Prophylactic ciprofloxacin treatment prevented high mortality, and modified systemic and intestinal immune function in tumour-bearing rats receiving dose-intensive CPT-11 chemotherapy

Infectious complications are a major cause of morbidity and mortality from dose-intensive cancer chemotherapy. In spite of the importance of intestinal bacteria translocation in these infections, information about the effect of high-dose chemotherapy on gut mucosal immunity is minimal. We studied prophylactic ciprofloxacin (Cipro) treatment on irinotecan (CPT-11) toxicity and host immunity in rats bearing Ward colon tumour. Cipro abolished chemotherapy-related mortality, which was 45% in animals that were not treated with Cipro. Although Cipro reduced body weight loss and muscle wasting, it was unable to prevent severe late-onset diarrhoea. Seven days after CPT-11, splenocytes were unable to proliferate (stimulation index=0.10±0.02) and produce proliferative and inflammatory cytokines (i.e., Interleukin (IL)-2, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) IL-1β, IL-6) on mitogen stimulation in vitro (P<0.05 vs controls), whereas mesenteric lymph node (MLN) cells showed a hyper-proliferative response and a hyper-production of pro-inflammatory cytokines on mitogen stimulation. This suggests compartmentalised effects by CPT-11 chemotherapy on systemic and intestinal immunity. Cipro normalised the hyper-responsiveness of MLN cells, and in the spleen, it partially restored the proliferative response and normalised depressed production of IL-1β and IL-6. Taken together, Cipro prevented infectious challenges associated with immune hypo-responsiveness in systemic immune compartments, and it may also alleviate excessive pro-inflammatory responses mediating local gut injury

Prostaglandin regulation of colony-stimulating factor production by lipopolysaccharide-stimulated murine leukocytes.

The production of colony-stimulating factor by lipopolysaccharide-stimulated murine peritoneal leukocytes and their adherent subpopulations (greater than 80% macrophages) was markedly enhanced by indomethacin at concentrations sufficient to block prostaglandin E synthesis. Addition of physiological concentrations of E-series prostaglandins reversed this enhancing effect of indomethacin in a dose-dependent manner. These results indicate that colony-stimulating factor production by stimulated leukocytes is regulated by E-series prostaglandins and suggest that prostaglandins function to limit myelopoiesis by inhibiting colony-stimulating factor production and concomitantly the induction of cell proliferation

Treatment of experimental sepsis-induced immunoparalysis with TNF

Following a severe septic abdominal infection induced by sublethal cecal ligation and puncture (CLP) in mice, a phase of depressed immune reactivity occurred two days after CLP characterized by a reduced capacity to produce TNF. To determine whether this reduced TNF production causes immunoparalysis as determined by increased susceptibility to bacterial infection and whether therapeutic TNF substitution can be beneficial during this phase, a super-infection with Salmonella enterica Serovar typhimurium or Listeria monocytogenes was induced two days after sublethal CLP. After CLP a state of true immunoparalysis developed during which Salmonella or Listeria super-infection led to increased lethality paralleled by increased bacterial numbers in spleens and livers. Injection of recombinant human TNF before or at the time of super-infection conferred protection to Salmonella but not to Listeria. In the latter case, the infection mortality was even enhanced. Thus, super-infection during the state of sepsis-induced immunoparalysis leads to increased lethality. TNF substitution during this state of immunoparalysis can be beneficial or deleterious, depending on the location of TNF activity in the animal, timing of TNF administration, or the type of super-infection. These results demonstrate that impaired TNF production capacity can account for some aspects of immunoparalysis, however, diagnostic parameters are required for a safe TNF substitution therapy