Corneal Nerve Alterations in Diabetes Mellitus

Ishida, Naoto; Rao, Gullapalli N; Cerro, Manuel del; Aquavella, James V.

doi:10.1001/archopht.1984.01040031122038

Cited by 55 publications

(38 citation statements)

References 22 publications

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“…Previous studies have suggested that chronic hyperglycaemia, corneal nerve alterations and disturbance in insulin action may play an important role in the development of such alterations, but the exact mechanisms that underlie these changes are not completely understood [5][6][7][8]. In accordance with the insulin action hypothesis, we have previously demonstrated that insulin receptor activation and other steps of insulin signalling pathways are impaired in lacrimal glands in animals with diabetes mellitus [9].…”

Section: Introductionsupporting

confidence: 53%

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

et al. 2005

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Aims/hypothesis: To assess the involvement of the AGE-specific receptor (AGER, also known as RAGE) axis and nuclear factor kappa-B (NFKB, also known as NF-kappaB) activation in the development of lacrimal gland and tear film dysfunction in diabetes, the present study evaluated: (1) lacrimal gland and tear film alterations in diabetic rats; and (2) the expression of AGE, AGER and NFKB in ocular tissues of normoglycaemic and diabetic rats. Materials and Methods: Diabetes was induced in male Wistar rats with intravenous streptozotocin. Tear secretion parameters were measured and NFKB expression was evaluated in lacrimal glands of control and diabetic rats by western blot. Immunohistochemistry with confocal microscopy was used to assess AGE, AGER and NFKB expression in lacrimal glands of both groups. Results: Lacrimal gland weight and tear film volume were lower in diabetic than in control rats (p=0.01 and 0.02, respectively). IL1B and TNF concentrations in tears were higher in diabetic than in control rats (p=0.007 and 0.02, respectively). NFKB protein was identified in rat cornea, conjunctiva and lacrimal glands. AGE, AGER and NFKB expression were greater in lacrimal glands of diabetic than in those of control rats. Conclusions/interpretation: Diabetes induces significant alterations in rat lacrimal gland structure and secretion. The higher expression of AGE, AGER and NFKB in lacrimal glands of diabetic rats suggests that these factors are involved in signalling and in subsequent inflammatory alterations related to dry eye in diabetes mellitus.

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Section: Introductionsupporting

confidence: 53%

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

et al. 2005

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“…A dense network of nerve endings derived from the stromal branches of trigeminal nerves penetrate the epithelium (41). The neurons and secreted products provide sensation and maintain homeostasis of the tissue (2,29,42). Because of its avascularity, the cornea requires atmospheric O 2 (45), and a reduction of O 2 availability impairs its physiology and function.…”

supporting

confidence: 39%

Hypoxia-induced changes in Ca²⁺ mobilization and protein phosphorylation implicated in impaired wound healing

