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Effects of adenosine and acetylcholine on the lacrimal gland
Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
2011 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)Alternativ tittel
Effekter av adenosin och acetylkolin på tårkörteln (svensk)
Abstract [en]

A balanced tear film is essential for a healthy ocular surface. Insufficient tear production may result in dry eye, a common disorder in the elderly population. Dry eye causes significant discomfort in the patients and may lead to visual impairment and ocular infections. The lacrimal gland secretes water, proteins and electrolytes to the aqueous layer of the tear film. Lacrimal gland secretion is tightly regulated by e.g. neuronally released acetylcholine. The effect of acetylcholine on lacrimal gland secretion was recently found to be potentiated by adenosine. Adenosine is an important signaling molecule acting upon the adenosine receptors: A1, A2A, A2B and A3.

The aim of this thesis was to study effects of adenosine and acetylcholine on intracellular signaling pathways and lacrimal gland secretion. Cholinergic stimulation of secretion was shown to be regulated by the mitogen activated protein kinase p38, a protein previously not known to be involved in exocrine secretion. p38 was activated in response to cholinergic stimulation and inhibition of p38 significantly diminished cholinergic secretion.

When investigating adenosine effects, potentiation of cholinergic secretion was observed by activation of the A2B receptor in addition to the previously studied A1 receptor. An A2 receptor agonist increased cholinergic rabbit lacrimal gland protein secretion at several concentrations. The increase was inhibited by antagonism of the A2B receptor, but not the A2A receptor. When investigating the intracellular signaling pathways following adenosine and acetylcholine receptor activation, adenosine was shown to increase of cAMP levels. An additional increase in cAMP levels was observed after parallel adenosine and cholinergic receptor activation. Inhibition of Ca2+ release from the endoplasmic reticulum had inhibitory effects of cholinergic stimulation of secretion. In addition, the expression of adenosine receptors in a mouse model of autoimmune dry eye was investigated. The results showed a lymphocyte dependent upregulation of A2A receptors in diseased mice compared to controls.

In conclusion, the results in this thesis provide significant contributions in the search of dry eye therapeutics through studies of adenosine and acetylcholine receptor activation.

sted, utgiver, år, opplag, sider
Växjö, Kalmar: Linnaeus Univeristy Press , 2011. , s. 76
Serie
Linnaeus University Dissertations ; 59/2011
Emneord [en]
Lacrimal gland, adenosine, adenosine receptors, signal transduction, exocrine secretion, tear film, dry eye, Sjögren’s syndrome, acetylcholine, mitogen activated protein kinase, p38
HSV kategori
Forskningsprogram
Naturvetenskap, Biomedicinsk vetenskap
Identifikatorer
URN: urn:nbn:se:lnu:diva-13636ISBN: 978-91-86491-97-0 (tryckt)OAI: oai:DiVA.org:lnu-13636DiVA, id: diva2:432893
Disputas
2011-09-09, Sal N2007, Smålandsgatan 26B, Kalmar, 09:30 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2011-08-09 Laget: 2011-08-01 Sist oppdatert: 2018-01-12bibliografisk kontrollert
Delarbeid
1. p38 mitogen activated protein kinase regulates exocrine secretion in rabbit lacrimal gland.
Åpne denne publikasjonen i ny fane eller vindu >>p38 mitogen activated protein kinase regulates exocrine secretion in rabbit lacrimal gland.
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:lnu:diva-13660 (URN)
Tilgjengelig fra: 2011-08-08 Laget: 2011-08-08 Sist oppdatert: 2012-01-03bibliografisk kontrollert
2. Adenosine A2 receptor presence, and synergy with cholinergic stimulation in rabbit lacrimal gland
Åpne denne publikasjonen i ny fane eller vindu >>Adenosine A2 receptor presence, and synergy with cholinergic stimulation in rabbit lacrimal gland
2010 (engelsk)Inngår i: Current Eye Research, ISSN 0271-3683, E-ISSN 1460-2202, Vol. 35, nr 6, s. 466-474Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

PURPOSE: Secretion from the lacrimal gland is an important part of the well-being of the eye, and a central part in the search for treatment of dry eye syndrome. Adenosine has stimulatory effects on the lacrimal gland, and can potentiate the effect of the cholinergic agonist carbachol (Cch). The aim of the present study is to investigate the presence of the adenosine A(2) receptor subtypes A(2A) and A(2B) in the rabbit lacrimal gland, and to characterize their role in regulated acinar cell secretion.

METHODS: Expression of the receptors was investigated using reverse transcriptase-PCR (RT-PCR) and immunofluorescence, and secretion effects were studied using a secretion assay in isolated lacrimal gland acinar cells.

RESULTS: Presence of both receptors was detected by RT-PCR and immunofluorescence. The secretion assay revealed a minor effect of stimulation of the A(2) receptors, and a strong synergistic effect with the cholinergic agonist Cch. The synergistic effect was significantly reduced by the A(2B) antagonist PSB 1115, but not by the A(2A) antagonist SCH 58261, indicating that A(2B) is the receptor responsible for this potentiation.

CONCLUSIONS: The study reveals the presence of the adenosine A(2) receptor subtypes as well as a role for them in lacrimal gland secretion, and especially in the synergy with purinergic and cholinergic stimulation.

HSV kategori
Forskningsprogram
Naturvetenskap, Biomedicinsk vetenskap
Identifikatorer
urn:nbn:se:lnu:diva-7814 (URN)20465439 (PubMedID)
Tilgjengelig fra: 2010-08-26 Laget: 2010-08-26 Sist oppdatert: 2017-12-12bibliografisk kontrollert
3. Intracellular events following adenosine and carbachol stimulation of rabbit lacrimal gland secretion
Åpne denne publikasjonen i ny fane eller vindu >>Intracellular events following adenosine and carbachol stimulation of rabbit lacrimal gland secretion
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:lnu:diva-13661 (URN)
Tilgjengelig fra: 2011-08-08 Laget: 2011-08-08 Sist oppdatert: 2012-01-03bibliografisk kontrollert
4. The adenosine A2a receptor is up-regulated in the lacrimal glands of NOD mice, an experimental model of Sjögren's syndrome
Åpne denne publikasjonen i ny fane eller vindu >>The adenosine A2a receptor is up-regulated in the lacrimal glands of NOD mice, an experimental model of Sjögren's syndrome
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:lnu:diva-13662 (URN)
Tilgjengelig fra: 2011-08-08 Laget: 2011-08-08 Sist oppdatert: 2012-01-03bibliografisk kontrollert

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