Alteration in Nerves and Neurotransmitter Stimulation of Lacrimal Gland Secretion in the TSP-1(−/−) Mouse Model of Aqueous Deficiency Dry Eye

The purpose of this study is to determine neural, vascular, protein secretion, and cellular signaling changes with disease progression in lacrimal glands of the thrombospondin-1(−/−) (TSP-1(−/−)) mouse model of dry eye compared to C57BL/6 wild type (WT) mice. Neural innervation was reduced in TSP-1(−/−) lacrimal glands compared to WT controls, whereas the number of blood vessels was increased. Intracellular Ca(2+) stores and the amount of lysosomes, mitochondria and secretory granules, but not the endoplasmic reticulum, were reduced in TSP-1(−/−) compared to WT acini at 12 weeks of age. Ex-vivo high KCl-evoked secretion was decreased in TSP-1(−/−) compared to WT lacrimal gland tissue pieces. The α(1D)-adrenergic agonist-stimulated response was increased in TSP-1(−/−) at 4 and 24 weeks but decreased at 12 weeks, and the ATP and MeSATP-stimulated peak [Ca(2+)](i) responses were decreased at 24 weeks. These changes were observed prior to appearance of mononuclear infiltrates. We conclude that in the lacrimal gland the absence of TSP-1: injures peripheral nerves; blocks efferent nerve activation, decreases protein secretion, and, alters intracellular Ca(2+) stores. Through these effects the absence of TSP-1 leads to disruption of ocular surface homeostasis and development of dry eye.