2002 Harry M. Vars Research Award. Keratinocyte growth factor stimulates the recovery of epithelial structure and function in a mouse model of total parenteral nutrition.
BACKGROUND
Keratinocyte growth factor (KGF) increases intestinal growth and is expressed by intestinal intraepithelial lymphocytes (IEL). Because total parenteral nutrition (TPN) leads to villus atrophy and a loss of epithelial function, we hypothesized that KGF administration could reverse these changes.


METHODS
Mice were randomized into three groups: oral feeding (Control); TPN; or TPN with recombinant human KGF. Mice were killed at 7 days, and the small bowel was harvested for histology, DNA, and protein content analysis. Epithelial cell proliferation was studied by 5-bromo-2-deoxyuridine (BrdU) incorporation, and apoptosis was detected by flow cytometry with Annexin V staining. Epithelial ion transport function was studied by Ussing chambers. Epithelial barrier function was assessed with transepithelial resistance and transmural passage of 3H-mannitol. Epithelial KGF receptors expression was studied by using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot.


RESULTS
TPN decreased intestinal DNA, protein content, villus height, and crypt cell proliferation. TPN also resulted in an increase in epithelial cell apoptosis. KGF administration significantly stimulated the recovery of mucosal structures including intestinal protein and DNA content, villus height, and crypt cell proliferation, and decreased epithelial apoptosis. KGF also up-regulate the epithelial KGF receptor expression. Moreover, KGF attenuated the TPN-induced increase in ion transport and increased the epithelial barrier function.


CONCLUSIONS
KGF administration reversed many of the adverse epithelial changes associated with TPN administration. Additionally, KGF up-regulated epithelial KGF receptor expression. It is possible that KGF may have a therapeutic efficacy in patients who are receiving TPN.
Yang
Hua
H
Department of Surgery, University of Michigan Medical School, C. S. Mott Children's Hospital, Ann Arbor, USA.
Wildhaber
Barbara
B
Tazuke
Yuko
Y
Teitelbaum
Daniel H
DH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D005434:Flow Cytometry; D006133:Growth Substances / Q000008:administration & dosage* / Q000378:metabolism*; D007410:Intestinal Diseases / Q000209:etiology* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000648:ultrastructure*; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000187:drug effects; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C496454:Fgf7 protein, mouse; D006133:Growth Substances; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor