Secretory phospholipase A2 is required to produce histologic changes associated with gastroduodenal reflux in a murine model.
OBJECTIVE
The earliest response of esophageal mucosa to gastric reflux is the development of oxidative damage and inflammation. These processes contribute to the development of metaplasia known as Barrett's esophagus, as well as the progression to malignancy. Secretory phospholipase A(2) is a mediator of inflammation with levels that are increased in Barrett's metaplasia and carcinoma when compared with levels in normal samples. Our goal is to determine the role of secretory phospholipase A(2) in the development of reflux-associated changes in the esophageal mucosa.


METHODS
Secretory phospholipase A(2)-deficient mice (C57BL/6, n = 5) and mice known to express high levels of secretory phospholipase A(2) (BALB/c, n = 5) underwent side-to-side surgical anastomosis of the first portion of the duodenum and gastroesophageal junction, allowing exposure of esophageal mucosa to duodenal and gastric contents duodeno-gastroesophageal anastomosis. Control animals (n = 5) of each strain underwent laparotomy with esophagotomy and repair. Tissue was frozen in embedding medium. Hematoxylin and eosin staining and Ki67 and secretory phospholipase A(2) immunohistochemistry were used to evaluate esophageal tissue and its response to duodeno-gastroesophageal anastomosis.


RESULTS
Immunofluorescent staining confirmed the absence of secretory phospholipase A(2) in C57BL/6 mice and its presence in BALB/c mice. Hematoxylin and eosin staining demonstrated significant thickening of the esophageal mucosa in response to gastroesophageal reflux in the presence of secretory phospholipase A(2). Mice known to express high levels of secretory phospholipase A(2) also demonstrated increased numbers of proliferating cells. Secretory phospholipase A(2)-deficient mice were immune to the early changes induced by mixed reflux.


CONCLUSIONS
The presence of secretory phospholipase A(2) appears necessary for early histologic changes produced by exposure of the esophagus to gastroduodenal contents. This enzyme is identified as a promising target for evaluation of mechanisms of carcinogenesis and chemoprevention of esophageal carcinoma.
Department of Surgery, Division of Cardiothoracic Surgery, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
Ashok
A
Babu
Xianzhong
X
Meng
Anirban M
AM
Banerjee
Fabia
F
Gamboni-Robertson
Joseph C
JC
Cleveland
Sagar
S
Damle
David A
DA
Fullerton
Michael J
MJ
Weyant
D000704:Analysis of Variance; D000818:Animals; D001471:Barrett Esophagus / Q000201:enzymology / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005764:Gastroesophageal Reflux / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054467:Phospholipases A2 / Q000172:deficiency / Q000378:metabolism*; D011230:Precancerous Conditions / Q000473:pathology; D011336:Probability; D011897:Random Allocation; D012680:Sensitivity and Specificity; D020858:Tissue and Organ Harvesting
D014408:Biomarkers, Tumor; D054467:Phospholipases A2