Keratinocyte growth factor improves epithelial function after massive small bowel resection

Abstract

BACKGROUND: Massive small bowel resection with subsequent short bowel syndrome (SBS) leads to the acute loss of epithelial cell (EC) absorptive function. Keratinocyte growth factor (KGF) has been shown to improve EC growth, although little is known about KGF activity on EC function after SBS. We hypothesized that KGF would improve epithelial function in a mouse SBS model. METHODS: Adult C57BL/6J mice were randomized to a 55% mid-small bowel resection (SBS), SBS with KGF administration (SBSKGF), or sham-operated (Control) group, and were killed at 7 days. Ussing chambers were used to study epithelial function. Short circuit current (Isc) was monitored. EC absorption was studied by measuring (1) glucose [3-O-methyl-D-[1-3H]glucose (3-OMG)] absorption; (2) sodium coupled amino acid (alanine) absorption; and (3) changes in Isc by using the absorptive agent D-glucose (stimulated Na+ absorption). Epithelial barrier function was measured with transepithelial resistance (TER) and transmural passage of 3H-mannitol (Papp). ECs were separated along the crypt-villus axis with laser capture microdissection. Epithelial KGF receptor (KGFR) mRNA expression was studied using real time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: KGF administration increased the basic ion transport activity and net transepithelial absorption of 3-OMG and sodium-coupled alanine absorption. SBS significantly decreased epithelial ion transport, including the Na+ absorption stimulated by D-glucose and L-alanine. KGF administration partially improves Na+ absorption. KGF had no apparent effect on the TER and 3H-mannitol permeability in this study. KGF upregulated EC KGFR mRNA expression, predominately in the crypt and lower portion of the villus. CONCLUSIONS: KGF administration improves epithelial absorptive function and stimulates intestinal proliferation after SBS. This suggests that KGF improves intestinal adaptation after SBS and may have clinical applicability.

IV administration of KGF significantly increased intestinal epithelial proliferation in a mouse short bowel syndrome model. KGF administration also improved epithelial nutrient absorption and upregulated epithelial cell KGF receptor expression.