Gastrointestinal tract injury during pelvic irradiation is observed in clinical practice with an incidence of 5 to 50 % and the symptoms show a broad spectrum like diarrhoea, rectal pain, bleeding, stricture or fistulae3,4
. Reducing the acute side effects in radiotherapy increases the patients` quality of life and administering the normal tissue protectors during treatment is one possible way to diminish the acute effects of radiotherapy2,10,11
. In this experimental study, we used G-CSF, a glycoprotein that acts as a neutrophil precursor promoter, to protect the normal tissue, administering it prior to the occurrence of radiation-induced injury. We observed that G-CSF significantly decreased the radiation-induced erosion on the gastrointestinal mucosa of the terminal ileum. However, the pre-treatment had no protective effect on the rectal mucosa.
One of the probable reasons for this protective effect of G-CSF is its inhibitory effect on the inflammatory response, which is triggered by irradiation via the participation of the bacterial flora. The well-documented major early histological changes following irradiation on the intestines are inhibition of mitoses in crypts, epithelial denudation, cryptic distortion and enhanced signs of inflammation12. Studies showed that early responses to irradiation might be physiological and triggering inflammation through direct activation of NF-κB may begin before the structural damage occurs13-15. Furthermore, the studies on both irradiated and inflammatory bowel samples show similar acute epithelial barrier dysfunction and this evidence addressed that normal intestinal flora may trigger the inflammatory response on the first line mechanisms5,13. Even in the very early stages, only ultrastructural changes may be responsible for the injured epithelial barrier, promoting the normal flora to become pathogen, which then recruits the inflammatory mediators. Therefore, induction of neutrophil influx before bacterial translocation takes place may decrease the damage14. Ağalar et al.16 have shown in a haemorrhagic shock model that prophylactic G-CSF usage may diminish the bacterial translocation incidence. Although we did not measure the amount of bacterial translocation, our results suggest that prophylactic administration of G-CSF might protect the irradiated tissue against the invasion of pathogen microorganisms and the associated inflammatory process.
Ionising radiation and tissue interactions mostly includes oxidative stress. Radiation ionises water into reactive oxygen species (ROS) like OH˙ and H˙ and these agents are responsible for cell and tissue damage. This is called the `indirect effect`17. On the other hand, neutrophils carry and release mediators such as interleukin (IL)-8 and ROS on pathogens for effective killing. Although leukocyte infiltration and accumulation in irradiated normal tissues are well described, the main consequences of neutrophilic infiltration are still not known. It may be a reason for parenchymal damage and vascular injury18. In the current study, the prophylactic administration of G-CSF supported the maintenance of epithelial structure against ionising radiation, suggesting that further stimulation of tissue neutrophil accumulation by G-CSF in the intestine may protect against radiation-induced mucosal injury. It appears likely that G-CSF inhibits the translocation of bacterial flora, which may become pathogenic as the mucosal barrier is broken down by irradiation. Furthermore, neutrophil influx established by G-CSF may also be effective against ROS-induced mucosal damage due to irradiation.
The results of the present study confirm that G-CSF maintains the intestinal mucosal structure when given as a pre-treatment before irradiation of the pelvic area. G-CSF stimulates the production of white blood cells and it is used in certain cancer patients to accelerate recovery from neutropenia after chemotherapy, allowing higher-intensity treatment regimens. Thus, it may be also relevant to expect G-CSF to support the radiotherapy as an adjuvant therapeutic. Nevertheless, further studies are required to investigate the exact mechanisms responsible for the protective effects of G-CSF.