| 1. |
- Ågren, Johan
(författare)
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Water transport through perinatal skin : Barrier function and aquaporin water channels
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- While constituting a well functioning interface with the aqueous environment in utero, the skin offers a poor barrier after very preterm birth. As a result, transepidermal water loss (TEWL) is high, a fact which has important clinical consequences in these infants. To investigate the transport of water through perinatal skin and the potential role of aquaporin (AQP), a water channel protein, in this process, we determined TEWL in a group of extremely preterm infants, and in an experimental rat model we analyzed the expression and distribution of AQP in perinatal skin in relation to TEWL, skin surface hydration and water content. The effects of antenatal corticosteroids (ANS) and of restricted intake of fluids and nutrients on barrier characteristics of the perinatal skin and its AQP expression were also studied.In infants born at 24 and 25 weeks of gestation TEWL was very high in the first days after birth and decreased with increasing postnatal age. At a postnatal age of 4 weeks, TEWL was still twice as high as previously reported in infants born at a gestational age of 25-27 weeks and four times higher than in infants born at term. In the rat model, immunohistochemical analysis revealed that AQP1 and AQP3 are abundantly expressed in the skin. AQP1 was expressed exclusively in dermal capillaries and AQP3 in basal layers of the epidermis. AQP1 and AQP3 mRNA as assessed by semiquantitative RT-PCR was higher in fetal than in adult skin. As in infants, TEWL and skin surface hydration were inversely related to gestational age in the rat. In preterm rat pups exposed to ANS, TEWL and skin surface hydration were lower than in unexposed controls, and AQP3 expression was selectively induced by ANS. In term newborn rat pups, restriction of fluid and nutrient intake resulted in a higher skin water content and higher TEWL early after birth, while at an age of 7 days TEWL was lower in fasting rat pups than in controls, although skin water content was still higher.To conclude, TEWL is very high in extremely preterm infants early after birth and then decreases at a slower rate than previously reported for a group of slightly more mature infants. This is the first time that the distribution and gene expression of AQP1 and AQP3 have been demonstrated in perinatal skin. The localization and expression of AQP in the skin might indicate that these water channels are involved in the regulation of skin hydration and transepidermal water transport in the fetus and newborn infant.
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| 2. |
- Flemström, Gunnar, et al.
(författare)
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Duodenal defence mechanisms: : Role of mucosal bicarbonate secretion
- 2002
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Ingår i: InflammoPharmacology. - : Springer Science and Business Media LLC. - 0925-4692 .- 1568-5608. ; 10:4-6, s. 327-332
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Tidskriftsartikel (refereegranskat)abstract
- The duodenal epithelium secretes bicarbonate at higher rates than does the stomach (or more distal small intestine) and the duodenal secretion is currently accepted as the most important defence mechanism against acid discharged from the stomach. HCO3 - entering the continuous layer of visco-elastic mucus gel on top of the epithelial surface maintains pH in its cell-facing portion at neutrality at acidities encountered in the healthy duodenum. The secretion is decreased in patients with acute and chronic duodenal ulcer disease and is inhibited by non-steroidal anti-inflammatory agents. Studies of the neurohumoral control of the duodenal alkaline secretion and of acid/base transport processes and intracellular signaling in duodenal enterocytes are currently of great research interest.
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| 3. |
- Flemström, Gunnar, et al.
(författare)
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Short fasting dramatically decreases rat duodenal secretory responsiveness to orexin A but not to VIP or melatonin
- 2003
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 285:6, s. G1091-G1096
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Tidskriftsartikel (refereegranskat)abstract
- Orexins are involved in the central nervous control of appetite and behavior, and in addition, they are present in endocrine cells and/or neurons in the intestine. The role of these peptides in peripheral regulation of intestinal secretion has not been investigated. We thus compared the effects of orexin A and some established secretagogues on duodenal HCO3- secretion in fed rats with effects in rats exposed to short (overnight) food deprivation. Rats were anesthetized with thiobarbiturate, a 12-mm segment of proximal duodenum with intact blood supply was cannulated in situ, and the alkaline secretion was titrated by pH stat. Secretagogues were supplied specifically to the duodenum by close intra-arterial infusion. Orexin A (60-600 pmol·kg-1·h-1) caused marked and dose-dependent stimulation of the duodenal secretion in fed animals but did not affect secretion in overnight food-deprived animals. Similarly, short fasting caused a 100-fold increase in the amount of the muscarinic agonist bethanechol (from 50 to 5,000 nmol·kg-1·h-1) required for stimulation of the secretion. In contrast, the secretory responses to VIP (50-1,000 pmol·kg-1·h-1) and melatonin (20-200 nmol·kg-1·h-1) were not affected. The appetite-regulating peptide orexin A is thus a stimulant of intestinal secretion, but the response to this peptide as well as the muscarinic agonist bethanechol is markedly dependent on previous intake of food. Overnight fasting is a standard experimental procedure in studies of gastrointestinal function and pathophysiology in humans and animals. Studies made on neuroendocrine control of intestinal secretion may require reevaluation with respect to feeding status.
