Rosiglitazone protects against severe hemorrhagic shock-induced organ damage in rats

Abstract

SummaryBackgroundHemorrhagic shock (HS) followed by resuscitation can induce the production of several inflammatory mediators and lead to multiple organ dysfunction. The molecular mechanism of biologic responses to rosiglitazone has an anti-inflammatory effect. The present study was designed to investigate the effects of rosiglitazone on physiopathology and inflammatory mediators after HS in rats.Material/MethodsHS was induced in rats by withdrawing 60% of the total blood volume from a femoral artery catheter, immediately followed by intravenous injection of 0.3 mg/kg rosiglitazone. Mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 12 h. Levels of biochemical parameters, including GOT, GPT, BUN, Cre, LDH, CPK, and lactate were measured at 30 min before induction of HS and 0, 1, 3, 6, 9, and 12 h after HS, while an equal volume of normal saline was replaced as fluid resuscitation. Inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), were measured in serum at 1 and 12 h after HS. The kidneys, liver, lungs, and small intestine were removed for histological assessment by hematoxylin and eosin stained at 48 h after HS.ResultsHS significantly increased blood GOT, GPT, BUN, Cre, LDH, CPK, lactate, glucose, TNF-α, IL-6 and MCP-1 levels, induced tachycardia, and decreased mean arterial pressure (MAP) in rats. Treatment with rosiglitazone improved survival rate, decreased the markers of organ injury, and suppressed the release of TNF-α, IL-6, and MCP-1 after HS in rats.ConclusionsTreatment with rosiglitazone suppresses the release of serum TNF-α, IL-6 and MCP-1, and ameliorates HS-induced organ damage in rats.

Mechanisms responsible for beneficial and adverse effects of rosiglitazone in a rat model of acute cardiac ischaemia–reperfusion

“…Supporting this suggestion is the finding that rosiglitazone did not prevent the cardiac mitochondrial dysfunction caused by ischaemia–reperfusion injury, because the level of cardiac mitochondrial ROS production, the mitochondrial membrane potential change and mitochondrial swelling were not different between the saline‐ and rosiglitazone‐treated group. In addition to its anti‐apoptotic effect, previous studies have demonstrated that rosiglitazone exerts an anti‐inflammatory effect and decreases the inflammatory cytokine TNF‐α (Shah et al 2005; Yang et al 2011). Moreover, previous studies have shown that the inflammatory process also plays a role in determining the size of infarct formed in the heart (Irwin et al 1999; Gu et al 2006).…”

Bretschneider Solution and Two Antianginal Drugs Protect Peripheral Tissue in an Animal Model of Hemorrhagic Shock

“…Renal tubular injury was scored by estimating the percentage of tubules in the cortex or the outer medulla that showed epithelial necrosis or had luminal necrotic debris, tubular dilation, and hemorrhage: 0, none; 1, <5%; 2, 5%–25%; 3, 25%–75%; and 4, >75%. 19 Small intestine injury was scored from 0 to 3 as follows: 0, normal (no damage); 1, mild (focal epithelial edema and necrosis); 2, moderate (diffuse swelling or necrosis of the villi); and 3, severe (diffuse necrosis of the villi with evidence of neutrophil infiltration in the submucosa and/or hemorrhage). 19 Liver injury was scored as follows: 0, no or minimal evidence of injury; 1, mild (cytoplasmic vacuolation and focal nuclear pyknosis); 2, moderate (extensive nuclear pyknosis, cytoplasmic hypereosinophilia, and loss of intercellular borders); and 3, severe (necrosis with disintegration of the hepatic cords, hemorrhage, and neutrophil infiltration).…”

“…19 Small intestine injury was scored from 0 to 3 as follows: 0, normal (no damage); 1, mild (focal epithelial edema and necrosis); 2, moderate (diffuse swelling or necrosis of the villi); and 3, severe (diffuse necrosis of the villi with evidence of neutrophil infiltration in the submucosa and/or hemorrhage). 19 Liver injury was scored as follows: 0, no or minimal evidence of injury; 1, mild (cytoplasmic vacuolation and focal nuclear pyknosis); 2, moderate (extensive nuclear pyknosis, cytoplasmic hypereosinophilia, and loss of intercellular borders); and 3, severe (necrosis with disintegration of the hepatic cords, hemorrhage, and neutrophil infiltration). 19 Heart injury was scored from 0 to 3 in each of the following items (5 items, maximum score of 15): cell necrosis, presence of polymorphonucleocytes and eosinophils, loss of cross striation, edema, and microscopic bleeding.…”

A narrative review of prehospital hemorrhagic shock treatment with non‐blood product medications

“…Pathologic samples reviewed by a blinded researcher also found less evidence of end organ damage (lung, small intestine, liver, kidney), and laboratory testing confirmed lower inflammatory markers. 37 This study followed a similar murine model which utilized ciglitazone and reported improved MAP and lactate levels, with lower levels of inflammatory markers and reduced pathology evidence of lung injury, though they did not report a survival benefit. 39 A study from 2004 did report a survival benefit as well as similarly reduced signals of end organ dysfunction and systemic inflammation in rats treated with 1 mg/kg intraperitoneal rosiglitazone following shock produced by administration of the drug zymosan.…”

“…Activation of peroxisome proliferator-activated receptors (PPARs) regulates the inflammatory response, with PPAR-γ specifically repressing gene transcription by interfering with the NF-κB signaling pathway, and decreasing the expression of TNF-α, IL-6 and MCP-1 among other inflammatory markers. 37,38 Rosiglitazone given to rats at 0.3 mg/kg IV following onset of hemorrhagic shock conferred a survival benefit in a group of eight rats (75% vs. 50% of untreated controls). Pathologic samples reviewed by a blinded researcher also found less evidence of end organ damage (lung, small intestine, liver, kidney), and laboratory testing confirmed lower inflammatory markers.…”