The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.
“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”
She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.
“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”
Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.
Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.
She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.
“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.
Neither Dr. Souza nor her colleagues had any relevant financial disclosures.
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