interleukin-6 to control levels in the renal cortex, indicating the protective effects on the proximal tubule occur primarily through modulation of the proinflammatory response in sepsis. CONCLUSIONS:These data reveal that the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor trametinib attenuates systemic inflammation and multiple organ damage in a clinically relevant model of sepsis. Because trametinib has been safely used in humans, we propose that this drug might represent a translatable approach to limit organ injury in septic patients.
journal_name
Crit Care Medjournal_title
Critical care medicineauthors
Smith JA,Mayeux PR,Schnellmann RGdoi
10.1097/CCM.0000000000001672subject
Has Abstractpub_date
2016-08-01 00:00:00pages
e711-20issue
8eissn
0090-3493issn
1530-0293journal_volume
44pub_type
杂志文章abstract:OBJECTIVE:The pathogenesis of acute gastric stress ulceration in the seriously ill is uncertain, and any role of Helicobacter pylori infection is unknown. We aimed to assess the relationship between H. pylori serological status and stress ulceration in seriously ill patients, as well as H. pylori serological status in ...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199907000-00010
更新日期:1999-07-01 00:00:00
abstract:OBJECTIVE:Spread of multidrug-resistant organisms within the intensive care unit (ICU) results in substantial morbidity and mortality. Novel strategies are needed to reduce transmission. This study sought to determine if the use of daily chlorhexidine bathing would decrease the incidence of colonization and bloodstream...
journal_title:Critical care medicine
pub_type: 杂志文章,多中心研究
doi:10.1097/CCM.0b013e31819ffe6d
更新日期:2009-06-01 00:00:00
abstract:OBJECTIVE:To investigate the interrelationship between cardiac surgery, age, circulating concentrations of the vitamin D hormone 1,25-dihydroxyvitamin D, and clinical outcome. DESIGN:Prospective, monocentric, two-arm parallel study. SETTING:Tertiary Heart and Diabetes Center in the Federal State of North Rhine-Westph...
journal_title:Critical care medicine
pub_type: 临床试验,杂志文章
doi:10.1097/CCM.0b013e31824e8c42
更新日期:2012-07-01 00:00:00
abstract:OBJECTIVE:In critically ill patients, hepatic dysfunction is regarded as a late organ failure associated with poor prognosis. We investigated the incidence and prognostic implications of early hepatic dysfunction (serum bilirubin >2 mg/dL within 48 hrs of admission). DESIGN:Prospective, multicenter cohort study. SETT...
journal_title:Critical care medicine
pub_type: 杂志文章,多中心研究
doi:10.1097/01.CCM.0000259462.97164.A0
更新日期:2007-04-01 00:00:00
abstract:BACKGROUND:Hemorrhage in trauma is a significant challenge, accounting for 30% to 40% of all fatalities, second only to central nervous system injury as a cause of death. However, hemorrhagic death is the leading preventable cause of mortality in combat casualties and typically occurs within 6 to 24 hrs of injury. In c...
journal_title:Critical care medicine
pub_type: 杂志文章,评审
doi:10.1097/CCM.0b013e31817e2ec5
更新日期:2008-07-01 00:00:00
abstract:OBJECTIVE:To alert health professionals to the need for early detection and prevention of shock in critically ill patients. By describing the associations between intramucosal acidosis in the gut and multiple system organ failure, the author demonstrates how noninvasive measurement of gut intramucosal pH can be used to...
journal_title:Critical care medicine
pub_type: 杂志文章,评审
doi:10.1097/00003246-199302001-00017
更新日期:1993-02-01 00:00:00
abstract:OBJECTIVES:To identify the prevalence, risk factors, and outcomes of intra-abdominal hypertension in a mixed multicenter ICU population. DESIGN:Prospective observational study. SETTING:Fifteen ICUs worldwide. PATIENTS:Consecutive adult ICU patients with a bladder catheter. INTERVENTIONS:None. MEASUREMENTS AND MAIN...
