Hepatic stellate cells promote hepatocyte engraftment in rat liver after prostaglandin-endoperoxide synthase inhibition.
OBJECTIVE
Hepatic inflammation occurs immediately after cells are transplanted to the liver, but the mechanisms that underlie this process are not fully defined. We examined cyclooxygenase pathways that mediate hepatic inflammation through synthesis of prostaglandins, prostacyclins, thromboxanes, and other prostanoids following transplantation of hepatocytes.


METHODS
We transplanted F344 rat hepatocytes into syngeneic dipeptidyl peptidase IV-deficient F344 rats. Changes in cyclooxygenase pathways were analyzed, and specific pathways were blocked pharmacologically; the effects on cell engraftment and native liver cells were determined.


RESULTS
Transplantation of hepatocytes induced hepatic expression of prostaglandin-endoperoxide synthases 1 and 2, which catalyze production of prostaglandin H2, as well as the downstream factor thromboxane synthase, which produces thromboxane A2 (a regulator of vascular and platelet responses in inflammation). Transplanted hepatocytes were in proximity with liver cells that expressed prostaglandin-endoperoxide synthases. The number of engrafted hepatocytes increased in rats given naproxen or celecoxib before transplantation but not in rats given furegrelate (an inhibitor of thromboxane synthase) or clopodigrel (an antiplatelet drug). Naproxen and celecoxib did not prevent hepatic ischemia or activation of neutrophils, Kupffer cells, or inflammatory cytokines, but they did induce hepatic stellate cells to express cytoprotective genes, vascular endothelial growth factor and hepatocyte growth factor, and matrix-type metalloproteinases and tissue inhibitor of metalloproteinase-1, which regulate hepatic remodeling.


CONCLUSIONS
Activation of cyclooxygenase pathways interferes with engraftment of transplanted hepatocytes in the liver. Pharmacologic blockade of prostaglandin-endoperoxide synthases stimulated hepatic stellate cells and improved cell engraftment.
Enami
Yuta
Y
Department of Surgery, Showa University Hospital and School of Medicine, Shinagawa-ku, Tokyo, Japan.
Bandi
Sriram
S
Kapoor
Sorabh
S
Krohn
Natan
N
Joseph
Brigid
B
Gupta
Sanjeev
S
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D000068579:Celecoxib; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000637:transplantation*; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000166:cytology; D008297:Male; D009288:Naproxen / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D011336:Probability; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology
D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D009288:Naproxen; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib