Antireflux surgery normalizes cyclooxygenase-2 expression in
squamous epithelium of the distal esophagus.
¡P
Vallbohmer
D, DeMeester
SR, Banki
F, Kuramochi
H, Shimizu D,
Hagen JA, Danenberg
KD, Danenberg
PV, Chandrasoma
PT, Peters JH,
DeMeester
TR.
Department of Surgery, Keck School of Medicine,
University of Southern
California, Los Angeles, California, USA.
BACKGROUND: In some patients GERD presents with
heartburn and regurgitation symptoms but a relative paucity of endoscopic and clinical findings, while in others
symptoms may be minor or absent yet there is significant mucosal damage on endoscopy including the presence of Barrett's
esophagus. The initial injury of gastroesophageal
reflux is to the squamous esophageal mucosa, but
while substantial research has been devoted to determining which genes are
involved in the progression of Barrett's to dysplasia
and cancer, little is known about the gene expression alterations in the squamous mucosa of patients with reflux. We
hypothesized that the expression of cyclooxygenase-2 (Cox-2) might be
increased in the squamous esophageal mucosal of
patients with reflux, and might be a molecular indicator of reflux injury.
Further, we hypothesized that Cox-2 expression in the squamous
mucosa would be reduced following the elimination of reflux with an antireflux operation. METHODS: Biopsies of the distal
esophageal squamous mucosa were taken 3 cm above
the squamocolumnar junction (SCJ) in 28 GERD
patients before and after Nissen fundoplication. Following microdissection
and RNA isolation, quantitative real-time PCR was used to measure Cox-2 gene
expression in paraffin-embedded (N = 16) and fresh frozen (N = 12) tissue.
Biopsies from patients (paraffin N = 15, frozen N = 14) with normal acid
exposure and no evidence of mucosal injury were analyzed as controls.
RESULTS: Median Cox-2 expression in the squamous
epithelium from paraffin embedded biopsies in patients with reflux disease
was significantly increased compared to controls (p = 0.04). The presence
of esophagitis or Barrett's esophagus did not
significantly alter the expression of Cox-2 compared to patients with nonerosive reflux disease (NERD). After antireflux surgery median Cox-2 expression values were
significantly reduced (p = 0.0003) and were normalized to levels similar to
controls without reflux (p = 0.74). Similar results were observed in the
prospectively obtained fresh frozen tissue. CONCLUSIONS: Cox-2 gene
expression is increased in the distal esophageal squamous
mucosa of most patients with GERD, and the elevation was similar whether
there was mucosal injury in the form of esophagitis
or Barrett's or no visible mucosal injury. This suggests that increased
Cox-2 expression may serve as a molecular marker of reflux disease. The
increased Cox-2 expression in patients with reflux was usually normalized
following antireflux surgery. These findings
demonstrate for the first time that gene expression can be altered by
surgical correction of reflux. Thus, in addition to symptom control and
improvement in the quality of life, perhaps future studies assessing the
efficacy of antireflux therapy should also focus
on the impact of the therapy on gene expression in the esophageal squamous mucosa.
PMID: 16863546 [PubMed -
indexed for MEDLINE]
Human esophageal microvascular endothelial cells respond to acidic pH
stress by PI3K/AKT and p38 MAPK-regulated induction of Hsp70 and Hsp27.
¡P
Rafiee
P, Theriot
ME, Nelson VM,
Heidemann
J, Kanaa
Y, Horowitz SA,
Rogaczewski
A, Johnson CP,
Ali I, Shaker R, Binion
DG.
Dept. of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. prafiee@mcw.edu
The heat shock response maintains cellular homeostasis
following sublethal injury. Heat shock proteins (Hsps) are induced by thermal, oxyradical,
and inflammatory stress, and they chaperone
denatured intracellular proteins. Hsps also
chaperone signal transduction proteins, modulating signaling cascades
during repeated stress. Gastroesophageal reflux
disease (GERD) affects 7% of the US population, and it is linked to
prolonged esophageal acid exposure. GERD is characterized by enhanced and
selective leukocyte recruitment from esophageal microvasculature, implying
activation of microvascular endothelium. We
investigated whether phosphatidylinositol
3-kinase (PI3K)/Akt and MAPK regulate Hsp induction in primary cultures of human esophageal microvascular endothelial cells (HEMEC) in response to
acid exposure (pH 4.5). Inhibitors of signaling pathways were used to
define the contribution of PI3K/Akt and MAPKs in
the heat shock response and following acid exposure. Acid significantly
enhanced phosphorylation of Akt
and MAPKs in HEMEC as well as inducing Hsp27 and
Hsp70. The PI3K inhibitor LY-294002, and Akt small interfering RNA inhibited Akt
activation and Hsp70 expression in HEMEC. The p38 MAPK inhibitor
(SB-203580) and p38 MAPK siRNA blocked Hsp27 and
Hsp70 mRNA induction, suggesting a role for MAPKs
in the HEMEC heat shock response. Thus acidic pH exposure protects HEMEC
through induction of Hsps and activation of MAPK
and PI3 kinase pathway. Acidic exposure increased
HEMEC expression of VCAM-1 protein, but not ICAM-1, which may contribute to
selective leukocyte (i.e., eosinophil)
recruitment in esophagitis. Activation of
esophageal endothelial cells exposed to acidic refluxate
may contribute to GERD in the setting of a disturbed mucosal squamous epithelial barrier (i.e., erosive esophagitis, peptic ulceration).
