The molecular basis of neurotrophic keratitis

Abstract

Endogenous proliferation of corneal epithelial cells is regulated by a bidirectional control process characterized by an adrenergic, CAMP-dependent 'off', and a cholinergic, muscarinic cGMP-dependent 'on' response. The adrenergic receptor@) are located in the plasma membrane (microsomal fraction), whereas the novel feature of the system is a cholinergic receptor specific for acetylcholine (ACH) located in the nuclear membrane. Exogenous substances which raise intracellular cAMP levels such as isoproterenol or PGE1, shut off epithelial mitosis; and, carbamylcholine or ACH raise intranuclear cGMP levels and increase mitosis by specific, regulatory stimulation of RNA-polymerase I1 activity. We believe that this regulatory system explains the transitory mitotic suppression induced by superficial corneal wounding (interruption of adrenergic fibres, 'chalone-effect'); and the marked, permanent depression of epithelial mitosis associated with decreased intracellular ACH levels which are produced by total corneal denervation, and which results in neurotrophic keratitis.

Neurotrophic Keratitis

“…The integration of these 2 reflex arcs ensures the stability of the tear film and, together with related neurotrophic factors (neurotrophins), the vitality of the epithelium and stroma [3]. Cavanagh et al [4,5] described the bi-directional regulation of corneal epithelial proliferation through sensory and autonomic sympathetic innervation. The impairment of sensory innervation, as demonstrated by Sigelman [2], causes a reduction in the lacrimation reflex and the vitality, metabolism and mitosis of epithelial cells, with subsequent deficiency in epithelial repair, stromal and intracellular oedema, loss of microvilli, and abnormal development of the basal lamina [2,6,7,8].…”

“…Studies have shown a decrease in SP and Ach resulting from injury to the corneal nerves [10,11], the ability of SP alone to stimulate the synthesis and growth of corneal epithelial cells [12], and epithelial proliferation in vitro by SP, cholecystokinin gene-related peptide and Ach [5,12,13]. Although studies performed in humans could not show that the treatment with SP alone promotes corneal re-epithelialization [14], Chikama et al [15] reported the complete recovery of a patient with NK after treatment with SP and insulin-like growth factor-1 (IGF-1) eye drops.…”

“…The study of NK has directed the attention of researchers to the role of neurotransmitters such as substance P (SP), calcitonin gene-related peptide, neuropeptide Y, vasoactive intestinal peptide, galanin, methionine-enkephalin, catecholamine, and acetylcholine (Ach) [5,9]. Studies have shown a decrease in SP and Ach resulting from injury to the corneal nerves [10,11], the ability of SP alone to stimulate the synthesis and growth of corneal epithelial cells [12], and epithelial proliferation in vitro by SP, cholecystokinin gene-related peptide and Ach [5,12,13].…”

Cataract Surgery and Dry Eye

“…Peptidergic transmitters in nerve fibers may be involved in neuroimmunomodulation of the cornea (Muller et al, 1996). Enhanced epithelial cell proliferation is strongly believed to be mediated by neurotransmitters and nerve growth factors released from corneal nerve endings (Cavanagh and Colley, 1989). For example, it has been reported that acetylcholine derived from the corneal sensory nerve endings, increases intracellular levels of cyclic guanosine monophosphate (cGMP), which is associated with epithelial mitosis in the cornea and therefore enhances epithelial cell growth (Cavanagh and Colley, 1989).…”

“…Enhanced epithelial cell proliferation is strongly believed to be mediated by neurotransmitters and nerve growth factors released from corneal nerve endings (Cavanagh and Colley, 1989). For example, it has been reported that acetylcholine derived from the corneal sensory nerve endings, increases intracellular levels of cyclic guanosine monophosphate (cGMP), which is associated with epithelial mitosis in the cornea and therefore enhances epithelial cell growth (Cavanagh and Colley, 1989). Substance P is a neuropeptide present in corneal nerves and has been found to stimulate DNA synthesis and promote corneal epithelial cell growth; it may also play a role in corneal epithelial wound healing.…”