The aging lacrimal gland: changes in structure and function

Abstract

The afferent nerves of the cornea and conjunctiva, efferent nerves of the lacrimal gland, and the lacrimal gland are a functional unit that works cooperatively to produce the aqueous component of tears. A decrease in the lacrimal gland secretory function can lead to dry eye disease. Because aging is a risk factor for dry eye disease, study of the changes in the function of the lacrimal gland functional unit with age is important for developing treatments to prevent dry eye disease. No one mechanism is known to induce the changes that occur with aging, although multiple different mechanisms have been associated with aging. These fall into two theoretical categories: programmed theories of aging (immunological, genetic, apoptotic, and neuroendocrine) and error theories of aging (protein alteration, somatic mutation, etc). Lacrimal glands undergo structural and functional alteration with increasing age. In mouse models of aging, it has been shown that neural stimulation of protein secretion is an early target of aging, accompanied by an increase in mast cells and lipofuscin accumulation. Hyperglycemia and increased lymphocytic infiltration can contribute to this loss of function at older ages. These findings suggest that an increase in oxidative stress may play a role in the loss of lacrimal gland function with age. For the afferent and efferent neural components of the lacrimal gland functional unit, immune or inflammatory mediated decrease in nerve function could contribute to loss of lacrimal gland secretion with age. More research in this area is critically needed.

Figure 1

Schematic of the neural regulation of lacrimal gland electrolyte, water, and protein secretion. Lacrimal gland secretion is stimulated by the sensory nerves in the cornea or conjunctiva, which, in turn, activate the efferent parasympathetic and sympathetic nerves that innervate the acini of the lacrimal gland. Lacrimal gland fluid flows onto the ocular surface through the lacrimal gland excretory ducts and is drained from the eye via the lacrimal drainage system. (Modified from Dartt DA.)

Figure 2

Polymeric immunoglobulin receptor (pIgR) trafficking and secretory component (SC) secretion in lacrimal gland acini, pIgR is synthesized in the endoplasmic reticulum (ER). pIgR exits from the trans-Golgi network (TGN) in two groups. One group exits via the regulated secretory vesicles (SVs), and the other group is packaged into vesicles to be inserted into the basolateral membrane. Additionally, pIgR inserted into the basolateral membrane may be endocytosed and transported through a series of endosomal compartments along the constitutive transcytotic pathway (red arrows). BE, basolateral endosomes; dlgA, dimeric IgA; sIgA, secretory IgA. (Modified from Evans et al.)

Figure 3

Electrolyte transport mechanisms driving water secretion across lacrimal gland acinar epithelium. NKA, Na⁺,K⁺-ATPase; AE, anion (CI⁻/HCO3⁻) exchanger; NHE, Na⁺/H⁺ exchanger; NKCC, Na⁺-K⁺-2CI⁻ cotransporter. (Reprinted from Selvin et al with permission of the authors and Am J Physiol Cell Physiol.)

Figure 4

Schematic of insulin resistance leading to hyperglycemia and oxidative stress by activating I kappa kinase and NF-KB that leads to the production of inflammatory cytokines and the receptor for advanced glycation end products (RAGE). Advanced Glycation End products (AGE); nuclear factor-KB (NF-KB), p38MAPK, NH2-terminal Jun kinases/stress activated protein kinases (JNK/SAPK); I kappa kinase (I-KK); I kappa Beta (1-KB).