J Neurogastroenterol Motil.  2010 Oct;16(4):374-388.

Viewpoints on Acid-Induced Inflammatory Mediators in Esophageal Mucosa

• Harnett KM
• Rieder F
• Behar J
• Biancani P

Abstract

We have focused on understanding the onset of gastroesophageal reflux disease by examining the mucosal response to the presence of acid in the esophageal lumen. Upon exposure to HCl, inflammation of the esophagus begins with activation of the transient receptor potential channel vanilloid subfamily member-1 (TRPV1) in the mucosa, and production of IL-8, substance P (SP), calcitonin gene related peptide (CGRP) and platelet activating factor (PAF). Production of SP and CGRP, but not PAF, is abolished by the neural blocker tetrodotoxin suggesting that SP and CGRP are neurally released and that PAF arises from non neural pathways. Epithelial cells contain TRPV1 receptor mRNA and protein and respond to HCl and to the TRPV1 agonist capsaicin with production of PAF. PAF, SP and IL-8 act as chemokines, inducing migration of peripheral blood leukocytes. PAF and SP activate peripheral blood leukocytes inducing the production of H2O2. In circular muscle, PAF causes production of IL-6, and IL-6 causes production of additional H2O2, through activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Among these, NADPH oxidase 5 cDNA is significantly up-regulated by exposure to PAF; H2O2 content of esophageal and lower esophageal sphincter circular muscle is elevated in human esophagitis, causing dysfunction of esophageal circular muscle contraction and reduction in esophageal sphincter tone. Thus esophageal keratinocytes, that constitute the first barrier to the refluxate, may also serve as the initiating cell type in esophageal inflammation, secreting inflammatory mediators and pro-inflammatory cytokines and affecting leukocyte recruitment and activity.

Keyword

Cytokines; Gastroesophageal reflux disease; Platelet activating factor; Substance P; TRPV1

MeSH Terms

Calcitonin Gene-Related Peptide
Capsaicin
Chemokines
Cytokines
DNA, Complementary
Epithelial Cells
Esophageal Sphincter, Lower
Esophagitis
Esophagus
Gastroesophageal Reflux
Humans
Inflammation
Interleukin-6
Interleukin-8
Keratinocytes
Leukocytes
Mucous Membrane
Muscle Contraction
Muscles
NADP
NADPH Oxidase
Neural Pathways
Oxidoreductases
Platelet Activating Factor
RNA, Messenger
Substance P
Tetrodotoxin
TRPV Cation Channels
Calcitonin Gene-Related Peptide
Capsaicin
Chemokines
Cytokines
DNA, Complementary
Interleukin-6
Interleukin-8
NADP
NADPH Oxidase
Oxidoreductases
Platelet Activating Factor
RNA, Messenger
Substance P
TRPV Cation Channels
Tetrodotoxin