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BACKGROUND & AIMS: The precise determination of non-alcoholic fatty liver disease (NAFLD) onset is challenging. Thus, the initial hepatic responses to fat accumulation, which may be fundamental to our understanding of NAFLD evolution and clinical outcomes, are largely unknown. Herein, we chronologically mapped the immunologic and metabolic changes in the liver during the early stages of fatty liver disease in mice and compared this with human NAFLD samples. METHODS: Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2-3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. RESULTS: We observed major immunologic changes in patients with NAS 2-3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult. CONCLUSION: The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections. LAY SUMMARY: Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease.
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BACKGROUND: The systemic antimicrobial prophylaxis is the standard treatment in the prevention of osteomyelitis after open fractures, with topical application of antimicrobials as an alternative due to their high concentrations at the site of the fracture, low systemic concentrations and fewer side effects. OBJECTIVES: This study aimed to evaluate the effectiveness of prophylaxis of osteomyelitis through experimental model of open fractures with the use of chitosan films, whether or not impregnated with ciprofloxacin. MATERIALS AND METHODS: In this experimental study, 24 Holtzman rats were distributed into 4 groups of 6 rats each. The CT (control of treatment) group: an open fracture model treated with systemic antimicrobial; the IC (infection control) group: an open fracture untreated model; the C (chitosan) group: an open fracture model treated using a chitosan film; and the CA (chitosan with antimicrobial) group: an open fracture model treated using a chitosan film impregnated with antimicrobial. After 3 weeks the animals were killed by an overdose of anesthetic, and a fragment osseous was removed for histological and microbiological analysis. The comparisons between the groups considered significant values of P ≤ 0.05. RESULTS: In cultures of the CT group, there was less bacterial growth compared to the results of the cultures of the IC (P = 0.005), C (P = 0.005) and CA (P = 0.009) groups. The inflammation was lower in the CT group compared to the IC (P = 0.014), C (P = 0.001) and CA (P = 0.007) groups. CONCLUSIONS: In this experimental model of open fracture, the chitosan film pure or impregnated with ciprofloxacin was not effective in the prophylaxis of osteomyelitis.