Acetylcholine-evoked calcium mobilization and ion channel activation in human labial gland acinar cells from patients with primary Sjögrens syndrome

摘要

Recent evidence has indicated that the salivary gland dysfunction associated with Sjögren's syndrome (SjS) is not necessarily due to immune-mediated destruction of acinar tissue. SjS sufferers may possess substantial reserves of acinar tissue but nevertheless be incapable of maintaining salivary flow rates in the normal range. We have investigated the ability of isolated labial gland acinar cells from SjS patients to fluid secrete by measuring agonist-evoked changes in intracellular Ca²⁺ ([Ca²⁺]i) using fura-2 microfluorimetry and activation of K⁺ and Cl⁻ channels using the patch-clamp whole cell technique. We can confirm that stimulation with a super-maximal dose of acetylcholine (ACh) increased [Ca²⁺]i equally in both control acinar cells and those derived from SjS patients. However, at submaximal concentrations, the dose–response curve for ACh was shifted to the right by approximately one order of magnitude in acinar cells from SjS patients compared to control acinar cells. Patch-clamp measurements consistent with the presence of Ca²⁺-activated K⁺ and Cl⁻ conductances were obtained from both control acinar cells and those obtained from SjS patients. Dose-dependent activation of the ion channels by acetylcholine was also right-shifted in acinar cells from SjS patients compared to control cells. Our data show that labial gland acinar cells from SjS patients were capable of responding to agonist stimulation by mobilizing [Ca²⁺]i and activating K⁺ and Cl⁻ channels consistent with the requirements of fluid secretion. However, the persistent loss of sensitivity to ACh observed in from SjS patients may account for the lack of saliva production observed in these patients in vivo.