Partitioning of paracellular conductance along the ileal crypt-villus axis: A hypothesis based on structural analysis with detailed consideration of tight junction structure-function relationships

Abstract

Current models of intestinal transport suggest cells which absorb ions are located on the villus while secretory cells are located in the crypt and putatively have paracellular pathways which are highly conductive to Na+. One approach to assess possible variation in small intestinal paracellular conductance along the crypt-villus axis is to morphometrically analyze the structural aspects of crypt and villus tight junctions (TJs) which relate to paracellular resistance. Such detailed analysis of junctional structure in this heterogeneous epithelium would permit one to compare intestinal TJ structure-function relationships with those in a structurally simpler epithelium such as that of toad urinary bladder. This comparison would also be of considerable interest since previous similar comparisons have failed to consider in detail the geometric dissimilarity between these two epithelia. We applied light, electron microscopic, and freeze-fracture morphometric techniques to guinea pig ileal mucosa to quantitatively assess, for both crypts and villi, linear TJ density, relative surface contributions, and TJ strand counts. Mean linear TJ densities were 76.8 m/cm2 for crypt cells and 21.8 m/cm2 for villus absorptive cells. Mean TJ strand counts were 4.45 for undifferentiated crypt cell TJs and 6.03 for villus absorptive cell TJs. The villus constituted 87% and the crypt 13% of total surface. We utilized these data to predict paracellular conductance of crypts vs. villi based on equations derived from those of Claude (P. Claude, J. Membrane Biol. 39:219-232, 1978). Such analysis predicts that 73% of ileal paracellular conductance is attributable to the crypt. Furthermore, we obtained literature values for paracellular resistance in mammalian ileum and toad urinary bladder and for toad bladder TJ structure and linear density and constructed a relationship which would allow us to more accurately compare TJ structure-function correlates between these two epithelia. Such a comparison, which considers both surface amplification and TJ structure and distribution in these epithelia, shows that one would predict in vitro measured values for paracellular resistance should be approximately two orders of magnitude less in mammalian ileum than in toad urinary bladder. This predicted discrepancy (115-fold) correlates well with the observed difference (100-fold).(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of Epithelial Morphology, Monolayer Permeability, and Cell Migration by Growth Arrest Specific 3/Peripheral Myelin Protein 22

“…The altered cell shape observed in PMP22-MDCK monolayers is likely the consequence of reduced cell density at confluence, in which a flattened morphology is necessary for maintaining functional cell-cell junctions. An elevated TER can be the result of such a phenomenon, because confluent monolayers with reduced cell density have less linear tight junctional length (Marcial et al, 1984), and paracellular junctions are more permeable than the cell itself (Stefani and Cereijido, 1983). However, after correction for junctional length, the effects of PMP22 overexpression on TER remained highly significant.…”

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

“…[23] It has been demonstrated that intestinal paracellular absorption in patients with active pulmonary TB is markedly decreased, but that this is unlikely to contribute significantly to lower plasma levels, as it represents less than 5% of the total absorptive area of the small intestine. [24] The patients in our study group were given rifampicin in a combination tablet either on an empty stomach with the addition of an antacid (sucralfate) or while given continuous feeds. It has been shown that antacids do not influence peak drug levels of rifampicin, but a high-fat meal can reduce C max by 36% and nearly double t max .…”

A Differentiation-dependent Splice Variant of Myosin Light Chain Kinase, MLCK1, Regulates Epithelial Tight Junction Permeability

“…However, this barrier is not static; its permeability characteristics change over the course of minutes, in response to luminal Na ϩ and glucose (1) or bacteria (2), or days, as enterocytes differentiate and migrate from crypt to villus (3,4). The crypt-villus axis exhibits a large gradient in tight junction permeability; the secretory crypt area contains large pores (50 -60Å), whereas the absorbing tip of the villus contains small pores (Ͻ5 Å) (4).…”