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| 4. |
- Holmqvist, Tomas, 1974-
(författare)
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Signaling via Orexin Receptors : A Pharmacological Study
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The orexin receptors are a pair of newly discovered G-protein coupled receptors which are activated by the neuropeptides orexins and play a role in sleep/vigilance, apetite/metabolism and neuroendocrine regulation. On a cellular level receptor activation results in, to name but a few effects, elevation of intracellular calcium and depolarisation. All cellular effects display an uncommon dependence of extracellular Ca2+, which has been shown to be due to influx of extracellular Ca2+ as a primary response.Here we provide evidence for a high specificity of orexin receptors for orexin peptides over other neuropeptides, despite previous reports of the opposite. Other neuropeptides could neither displace orexin-A from orexin receptors, nor affect functional responses induced by orexin peptides via orexin receptors. In an effort to assess the determinants of orexin-A binding to orexin receptors orexin-A was truncated/mutated and tested for functional responses. It was found that alterations in the orexin-A sequence had more prominent effects on the activation of OX1 than on OX2 receptors.When the signaling of orexin receptors was investigated in neuron-like cells it was found that they couple to Ca2+-metabolism and PLC activation in a manner similar to that in non-neuronal cells. Investigations of OX1 receptor regulation of adenylyl cyclases showed orexin receptors to have a dual effect on the production of cAMP. A high-affinity inhibitory coupling and a low-affinity stimulatory coupling. The stimulatory coupling was determined to consist of two components, a low potency GS-coupling and a high-potency PKC coupling.In conclusion we have shown that orexin receptors are preferentially activated by orexin peptides and the receptors couple to Ca2+-metabolism in a similar way in different contexts. Orexin receptors couple to both the phospholipase C and the adenylyl cyclase pathway and to some extent these pathways converge in the production of cAMP.
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| 5. |
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| 6. |
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| 7. |
- Sjöblom, Markus, et al.
(författare)
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Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretion
- 2003
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Ingår i: Journal of Pineal Research. - 0742-3098 .- 1600-079X. ; 34:4, s. 288-293
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid-induced stimulation of the secretion. Rats were anaesthetized (Inactin(R)) and a 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ . Mucosal HCO secretion (pH-stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 mu m increased (P < 0.05) the secretion from 7.20 +/- 1.35 to 13.20 +/- 1.51 mu Eq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 +/- 0.82 to 12.35 +/- 1.51 mu Eq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid-induced secretion.
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| 8. |
- Sjöblom, Markus, et al.
(författare)
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Melatonin-induced calcium signaling in clusters of human and rat duodenal enterocytes
- 2003
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 284:6, s. G1034-G1044
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Tidskriftsartikel (refereegranskat)abstract
- The amount of melatonin present in enterochromaffin cells in the alimentary tract is much higher than that in the central nervous system, and melatonin acting at MT2 receptors mediates neural stimulation of mucosal HCO3- secretion in duodenum in vivo. We have examined effects of melatonin and receptor ligands on intracellular free calcium concentration ([Ca2+](i)) signaling in human and rat duodenal enterocytes. Clusters of interconnecting enterocytes (10-50 cells) were isolated by mild digestion ( collagenase/dispase) of human duodenal biopsies or rat duodenal mucosa loaded with fura-2 AM and attached to the bottom of a temperature-controlled perfusion chamber. Clusters provided viable preparations and respond to stimuli as a syncytium. Melatonin and melatonin receptor agonists2-iodo-N-butanoyl-5-methoxytryptamine and 2-iodomelatonin (1.0-100 nM) increased enterocyte [Ca2+](i), EC50 of melatonin being 17.0 +/- 2.6 nM. The MT2 receptor antagonists luzindole and N-pentanoyl-2-benzyltryptamine abolished the [Ca2+](i) responses. The muscarinic antagonist atropine ( 1.0 muM) was without effect on basal [Ca2+](i) and did not affect the response to melatonin. In the main type of response, [Ca2+](i) spiked rapidly and returned to basal values within 4-6 min. In another type, the initial rise in [Ca2+](i) was followed by rhythmic oscillations of high amplitude. Melatonin-induced enterocyte [Ca2+](i) signaling as well as mucosal cell-to-cell communication may be involved in stimulation of duodenal mucosal HCO3- secretion.
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