title: Delayed Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Inhibition by Trametinib Attenuates Systemic Inflammatory Responses and Multiple Organ Injury in Murine Sepsis.
abstract: 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.
  
  
  
  Controlled in vivo laboratory study.
  
  
  
  University animal research laboratory.
  
  
  
  Male C57BL/6 mice.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1Department of Medicine, University of Colorado Denver, Aurora, CO. 2Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR. 3Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Smith
authors.forename: Philip R
authors.initials: PR
authors.lastname: Mayeux
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018805:Sepsis
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D012333:RNA, Messenger; C560077:trametinib; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases