The Genetic Background of Hypertensive, Septic Rats Determines Outcome Improvement With Antibiotic and G-CSF Prophylaxis

Abstract

Hypertension is proposed as a risk factor among others (high age, diabetes mellitus, and pre- and intraoperative bleeding) for adverse outcomes, such as severe infections, leading to sepsis and to multiple organ failure as the most deleterious complication. Hypertension was modeled with spontaneous hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats and the infective complication by polymicrobial, peritoneal contamination, and infection (PCI). The concept of clinic modeling randomized trials was used to simulate clinical complexity, including a relevant antibiotic prophylaxis in combination with granulocyte-colony stimulating factor (G-CSF) and clinical trial conditions. Outcome parameters were: survival, systemic cytokines (protein), and organ-specific cytokine levels (mRNA). With low complexity (no prophylaxis), 28% of the animals in the Wistar and 50% in the SHR group survived (P=0.17). Tumor necrosis factor-alpha levels were lower in the liver of SHR vs. Wistar rats with PCI (P<0.01). The anti-inflammatory cytokine interleukin (IL)-10 was expressed on a higher level in SHR with PCI compared with Wistar rats (P<0.01). With increased complexity (antibiotic and G-CSF prophylaxis) the survival rate was increased from 50% in Wistar rats to 89% in SHR (P<0.01) and the mRNA expression of IL-6 was decreased in the kidney of SHR (P<0.05). Survival rate was 44% in the DS rats vs. 67% of the Wistar rats (P=0.18). The mRNA expression of tumor necrosis factor-alpha and IL-10 was reduced (P<0.01) by pretreatment in the liver of DS rats with PCI. The hypertensive, genetically distinct SHR and DS rats express different patterns of pro- and anti-inflammatory cytokine levels after PCI. G-CSF and antibiotic prophylaxis increases only in SHR survival and decreases IL-6 mRNA expression in the kidney significantly.

Dependence of Positive Effects of Granulocyte Colony‐stimulating Factor on the Antibiotic Regimen: Evaluation in Rats with Polymicrobial Peritonitis

“…These bactericidal functions are further enhanced by suppression of normal granulocyte apoptosis [14]. Several other studies support our results [15, 16, 17], reporting beneficial effects of G‐CSF in septic animals [18, 19, 20].…”

Fever induction by systemic stimulation with macrophage-activating lipopeptide-2 depends upon TLR2 but not CD36

“…45,46 It was also reported that the expression of IL-10, which is an antipyretic cytokine, 22 is stronger in bacterially-infected SHRs compared with WKY rats. 47 Taken together, these data from literature suggest that there are several possibilities to explain the reduced fever of SHRs seen in our experiments, in addition to the moderate reduction of circulating IL-6. We are unable to decide which one of the proposed mechanisms is the strongest operator for the attenuation of fever in SHR, but a significant participation of the lack of CD36 is, in our eyes, rather unlikely.…”

Genetic Background Influences the Propagation of Tau Pathology in Transgenic Rodent Models of Tauopathy

“…In the end, the rat lines were developed based on an SHR or Wistar-Kyoto background, and the two lines are genetically different (H'Doubler et al, 1991). Interestingly, chronic inflammation in SHR probably causes an altered reaction to acute immune challenges (Bernard et al, 1998;Bauhofer et al, 2003). The SHR rats demonstrated resistance to LPS stimuli and had better survival rates than the Wistar-Kyoto counterparts.…”