Abstract
In asthmatic patients, inhalation of hyperosmolar saline or D-mannitol (D-M) elicits bronchoconstriction, but in healthy subjects exercise causes bronchodilation. Hyperventilation causes drying of airway surface liquid (ASL) and increases its osmolarity. Hyperosmolar challenge of airway epithelium releases epithelium-derived relaxing factor (EpDRF), which relaxes the airway smooth muscle. This pathway could be involved in exercise-induced bronchodilation. Little is known of ASL hyperosmolarity effects on epithelial function. We investigated the effects of osmolar challenge maneuvers on dispersed and adherent guinea-pig tracheal epithelial cells to examine the hypothesis that EpDRF-mediated relaxation is associated with epithelial cell shrinkage. Enzymatically-dispersed cells shrank when challenged with ≥10 mOsM added D-M, urea or NaCl with a concentration-dependence that mimics relaxation of the of isolated perfused tracheas (IPT). Cells shrank when incubated in isosmolar N-methyl-D-glucamine (NMDG) chloride, Na gluconate (Glu), NMDG-Glu, K-Glu and K2SO4, and swelled in isosmolar KBr and KCl. However, isosmolar challenge is not a strong stimulus of relaxation in IPTs. In previous studies amiloride and 4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS) inhibited relaxation of IPT to hyperosmolar challenge, but had little effect on shrinkage of dispersed cells. Confocal microscopy in tracheal segments showed that adherent epithelium is refractory to low hyperosmolar concentrations that induce dispersed cell shrinkage and relaxation of IPT. Except for gadolinium and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), actin and microtubule inhibitors and membrane permeabilizing agents did not affect on ion transport by adherent epithelium or shrinkage responses of dispersed cells. Our studies dissociate relaxation of IPT from cell shrinkage after hyperosmolar challenge of airway epithelium.
Highlights
In healthy subjects, bronchodilation accompanies exercise (Gelb et al, 1985; Silverman et al, 2005)
We investigated the effects of osmolar challenge maneuvers on dispersed and adherent guinea-pig tracheal epithelial cells to examine the hypothesis that epithelium-derived relaxing factor (EpDRF)-mediated relaxation is associated with epithelial cell shrinkage
HYPEROSMOLAR CHALLENGE OF isolated perfused tracheas (IPT) FOLLOWING PERFUSION WITH ISOSMOLAR SOLUTION (HYPEROSMOLAR JUMP PROTOCOL) We investigated the effects of isosmolar KBr and K2SO4 in the IPT inasmuch as these two osmolytes affected cell volume oppositely
Summary
Bronchodilation accompanies exercise (Gelb et al, 1985; Silverman et al, 2005). Exercise leads to evaporative water loss, dehydration of the airway surface liquid (ASL), and increases ASL osmolarity (Freed and Davis, 1999; Anderson and Daviskas, 2000; Anderson, 2010, 2012). Exercise may precipitate bronchoconstriction (exercise-induced bronchoconstriction, EIB) (Weiler et al, 2010; Anderson and Kippelen, 2012; Hallstrand, 2012). EIB is attenuated by leukotriene modifier drugs and glucocorticoids (Kemp, 2009). Asthmatic patients who experience EIB exhibit dysfunction in a compensatory Na+-absorptive pathway that regulates ASL (Schmitt et al, 2011). What accounts for the phenotype shift from bronchodilation during exercise to EIB is unknown
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