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Identifier 000382672
Title The role of insulin resistance in sepsis induced acute lung ingury
Alternative Title Ο ρόλος της αντίστασης στην ινσουλίνη στην επαγόμενη από σήψη φλεγμονώδη αντίδραση του πνεύμονα
Author Θεοδωράκης, Εμμανουήλ
Thesis advisor Βαπορίδη, Αικατερίνη
Reviewer Τσατσάνης, Χρήστος
Ηλιόπουλος, Αριστείδης
Abstract Sepsis and ARDS are among the most common causes of morbidity and mortality in the ICU. Hyperinsulinaemia and insulin resistance are often present in ICU patients due to stress response, obesity or even due to insulin therapy. Macrophages are central mediators of inflammatory responses in sepsis, and insulin, among other metabolic factors, affects their function. Macrophages can present either with a pro-inflammatory (M1) activation phenotype or with an anti-inflammatory, alternative (M2) activation phenotype. Alternative macrophage activation is protective in animal models of acute inflammation. Our preliminary data imply that insulin affects macrophage phenotype and their responsiveness to pro-inflammatory insults. The aim of this study is to elucidate the impact of hyperinsulinaemia and HFD-induced insulin resistance on macrophage polarization and its effect on sepsis and secondary ARDS. Male C57BL/6 WT mice were fed normal diet (ND) or high fat diet (HFD, 60% fat) for 5 days or 8 weeks. Glucose tolerance was tested in vivo by serial glucose measurements after glucose loading (1mg/gr). HFD and ND-fed mice underwent cecal ligation and puncture (CLP) or sham operation. BAL fluid and cells, serum and lungs were collected 6h post-operatively. Protein, IL-6 and MIP2 were measured in BAL and insulin and cytokines were measured in serum. Histological analysis was performed in formalin-fixed paraffin embedded lung sections. Survival rate was monitored for 7 days in HFD and ND-fed mice subjected to CLP, treated with imipenem-cilastatin (500ug every 12 hours). Alveolar cells that were isolated from BAL fluid were stained for M1/M2 markers and were analyzed by FACS. Glucose tolerance was impaired in HFD-fed mice. This was the case, also, regarding insulin. Hyperinsulinemia was recorded after 8 weeks of HFD. Both results implement insulin 8 resistance. In vivo, CLP-induced mortality was slightly better for HFD-fed mice. BAL and Serum IL-6 and MIP2 were lower in HFD-fed mice than ND-fed mice which suggest a protective role of M2 macrophages in sepsis and ARDS. Lung histological analysis of all CLP mice demonstrated inflammatory cell infiltration and alveolar wall thickening, which were far less in extent in HFD-fed mice. FACS analysis of stained alveolar cells demonstrated an increase of Arg1 expression in HFD-fed mice, which implies M2 macrophages are prevalent in inflammation of HFD-fed mice. HFD promotes insulin resistance and alternative macrophage activation and reduces systemic and pulmonary inflammatory response to sepsis.
Language English
Issue date 2014-01-22
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/c/1/e/metadata-dlib-1393223135-543754-12577.tkl Bookmark and Share
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