Protease-activated receptors (PARs) are widely distributed in human airways. They couple to G- proteins and are activated after proteolytic cleavage of the N terminus of the receptor. Evidence is growing that PAR subtype 2 plays a pivotal role in inflammatory airway diseases, such as allergic asthma or bronchitis. However, nothing is known about the effects of PAR-2 on electrolyte transport in the native airways. PAR-2 is expressed in airway epithelial cells, where they are activated by mast cell tryptase, neutrophil proteinase 3, or trypsin. Recent studies produced conflicting results about the functional consequence of PAR-2 stimulation. Here we report that stimulation of PAR-2 receptors in mouse and human airways leads to a change in electrolyte transport and a shift from absorption to secretion. Although PAR-2 appears to be expressed on both sides of the epithelium, only basolateral stimulation results in inhibition of amiloride sensitive Na+ conductance and stimulation of both luminal Cl- channels and basolateral K+ channels. The present data indicate that these changes occur through activation of phospholipase C and increase in intracellular Ca2+, which activates basolateral SK4 K+ channels and luminal Ca2+-dependent Cl- channels. In addition, the present data suggest a PAR-2 mediated release of prostaglandin E2, which may contribute to the secretory response. In conclusion, these results provide further evidence for a role of PAR-2 in inflammatory airway disease: stimulation of these receptors may cause accumulation of airway surface liquid, which, however, may help to flush noxious stimuli away from the affected airways.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a protein kinase A and ATP-regulated Cl ؊ channel that also controls the activity of other membrane transport proteins, such as the epithelial Na Inhibition by Cl ؊ was reduced in trimeric channels with a truncated COOH terminus of ␤ENaC and ␥ENaC, and it was no longer detected in dimeric ␣⌬C␤ ENaC channels. Deletion of the NH 2 terminus of ␣-, ␤-, or ␥ENaC, mutations in the NH 2 -terminal phosphatidylinositol bisphosphate-binding domain of ␤ENaC and ␥EnaC, and activation of phospholipase C, all reduced ENaC activity but allowed for Cl ؊ -dependent inhibition of the remaining ENaC current. The results confirm a role of the carboxyl terminus of ␤ENaC for Cl ؊ -dependent inhibition of the Na ؉ channel, which, however, may only be part of a complex regulation of ENaC by CFTR.

These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.