Lone S. Bertelsen

Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells

Obesity is associated with increased levels of leptin. The mitogenic actions of leptin have been identified in various cell types. Because obesity may be a risk factor for colonic cancer, the proliferative and antiapoptotic effects of leptin on colonic cancer cells and the role of mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3‐K) signalling were investigated.

Salmonella Infection Induces a Hypersecretory Phenotype in Human Intestinal Xenografts by Inducing Cyclooxygenase 2

ABSTRACT Enteric Salmonella infection is accompanied by inflammation and diarrhea, and yet little is known about its effects on intestinal epithelial physiology. Since species differences limit the utility of animal tissues and cell lines lack relevant cell-cell interactions, we have used a human model of fetal intestine grown as xenografts in SCID mice. We investigated here the effects of Salmonellaenterica serovar Typhimurium SL1344 on xenograft ion transport. Harvested xenografts were stripped of seromuscular layers by blunt dissection, infected with Salmonella, and mounted in Ussing chambers. Salmonella infection for 1 h increased baseline ion transport without altering tissue conductance or morphology. The increased transport was blocked by the cyclooxygenase inhibitor, indomethacin, or the specific Cox-2 inhibitor, NS-398. Further, xenografts infected for 2 h showed increased secretory responses to the calcium-dependent agonist, carbachol, and the cyclic AMP-dependent agonists prostaglandin E2 (PGE2) and forskolin, which were blocked by indomethacin. Western blot experiments revealed that infection was accompanied by increased cyclooxygenase 2 (Cox-2) expression, with no change in Cox-1 levels. Immunoassay demonstrated basolateral PGE2 release, which was inhibited by indomethacin. Histological examination of infected xenografts illustrated that upregulated Cox-2 expression was restricted to the epithelium and that little or no invasion of the tissue by Salmonella occurred for up to 2 h. In summary, Salmonella infection rapidly increases Cox-2 expression in human intestinal tissue, accounting for increased epithelial ion transport characteristic of infectious diarrhea.

Hypertonic saline reduces neutrophil-epithelial interactions in vitro and gut tissue damage in a mouse model of colitis

Transepithelial migration of polymorphonuclear neutrophils (PMN) plays a crucial role in inflammatory conditions of the intestine, such as inflammatory bowel diseases. Hypertonic saline (HS) exerts various inhibitory effects on PMN function. We hypothesized that HS could inhibit transepithelial migration of PMN and thereby prevent inflammatory events in experimental colitis. Isolated human PMN were treated with HS (40 mM), and their transmigration across a monolayer of T84 epithelial cells was induced by N-formyl-methionyl-leucyl-phenylalanine. Monolayer disruption was assessed by monitoring changes in transepithelial conductance in an Ussing chamber. Colitis in mice was induced by oral administration of dextran sulfate sodium (DSS). Animals were treated with 4 or 8 ml/kg of 7.5% saline intraperitoneally two times daily for 7 days. Controls received equivalent volumes of normal saline (NS, n = 6) or no intraperitoneal treatment (DSS, n = 12). The severity of inflammation was evaluated based on disease activity index and histology score. HS treatment of PMN in vitro significantly reduced cell migration and the disruption of T84 monolayers compared with untreated control cells (n = 5, P < 0.05). This effect of HS was dose dependent. HS treatment in vivo also reduced colitis-induced gut tissue damage, as indicated by an improved histology score compared with the NS and DSS groups. We conclude that HS inhibits transepithelial migration of PMN in vitro and gut tissue damage in vivo in a mouse model of colitis. Thus HS may have clinical value to reduce PMN-mediated intestinal damage.