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1 Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Medicine B, University of Munster, Munster, Germany
4 Transplant Surgery, MCW, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: prafiee{at}mcw.edu.
The heat shock response maintains cellular homeostasis following sub-lethal injury. Heat shock proteins (Hsp's) are induced by thermal, oxyradical and inflammatory stress, and chaperone denatured intracellular proteins. Hsps also chaperone signal transduction proteins, modulating signaling cascades during repeated stress. Gastroesophageal reflux disease (GERD) affects 7% of the U.S. population, and 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 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 LY294002, and Akt siRNA inhibited Akt activation and Hsp70 expression in HEMEC. The p38 MAPK inhibitor (SB203580) 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).
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