A Preliminary Study On The D-galactose Induced Aging Rats Model Of Sepsis

Background: Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. The disparity between clinical and basic studies is a problem,and this is likely due,in part, to the fact that most laboratory animals used for sepsis research are not old while the majority of sepsis cases occur in the geriatric population. Recently, the D-galactose (D-gal)-induced mimetic aging rat model has been widely used in studies of age-associated diseases, which have shown that chronic D-gal exposure induces premature aging similar to natural aging in rats. Therefore,establisheda sepsis model in D-gal-induced aging rats may serve as a suitable model for preclinical studies of elderly patients with sepsis.Objective: 1. To investigate the mortality, inflammatory response, organ function and physiologic parameters of sepsis following caecal ligation and puncture (CLP) in D-gal-induced aging rats; 2. To explore the association with sepsis in the elderly.Methods: This study involves two parts. 1. Twelve-week-old male Sprague-Dawley rats were divided into low-dose D-gal (L D-gal, 125 mg/kg/d), high-dose D-gal(H D-gal, 500 mg/kg/d) and control groups. After daily subcutaneous injection of D-gal for six weeks, we measured MDA level and SOD activity, and also observed the organ function and physiologic parameters. 2. The CLP method was used to establish a sepsis model on the D-gal induced aging rats.And the mortality, inflammatory response,organ function,microRNA-155 and physiologic parameters were compared among the three groups.Results: 1. MDA level and SOD activity were measured after daily subcutaneous injection of D-gal for six weeks, and significant differences were found among the three groups (H D-gal vs. control, P<0.01 for MDA and SOD; L D-gal vs. control, P<0.01 for MDA and SOD; H D-gal vs. L D-gal, P=0.017 for MDA, P=0.034 for SOD; 2. The mortality was 73.3%, 40% and 33.3% in the H D-gal, L D-gal and control groups, respectively; 3. Blood urea nitrogen, creatinine, plasma neutrophil gelatinase-associated lipocalin, interleukin-6,interleukin-10, tumor necrosis factor-a and microRNA-155 were markedly increased in the H D-gal group after establishment of the sepsis model (H D-gal vs. control, P<0.05 at 12 h and 24 h post-CLP); 4. The rate of severe AKI (RIFLE-F) at 24 h post-CLP was 43% for both the control and L D-gal groups and 80% for the H D-gal group; 5. The H D-gal group was more likely to suffer lower systolic pressure, heart rateand hypothermiaafter establishment of the sepsis model.Conclusion: High-dose-D-gal-induced aging rats are more likely to die from sepsis than are young rats, and probability this is associated with increased severity of septic AKI and an increased inflammatory response. Therefore, use of the high-dose-D-gal-induced aging rat model of sepsis for preclinical studies can provide more useful information for the treatment of sepsis in elderly patients.