journal_title:Critical care medicine
pub_type: 杂志文章,多中心研究
doi:10.1097/CCM.0000000000003623
更新日期:2019-04-01 00:00:00
abstract:OBJECTIVE:To examine the hypothesis that heat stress applied after the administration of bacterial endotoxin is protective. DESIGN:Prospective, randomized, laboratory study. SETTING:University research laboratory. SUBJECTS:One hundred eleven adult male Sprague-Dawley rats (weight range 250 to 400 g). INTERVENTIONS:...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199710000-00025
更新日期:1997-10-01 00:00:00
abstract:BACKGROUND:We have previously described a method for the precise delivery of inhaled nitric oxide (iNO) via a conventional, continuous-flow, pressure-limited, time-cycled ventilator. Because of the augmented effect of iNO decreasing pulmonary vascular resistance with high-frequency oscillatory ventilation (HFOV), we de...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199911000-00038
更新日期:1999-11-01 00:00:00
abstract:OBJECTIVES:The aim of this study was to evaluate the relative frequency of pediatric in-hospital cardiopulmonary resuscitation events occurring in ICUs compared to general wards. We hypothesized that the proportion of pediatric cardiopulmonary resuscitation provided in ICUs versus general wards has increased over the p...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0b013e31828cf0c0
更新日期:2013-10-01 00:00:00
abstract:OBJECTIVE:The acute respiratory distress syndrome may complicate postpartum hemorrhagic shock and resuscitation, but its mechanisms are not yet well defined. We studied the lung inflammatory response to postpartum hemorrhagic shock and resuscitation in a rabbit model and the role of the nuclear factor-κB pathway. DESI...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0b013e3182451c17
更新日期:2012-05-01 00:00:00
abstract:OBJECTIVE:To assess whether paralysis alters pulmonary deposition of albuterol delivered by metered dose inhaler and spacer to small animals. DESIGN:A parallel group study of intubated and ventilated rabbits. INTERVENTIONS:Animals in group 1 (n = 7) were paralyzed with intravenous pancuronium, and ventilated at a rat...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199701000-00026
更新日期:1997-01-01 00:00:00
abstract:OBJECTIVES:To compare 1-year all-cause mortality and major adverse cardiovascular events in cardiac arrest survivors with and without posttraumatic stress disorder symptomatology at hospital discharge. DESIGN:Prospective, observational cohort. SETTING:ICUs at a tertiary-care center. PATIENTS:Adults with return of sp...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0000000000003713
更新日期:2019-06-01 00:00:00
abstract:OBJECTIVES:To determine whether aerosolized antibiotics can be delivered efficiently to the lower respiratory tract in mechanically ventilated patients and to define possible clinical responses to these agents. DESIGN:Prospective serial study with cases as their own control. SETTING:A 10-bed respiratory care unit for...
journal_title:Critical care medicine
pub_type: 临床试验,杂志文章
doi:10.1097/00003246-199801000-00013
更新日期:1998-01-01 00:00:00
abstract:OBJECTIVE:To determine the activation of nuclear factor-[kappa]B in peripheral blood CD14+ monocyte/macrophages and CD3+, CD4+, and CD8+ T cells in children with sepsis. DESIGN:Observational study. SETTING:University hospital. PATIENTS:Twenty-six children with sepsis (nine females and 17 males, aged between 10 days ...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/01.ccm.0000284502.38701.e6
更新日期:2007-10-01 00:00:00
abstract:OBJECTIVE:To determine daily amino acid and total protein losses in patients with acute renal failure receiving total parenteral nutrition (TPN) during treatment by continuous arteriovenous hemofiltration with hemodialysis (CAVHD). DESIGN:Prospective, nonrandomized study. SETTING:Patients in the ICU of a regional nep...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199112000-00012
更新日期:1991-12-01 00:00:00
abstract:OBJECTIVES:In patients with acute hypoxemic respiratory failure, noninvasive ventilation and high-flow nasal cannula oxygen are alternative strategies to conventional oxygen therapy. Endotracheal intubation is frequently needed in these patients with a risk of delay, and early predictors of failure may help clinicians ...
