Extended liver resection after preoperative chemotherapy: influence on regeneration and endoplasmic reticulum stress response.
BACKGROUND
The increasing interest in preoperative chemotherapy (CH) of liver metastasis after colorectal carcinoma has focused surgical concerns on the influence of CH on hepatic tolerance during intraoperative ischemia. In this context, CH was described to lead to massive parenchyma harm but also to induce protective cascades initiated by stressed endoplasmic reticulum (ER). The aim of this study was to investigate whether ischemic resection after systemic CH affects liver regeneration and induces antiapoptotic mechanisms on the ER.


METHODS
Rats were randomized into two groups and treated either by intraperitoneally injected CH (n = 12) or saline (PL, n = 12); 24 h later, 2/3 of the liver was resected paired +/- Pringle's maneuver (PM) under general anesthesia. Tissue samples were taken from resected left-lateral lobe immediately and 24 h/7 days after the operation from the remaining proliferated right lobe. PCNA (Western blotting) and Ki67 (immunohistochemistry) were analyzed as proliferating markers. ER stress (elF2alpha, GRP78, cleaved caspase 3) was analyzed by Western blotting after 24 h.


RESULTS
Only the PL group without PM showed an increase in protein reactivity for PCNA and Ki67. During 7 days of observation, the livers regained weight steadily in both groups. An upregulation of cleaved caspase 3 as indicator for cellular apoptosis was detected in PL animals with PM compared to CH with PM; by contrast, elF2alpha and GRP78, as markers of ER stress-inducing protective mechanisms, were significantly augmented in CH with PM.


CONCLUSIONS
It is concluded that CH leads to a delay in liver regeneration but is no contraindication for ischemia. On the contrary, CH seems to cause a preconditioning of livers leading to the induction of antiapoptotic chaperones in our short-term model.
Manekeller
Steffen
S
Department of Surgery, Faculty of Medicine, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany. Steffen.Manekeller@ukb.uni-bonn.de
Seinsche
Alexandra
A
Sioutis
Maria
M
Hirner
Andreas
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology*; D006498:Hepatectomy / Q000379:methods*; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D018832:Molecular Chaperones / Q000502:physiology; D011300:Preoperative Care; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018832:Molecular Chaperones; C513196:PDIA3 protein, rat; D019704:Protein Disulfide-Isomerases