BACKGROUND & AIMS: Although defects in tight junction (TJ) epithelial paracellular barrier function are believed to be a primary cause of inflammation, the mechanisms responsible remain largely unknown. METHODS: We generated knockout mice of stomach-type claudin-18, a major component of TJs in the stomach. RESULTS: Cldn18(-/-) mice were afflicted with atrophic gastritis that started on postnatal day 3. This coincided with a decrease in intragastric pH due to H(+) secretion from parietal cells and concomitant up-regulation of the cytokines, interleukin-1β, cyclooxygenase-2, and KC, resulting in spasmolytic polypeptide-expressing metaplasia (SPEM). Oral administration of hydrochloric acid on postnatal day 1 induced the expression of these cytokines in Cldn18(-/-) infant stomach, but not in Cldn18(+/+) mice. A paracellular H(+) leak in Cldn18(-/-) stomach was detected by electrophysiology and H(+) titration, and freeze-fracture electron microscopy showed structural defects in the TJs, in which the tightly packed claudin-18 (stomach-type)-based TJ strands were lost, leaving a loose meshwork of strands consisting of other claudin species. CONCLUSIONS: These findings provide evidence that claudin-18 normally forms a paracellular barrier against H(+) in the stomach and that its deficiency causes paracellular H(+) leak, a persistent up-regulation of proinflammatory cytokines, chronic recruitment of neutrophils, and the subsequent development of SPEM in atrophic gastritis.
BACKGROUND & AIMS: Although defects in tight junction (TJ) epithelial paracellular barrier function are believed to be a primary cause of inflammation, the mechanisms responsible remain largely unknown. METHODS: We generated knockout mice of stomach-type claudin-18, a major component of TJs in the stomach. RESULTS:Cldn18(-/-) mice were afflicted with atrophic gastritis that started on postnatal day 3. This coincided with a decrease in intragastric pH due to H(+) secretion from parietal cells and concomitant up-regulation of the cytokines, interleukin-1β, cyclooxygenase-2, and KC, resulting in spasmolytic polypeptide-expressing metaplasia (SPEM). Oral administration of hydrochloric acid on postnatal day 1 induced the expression of these cytokines in Cldn18(-/-) infant stomach, but not in Cldn18(+/+) mice. A paracellular H(+) leak in Cldn18(-/-) stomach was detected by electrophysiology and H(+) titration, and freeze-fracture electron microscopy showed structural defects in the TJs, in which the tightly packed claudin-18 (stomach-type)-based TJ strands were lost, leaving a loose meshwork of strands consisting of other claudin species. CONCLUSIONS: These findings provide evidence that claudin-18 normally forms a paracellular barrier against H(+) in the stomach and that its deficiency causes paracellular H(+) leak, a persistent up-regulation of proinflammatory cytokines, chronic recruitment of neutrophils, and the subsequent development of SPEM in atrophic gastritis.
Authors: Beiyun Zhou; Per Flodby; Jiao Luo; Dan R Castillo; Yixin Liu; Fa-Xing Yu; Alicia McConnell; Bino Varghese; Guanglei Li; Nyam-Osor Chimge; Mitsuhiro Sunohara; Michael N Koss; Wafaa Elatre; Peter Conti; Janice M Liebler; Chenchen Yang; Crystal N Marconett; Ite A Laird-Offringa; Parviz Minoo; Kunliang Guan; Barry R Stripp; Edward D Crandall; Zea Borok Journal: J Clin Invest Date: 2018-02-05 Impact factor: 14.808
Authors: Gabriel R Linares; Robert Brommage; David R Powell; Weirong Xing; Shin-Tai Chen; Fatima Z Alshbool; K-H William Lau; Jon E Wergedal; Subburaman Mohan Journal: J Bone Miner Res Date: 2012-07 Impact factor: 6.741
Authors: Guanglei Li; Per Flodby; Jiao Luo; Hidenori Kage; Arnold Sipos; Danping Gao; Yanbin Ji; LaMonta L Beard; Crystal N Marconett; Lucas DeMaio; Yong Ho Kim; Kwang-Jin Kim; Ite A Laird-Offringa; Parviz Minoo; Janice M Liebler; Beiyun Zhou; Edward D Crandall; Zea Borok Journal: Am J Respir Cell Mol Biol Date: 2014-08 Impact factor: 6.914