Roles of Cytoskeleton and Tyrosine Receptor Mediated Signal Transduction in the Restitution of Isolated Guinea Pig Gastric Mucosa

Abstract

Background: The immediate response of the GI-epithelium to a superficial injury is primarily directed to restore the disturbed epithelial continuity in a process called restitution. The involvement of both structural (cytoskeleton) and humoral (growth factors and cytokines) signal transduction systems in the process has been documented. Previously, in experimental circumstances the role of the two systems has been examined as two distinct units. Nevertheless, in normal conditions in vivo, the two systems are presumably acting simultaneously. This study investigates the functional roles of cytoskeleton and tyrosine receptor mediated signalling in the regulation of restitution. Methods: Guinea pig gastric mucosa was mounted in Ussing-chamber, injured with 1.25 M NaCl and subsequently perfused for 4 h. Simultaneously, the electrophysiological resistance of the tissue (R) was recorded. During the recovery, the tissue was exposed bilaterally either to modulators of cytoskeleton (cytochalasin B/lysophosphatidic acid) or of tyrosine receptor mediated signalling (genistein/epidermal growth factor + transforming growth factor- α ). After the experiment, the tissue was analysed morphologically and the proliferative index (PI) was determined morphometrically. Results : Exposure of the tissue to cytochalasin caused a significant decrease of both restitution (tissue resistance) and proliferation (PI), whereas simultaneous treatment with EGF + TGF α restored both restitution and proliferation. Correspondingly, exposure of the tissue to genistein during restitution impaired the process as well as induction of proliferation, while simultaneous exposure to lysophosphatidic acid restored the processes. Exposure of the tissue to EGF + TGF α and lysophosphatidic acid simultaneously resulted in a mild, but insignificant additive inductions of both restitution and proliferation. Conclusions : Restitution is controlled by both structural and humoral signalling systems. If one of the regulating systems fails, stimulation of the other restores the process. Simultaneous stimulation of both systems has a minor additive effect on both restitution and proliferation.