title: 4-Phenylbutyric Acid Reveals Good Beneficial Effects on Vital Organ Function via Anti-Endoplasmic Reticulum Stress in Septic Rats.
abstract: Sepsis and septic shock are the common complications in ICUs. Vital organ function disorder contributes a critical role in high mortality after severe sepsis or septic shock, in which endoplasmic reticulum stress plays an important role. Whether anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to sepsis and the underlying mechanisms are not known.
  
  
  
  Laboratory investigation.
  
  
  
  State Key Laboratory of Trauma, Burns and Combined Injury.
  
  
  
  Sprague-Dawley rats.
  
  
  
  Using cecal ligation and puncture-induced septic shock rats, lipopolysaccharide-treated vascular smooth muscle cells, and cardiomyocytes, effects of 4-phenylbutyric acid on vital organ function and the relationship with endoplasmic reticulum stress and endoplasmic reticulum stress-mediated inflammation, apoptosis, and oxidative stress were observed.
  
  
  
  Conventional treatment, including fluid resuscitation, vasopressin, and antibiotic, only slightly improved the hemodynamic variable, such as mean arterial blood pressure and cardiac output, and slightly improved the vital organ function and the animal survival of septic shock rats. Supplementation of 4-phenylbutyric acid (5 mg/kg; anti-endoplasmic reticulum stress), especially administered at early stage, significantly improved the hemodynamic variables, vital organ function, such as liver, renal, and intestinal barrier function, and animal survival in septic shock rats. 4-Phenylbutyric acid application inhibited the endoplasmic reticulum stress and endoplasmic reticulum stress-related proteins, such as CCAAT/enhancer-binding protein homologous protein in vital organs, such as heart and superior mesenteric artery after severe sepsis. Further studies showed that 4-phenylbutyric acid inhibited endoplasmic reticulum stress-mediated cytokine release, apoptosis, and oxidative stress via inhibition of nuclear factor-κB, caspase-3 and caspase-9, and increasing glutathione peroxidase and superoxide dismutase expression, respectively.
  
  
  
  Anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to septic shock. This beneficial effect of 4-phenylbutyric acid is closely related to the inhibition of endoplasmic reticulum stress-mediated oxidative stress, apoptosis, and cytokine release. This finding provides a potential therapeutic measure for clinical critical conditions, such as severe sepsis.
authors.affiliation: All authors: State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, P.R. China.
authors.forename: Liangming
authors.initials: L
authors.lastname: Liu
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
authors.forename: JiaTao
authors.initials: J
authors.lastname: Zang
authors.forename: Guangming
authors.initials: G
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Lan
authors.forename: Tao
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005979:Glutathione Peroxidase / Q000096:biosynthesis; D006439:Hemodynamics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology; D016328:NF-kappa B / Q000096:biosynthesis; D063305:Organ Dysfunction Scores; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D020169:Caspases