Adenovirus-mediated hAQP1 expression in irradiated mouse salivary glands causes recovery of saliva secretion by enhancing acinar cell volume decrease

Abstract

Head and neck irradiation (IR) during cancer treatment causes by-stander effects on the salivary glands leading to irreversible loss of saliva secretion. The mechanism underlying loss of fluid secretion is not understood and no adequate therapy is currently available. Delivery of an adenoviral vector encoding human aquaporin-1 (hAQP1) into the salivary glands of human subjects and animal models with radiation-induced salivary hypofunction leads to significant recovery of saliva secretion and symptomatic relief in subjects. To elucidate the mechanism underlying loss of salivary secretion and the basis for AdhAQP1-dependent recovery of salivary gland function we assessed submandibular gland function in control mice and mice 2 and 8 months after treatment with a single 15-Gy dose of IR (delivered to the salivary gland region). Salivary secretion and neurotransmitter-stimulated changes in acinar cell volume, an in vitro read-out for fluid secretion, were monitored. Consistent with the sustained 60% loss of fluid secretion following IR, a carbachol (CCh)-induced decrease in acinar cell volume from the glands of mice post IR was transient and attenuated as compared with that in cells from non-IR age-matched mice. The hAQP1 expression in non-IR mice induced no significant effect on salivary fluid secretion or CCh-stimulated cell volume changes, except in acinar cells from 8-month group where the initial rate of cell shrinkage was increased. Importantly, the expression of hAQP1 in the glands of mice post IR induced recovery of salivary fluid secretion and a volume decrease in acinar cells to levels similar to those in cells from non-IR mice. The initial rates of CCh-stimulated cell volume reduction in acinar cells from hAQP1-expressing glands post IR were similar to those from control cells. Altogether, the data suggest that expression of hAQP1 increases the water permeability of acinar cells, which underlies the recovery of fluid secretion in the salivary glands functionally compromised post IR.

Neurturin Gene Therapy Protects Parasympathetic Function to Prevent Irradiation-Induced Murine Salivary Gland Hypofunction

“…It has been previously shown that by 60 days post-IR there is a reproducible chronic loss of saliva. 18 , 19 , 20 As expected, IR significantly reduced saliva secretion more than 50% compared with non-IR controls ( Figure 4 ), and treatment with the control vector (AdC+IR) did not improve saliva secretion. However, treatment with all three doses of AdNRTN before IR improved salivary secretion so that it was similar to non-IR control levels ( Figure 4 ).…”

Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway

“…Our present findings revealed that reduction of SOCE in acinar cells after irradiation could fully account for the impairment of salivary fluid secretion and that of agonist-stimulated decrease in acinar cell volume (31). We showed that this impairment of SOCE was due to loss of STIM1, which occurred downstream of caspase-3 activation.…”

“…Salivary gland irradiation was accomplished by placing each animal into a specially built Lucite jig such that the animal could be immobilized without the use of anesthetics. In addition, the jig was fitted with a Lucite cone that surrounded the head and prevented head movement during the radiation exposure (14, 31). Lead shields were designed to cover the jigs with the mice with a small aperture in the lead shield that allowed radiation to the salivary gland area of the immobilized animal.…”

Generation of orthotopically functional salivary gland from embryonic stem cells

“…Salivary glands play an essential role in oral health, and the reduction of saliva flow causes deterioration of the quality of life 55 . Previous studies have rescued the partial salivary gland function through the recovery of salivary production by stem cell transplantation or the over-expression of water-channel proteins 56 – 58 . We have proposed a concept of bioengineered salivary gland organ replacement, but not tissue repair, via the transplantation of a bioengineered germ in a mouse model of salivary defect 9 .…”