Effects of the Peroxisome Proliferator-Activated Receptors (PPARs) Gamma Agonist on Cecal Ligation and Puncture-Induced Changes in Proinflammatory and Anti Inflammatory Cytokines, Nitric Oxide Production, Renal and Hepatic Injury
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- Category: Vol. 82, September 2014
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Effects of the Peroxisome Proliferator-Activated Receptors (PPARs) Gamma Agonist on Cecal Ligation and Puncture-Induced Changes in Proinflammatory and Anti Inflammatory Cytokines, Nitric Oxide Production, Renal and Hepatic Injury, HASSAN EISSA, LAILA RASHED, MOHAMMAD E. SALEH, SAMAR EL-SHEIKH and AHAMED F. NOFAL
Abstract
Objective: Sepsis is a disorder characterized by systemic inflammatory response caused by an infectious agent and may progress to multiple organ dysfunction and death. Overwhelm-ing inflammatory response is believed to underlie tissue damage and preceding multiple organ dysfunction syndrome. Thus, a therapeutic strategy to inhibit excessive inflammation in sepsis is needed. The nuclear receptor peroxisome prolif-erator-activated receptors (PPARs) gamma agonists exhibit anti-inflammatory properties in different immune cells. The aim of the present work is to study the effect of administration of PPARs gamma agonist, pioglitazone, on the production of proinflammatory cytokines (tumor necrosis factor-a [TNF-a] and interleukin-6 [IL-6]), anti-inflammatory cytokine (interleukin-10 [IL-10]), nitric oxide, and the changes in systolic blood pressure as well as renal injury (assessed by serum creatinine and histopathological examination) and hepatic injury (assessed by serum alanine aminotransferase activity) induced by cecal ligation and puncture model of sepsis.
Material and Methods: The study was carried out using 36 male albino rats belonging to the local strain. Rats were randomly divided into three groups, each contained 12 rats: Sham operated group (control group, group I), cecal ligation and puncture (CLP) group (CLP group, group II), and cecal ligation and puncture group with intraperitoneal injection of pioglitazone (CLP+pioglitazone, group III). Pioglitazone was injected intraperitoneally at a dose of 5mg/kg body weight 6 hours after CLP. At the end of the test period (18 hours), before animals were sacrificed, systolic blood pressure was measured and blood samples were withdrawn from retro-orbital plexus, serum was prepared and stored for biochemical analysis. One kidney was removed from each rat for histo-pathological examination for assessing acute renal injury.
Results: Cecal ligation and puncture (group II) produced, compared to control group, significant (p<0.05) increases in the mean values of serum levels of TNF-a, IL-6, IL-10, and total nitrite, an index of nitric oxide production. Systolic blood pressure significantly (p<0.05) decreased while the mean values of serum creatinine and histopathological score of acute kidney injury significantly (p<0.05) increased. Moreover, mean value serum alanine aminotransferase activity, an index of hepatocyte injury significantly (p<0.05) increased. Intrap-eritoneal injection of pioglitazone 6 hours after cecal ligation and puncture in rats (group III) at a dose of 5mg/kg, produced, compared to group II, significant (p<0.05) decreases in the mean values of serum levels of TNF-a, IL-6, and total nitrite, significant (p<0.05) increases in the mean values of serum levels of IL- 10, and systolic blood pressure. The mean values of serum creatinine, histopathological score of acute kidney injury, and serum alanine aminotransferase activity signifi-cantly (p<0.05) decreased compared to group II. Group III demonstrated, compared to control group, significant (p<0.05) increases in the mean values of serum levels of TNF-a, IL-6, IL- 10, and total nitrite. Systolic blood pressure significantly (p<0.05) decreased while the mean values of serum creatinine, histopatho logical score of acute kidney injury, and serum alanine aminotransferase activity significantly (p<0.05) in-creased.
Conclusion and Recommendations: Administration of pioglitazone, a PPAR gamma agonist, to rats subjected to cecal ligation and punctures decreased mortality, proinflam-matory cytokines production, increased anti-inflammatory cytokine production and systolic blood pressure, and decreased renal and hepatic injury compared to rats subjected to cecal ligation and punctures. Further studies will be needed to evaluate the effects of PPAR-gamma at different time intervals following sepsis and to understand the impact of enhancing PPAR-gamma activity before PPAR-gamma agonists can be considered in the treatment of sepsis.