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Cytopathology and Exocrine Dysfunction Induced in Ex Vivo Rabbit Lacrimal Gland Acinar Cell Models by Chronic Exposure to Histamine or Serotonin

¹From the Departments of Physiology and Biophysics, ³Ophthalmology, and ⁵Cell and Neurobiology and the ⁴Zilkha Neurogenetics Institute, Keck School of Medicine, Los Angeles, California; and the ²Mork Family Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California.

PURPOSE. Lacrimal immunohistopathology has diverse clinical presentations, suggesting that inflammatory mediators exert diverse influences. Chronic exposure to agonistic acetylcholine receptor autoantibodies has been studied previously; the present work addressed mediators that signal through other G protein–coupled receptors.

METHODS. Acinus-like structures and reconstituted acinar epithelial monolayers from rabbit lacrimal glands were exposed to varying concentrations of histamine or 5-hydroxytryptamine (5-HT) for 20 hours. Net and vectorial β-hexosaminidase secretion, cytosolic Ca²⁺ (Ca_i) elevation, apical recruitment of p150^Glued, actin microfilament meshwork organization, and ultrastructure were assessed.

RESULTS. Histamine and 5-HT acutely stimulated β-hexosaminidase secretion at lower, but not higher, concentrations. Neither of them acutely elevated Ca_i levels. Both recruited p150^Glued at concentrations that failed to induce secretion. Chronic exposure to 10 mM histamine inhibited carbachol (CCh)-induced β-hexosaminidase secretion and prevented the formation of continuous monolayers; 1 mM 5-HT partially inhibited secretion at the apical medium. Neither altered secretion to the basal medium. Chronic exposure to histamine or 5-HT partially decreased CCh induced Ca_i elevations and p150^Glued recruitment, even at concentrations that did not inhibit secretion. Both expanded acinar lumina and thickened microfilament meshworks, and both caused homotypic fusion of secretory vesicles and formation of aqueous vacuoles in the apical and basal cytoplasm. Chronic exposure to forskolin, which activates adenylyl cyclase, induced similar cytopathologic changes but impaired secretion modestly and only at the highest concentration tested.

CONCLUSIONS. Inflammatory mediators that signal through G protein–coupled receptors cause acinar cell cytopathology and dose-dependent reductions of CCh-induced β-hexosaminidase secretion. Although agonistic acetylcholine receptor autoantibodies may cause pervasive functional quiescence, inflammatory mediators may cause varying degrees of exocrine dysfunction.