journal_title:Critical care medicine
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1097/CCM.0000000000002818
更新日期:2018-02-01 00:00:00
abstract:OBJECTIVE:To compare measurement of cardiac output by the CO2 rebreathing method vs. the thermodilution cardiac output technique in the setting of acute respiratory failure in patients with chronic obstructive pulmonary disease. DESIGN:Prospective, comparative study of two methods in a consecutive sample. SETTING:Int...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199401000-00017
更新日期:1994-01-01 00:00:00
abstract::Computerized gamma scintigraphy revealed a significant (p less than 0.001) rising lung:heart radioactivity ratio, which has been called "slope of injury" or "slope index", with both 99mTechnetium-tagged human serum albumin (99mTc-HSA) and 99mTechnetium-tagged red blood cells (99Tc-RBC) after 0.05 or 0.2 ml/kg iv oleic...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-198201000-00008
更新日期:1982-01-01 00:00:00
abstract::The hospital records of 7 patients with severe bronchopulmonary dysplasia (BPD) were reviewed. All patients were ventilator dependent for prolonged periods (mean duration intermittent mandatory ventilation (IMV) 14.3 +/- 3.5 months) but eventually were successfully weaned from mechanical ventilation and sent home. The...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-198112000-00001
更新日期:1981-12-01 00:00:00
abstract::End tidal CO2 tension (PetCO2) and transcutaneous CO2 tension (PtcCO2) were compared with arterial CO2 (PaCO2) before and after withdrawal of mechanical ventilation in 20 patients predisposed to hypercarbia. With stable PaCO2 during mechanical ventilation, the correlation coefficient (r) between PaCO2 and PetCO2 was ....
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-198708000-00011
更新日期:1987-08-01 00:00:00
abstract:OBJECTIVES:Fever is common and associated with increased mortality among patients admitted to adult ICUs, yet recent literature suggests that the incidence of fever may be decreasing. The objective of this study was to determine whether the incidence of fever in adult ICUs changed over time and the factors responsible ...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0b013e31828a43b2
更新日期:2013-08-01 00:00:00
abstract::Prolonged artificial ventilation may result in worsening gas exchange and pulmonary compliance in patients with otherwise normal lungs. Prolonged hyperinflations to 40 cm H2O can completely reverse deterioration of gas exchange and compliance in such patients. Similar efforts have effectively recruited atelectatic lun...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-198712000-00001
更新日期:1987-12-01 00:00:00
abstract:BACKGROUND:The early detection of bacterial meningitis is crucial for successful outcome. Heparin-binding protein, a potent inducer of increased vascular permeability, is released from activated neutrophils in severe sepsis. OBJECTIVE:In this study we investigated whether heparin-binding protein levels in cerebrospina...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0b013e318206c396
更新日期:2011-04-01 00:00:00
abstract:OBJECTIVE:To evaluate the in vivo production of prostacyclin and thromboxane A2 during the initial phase of experimental fat embolism as assessed, respectively, by determinations of urine 2,3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxane B2 excretion. DESIGN:Randomized, controlled trial. SETTING:Animal ...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-199707000-00025
更新日期:1997-07-01 00:00:00
abstract::Prolonged therapeutic paralysis with pancuronium is commonly used in ICUs to facilitate mechanical ventilation of patients with respiratory failure. Sedation is usually given concomitantly to reduce patient discomfort, but assessment of its adequacy is made difficult by the paralysis. We recently cared for a former IC...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/00003246-198401000-00018
更新日期:1984-01-01 00:00:00
abstract:OBJECTIVE:To assess the coping strategies used by family decision makers of adult critical care patients during and after the critical care experience and the relationship of coping strategies to posttraumatic stress symptoms experienced 60 days after hospitalization. DESIGN:A single-group descriptive longitudinal cor...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0000000000000934
更新日期:2015-06-01 00:00:00
abstract:OBJECTIVES:In this study, we evaluated the inflammatory response in patients with severe acute respiratory infection due to the Middle East respiratory syndrome and non-Middle East respiratory syndrome and assessed the presence of distinct inflammatory subphenotypes using latent class analysis. DESIGN:Prospective coho...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0000000000004724
更新日期:2021-02-01 00:00:00
abstract:OBJECTIVES:Cardiac arrest etiology may be an important source of between-patient heterogeneity, but the impact of etiology on organ injury is unknown. We tested the hypothesis that asphyxial cardiac arrest results in greater neurologic injury than cardiac etiology cardiac arrest (ventricular fibrillation cardiac arrest...
journal_title:Critical care medicine
pub_type: 杂志文章
doi:10.1097/CCM.0000000000003070
更新日期:2018-06-01 00:00:00
abstract:OBJECTIVE:Cocaine, which first made its appearance >1,000 yrs ago, is now widely used throughout the world. The physiologic responses to cocaine may cause severe pathologic effects. This review highlights the many critical care challenges resulting from these effects. DESIGN:Historical vignettes, epidemiologic factors...
journal_title:Critical care medicine
pub_type: 杂志文章,评审
doi:10.1097/01.CCM.0000063258.68159.71
更新日期:2003-06-01 00:00:00