Lee

Derricks

Minns

et al. 2014

American Journal of Physiology-Cell Physiology

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Lee A, Derricks K, Minns M, Ji S, Chi C, Nugent MA, Trinkaus-Randall V. Hypoxia-induced changes in Ca 2ϩ mobilization and protein phosphorylation implicated in impaired wound healing. Am J Physiol Cell Physiol 306: C972-C985, 2014. First published March 26, 2014; doi:10.1152/ajpcell.00110.2013.-The process of wound healing must be tightly regulated to achieve successful restoration of injured tissue. Previously, we demonstrated that when corneal epithelium is injured, nucleotides and neuronal factors are released to the extracellular milieu, generating a Ca 2ϩ wave from the origin of the wound to neighboring cells. In the present study we sought to determine how the communication between epithelial cells in the presence or absence of neuronal wound media is affected by hypoxia. A signal-sorting algorithm was developed to determine the dynamics of Ca 2ϩ signaling between neuronal and epithelial cells. The cross talk between activated corneal epithelial cells in response to neuronal wound media demonstrated that injury-induced Ca 2ϩ dynamic patterns were altered in response to decreased O 2 levels. These alterations were associated with an overall decrease in ATP and changes in purinergic receptor-mediated Ca 2ϩ mobilization and localization of N-methyl-D-aspartate receptors. In addition, we used the cornea in an organ culture wound model to examine how hypoxia impedes reepithelialization after injury. There was a change in the recruitment of paxillin to the cell membrane and deposition of fibronectin along the basal lamina, both factors in cell migration. Our results provide evidence that complex Ca 2ϩ -mediated signaling occurs between sensory neurons and epithelial cells after injury and is critical to wound healing. Information revealed by these studies will contribute to an enhanced understanding of wound repair under compromised conditions and provide insight into ways to effectively stimulate proper epithelial repair. hypoxia; wound healing; imaging; cell communication DAMAGE TO TISSUE activates intricate underlying mechanisms that mediate the healing process. Communication between cells is generated immediately after injury and continues during the migration phase and the later phases of proliferation and extracellular matrix reassembly (13,14,23). This reepithelialization requires the precise control of glutamatergic and purinergic signaling pathways. Injured cells release nucleotides that serve as ligands for cell-surface purinergic receptors, and injured neurons release components, including ATP and glutamate, that bind their respective receptors. The release of nucleotides can modulate Ca 2ϩ homeostasis (4,11,43,52,54).Neuronal transmitters such as glutamate bind to metabotropic G protein-coupled receptors or to ionotropic receptors, including 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. It has been reported that epithelial cells do not respond to AMPA or kainate, but they do respond to glutamate in neuronal wound media and to NM...

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“…These findings suggest that more than to induce a signaling cascade that leads to oxidative damage and inflammatory alterations, it may impair routine biochemical intracellular events, culminating with reduced tear secretion and dry eye syndrome (28) . Corneal nerve alterations, probably caused by direct hyperglycemic and/or microvascular damage to the tissue lead to neurotrophic lesion and block the feedback mechanism that controls tear secretion (18,41) . They seem to occur later in the process, but certainly have a crucial role in severe presentations of the diabetic dry eye.…”

Section: Molecular Mechanisms Of Diabetic Alterations In Ocular Surfamentioning

confidence: 40%

“…Together, these changes lead to edema, ischemia and hypoxia-induced neovascularization in the retina, proteinuria, mesangial matrix expansion and glomerulosclerosis in the kidney, and multifocal axonal degeneration in peripheral nerves ( Figure 1). Although microvascular diabetic alterations have never been studied in lacrimal gland or ocular surface, a well-known complication, in part attributed to peripheral nerve degeneration, is diabetic neurotrophic keratopathy (18)(19) . In diabetic arteries, endothelial dysfunction seems to involve both insulin resistance specific to the phosphatidylinositol-3 kinase/Akt pathway (20)(21)(22)(23) and hyperglycemia (12) .…”

Section: Diabetes Mellitus: An Overview Of the Problemmentioning

confidence: 42%

Tear film and ocular surface changes in diabetes mellitus

Alves¹,

Carvalheira²,

Módulo³

et al. 2008

Arq. Bras. Oftalmol.

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Corneal Nerve Alterations in Diabetes Mellitus

Abstract: \s=b\The morphologic status of corneal innervation was studied in rats with strep-

Cited by 55 publications

References 22 publications

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

Hypoxia-induced changes in Ca²⁺ mobilization and protein phosphorylation implicated in impaired wound healing

Tear film and ocular surface changes in diabetes mellitus

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Corneal Nerve Alterations in Diabetes Mellitus

Abstract: \s=b\The morphologic status of corneal innervation was studied in rats with strep-

Cited by 55 publications

References 22 publications

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats

Hypoxia-induced changes in Ca2+ mobilization and protein phosphorylation implicated in impaired wound healing

Tear film and ocular surface changes in diabetes mellitus

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Hypoxia-induced changes in Ca²⁺ mobilization and protein phosphorylation implicated in impaired wound healing