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F Sundler

Publications and source records attributed to F Sundler.

At least 37 records · Page 2Linked to original sources
PubMed1999

PACAP is an islet neuropeptide which contributes to glucose-stimulated insulin secretion.

Pituitary adenylate cyclase activating peptide (PACAP) is a ubiquitously distributed neuropeptide which also is localized to pancreatic islets and stimulates insulin secretion. We examined whether endogenous PACAP within the islets might contribute to glucose-stimulated insulin secretion by immunoneutralizing endogenous PACAP. Immunocytochemistry showed that PACAP immunoreactivity is expressed in nerve terminals within freshly isolated rat islets, but not in islets that had been cultured for 48 h. In contrast, islet endocrine cells did not display PACAP immunoreactivity. Addition of either of two specific PACAP antisera markedly inhibited glucose (11.1 mmol/l)-stimulated insulin secretion from freshly isolated rat islets, whereas a control rabbit serum did not affect glucose-stimulated insulin secretion. In contrast, the PACAP antisera had no effect on glucose-stimulated insulin secretion in cultured islets. Based on these results we therefore suggest that PACAP is an islet neuropeptide which is required for the normal insulinotropic action of glucose.

Animals↗
PubMed1999

Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice.

The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1(+) T cells (NKT cells), and gamma/delta T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1(+) cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3(+) T cell infiltration as well as increased levels of interleukin (IL)-4, IL-5, and IL-12 in bronchoalveolar lavage fluid in a murine model of allergic asthma. Moreover, systemic allergen-specific immunoglobulin (Ig)E and IgG2a levels and the number of IL-4 and interferon gamma-producing splenic cells were diminished in mice depleted of NK1.1(+) cells before the priming regime. Depletion of NK1.1(+) cells during the challenge period only did not influence pulmonary eosinophilic inflammation. CD1d1 mutant mice, deficient in NKT cells but with normal NK cells, developed lung tissue eosinophilia and allergen-specific IgE levels not different from those observed in wild-type mice. Mice deficient in gamma/delta T cells showed a mild attenuation of lung tissue eosinophilia in this model. Taken together, these findings suggest a critical role of NK cells, but not of NKT cells, for the development of allergen-induced airway inflammation, and that this effect of NK cells is exerted during the immunization. If translatable to humans, these data suggest that NK cells may be critically important for deciding whether allergic eosinophilic airway disease will develop. These observations are also compatible with a pathogenic role for the increased NK cell activity observed in human asthma.

Allergens↗
PubMed1999

Pituitary adenylate cyclase-activating polypeptide and islet amyloid polypeptide in primary sensory neurons: functional implications from plasticity in expression on nerve injury and inflammation.

Primary sensory neurons serve a dual role as afferent neurons, conveying sensory information from the periphery to the central nervous system, and as efferent effectors mediating, e.g., neurogenic inflammation. Neuropeptides are crucial for both these mechanisms in primary sensory neurons. In afferent functions, they act as messengers and modulators in addition to a principal transmitter; by release from peripheral terminals, they induce an efferent response, "neurogenic inflammation," which comprises vasodilatation, plasma extravasation, and recruitment of immune cells. In this article, we introduce two novel members of the sensory neuropeptide family: pituitary adenylate cyclase-activating polypeptide (PACAP) and islet amyloid polypeptide (IAPP). Whereas PACAP, a vasoactive intestinal polypeptide-resembling peptide, predominantly occurs in neuronal elements, IAPP, which is structurally related to calcitonin gene-related peptide, is most widely known as a pancreatic beta-cell peptide; as such, it has been recognized as a constituent of amyloid deposits in type 2 diabetes. In primary sensory neurons, under normal conditions, both peptides are predominantly expressed in small-sized nerve cell bodies, suggesting a role in nociception. On axotomy, the expression of PACAP is rapidly induced, whereas that of IAPP is reduced. Such a regulation of PACAP suggests that it serves a protective role during nerve injury, but that of IAPP may indicate that it is an excitatory messenger under normal conditions. In contrast, in localized adjuvant-induced inflammation, expression of both peptides is rapidly induced. For IAPP, studies in IAPP-deficient mice support the notion that IAPP is a pronociceptive peptide, because these mutant mice display a reduced nociceptive response when challenged with formalin.

Amyloid↗
PubMed1999

Expression of calcitonin gene-related peptide-1 receptor mRNA in human tooth pulp and trigeminal ganglion.

Numerous nerve fibres containing calcitonin gene-related peptide (CGRP) were found by immunocytochemistry in human molar pulp. These nerves were often seen around small blood vessels and as free endings without vascular contact. In the trigeminal ganglion a large number of CGRP-immunoreactive nerve-cell bodies, mostly of small to medium size, was encountered. Reverse transcriptase-polymerase chain reaction, using specific sense and antisense primers, detected mRNA expression of the human CGRP1 receptor in the pulp tissue and the trigeminal ganglion. Thus, both CGRP-containing nerve fibres and CGRP1 receptor mRNA are present in human tooth pulp, where they may be involved in the regulation of vascular tone and other local reactions to injury.

Adult↗
PubMed1999

Increased expression, axonal transport and release of pituitary adenylate cyclase-activating polypeptide in the cultured rat vagus nerve.

The expression and axonal transport of pituitary adenylate cyclase-activating polypeptide (PACAP) was studied in the cultured vagus nerve of the rat by immunocytochemistry and in situ hybridization. The number of neurons immunoreactive for PACAP increased markedly within the nodose ganglion during a 24-48 h culture period, as did the number of cells containing messenger RNA for PACAP. PACAP was found to be axonally transported and accumulated at the site of a crush injury. The peptide was also released at this site. Addition of PACAP to regenerating nerves in culture did not affect axonal outgrowth, neither did antibodies against PACAP. Separate experiments showed that neither PACAP-27 nor PACAP-38 affected proliferation of non-neuronal cells measured as the incorporation of [3H]thymidine. In contrast, forskolin, another potent stimulator of adenylate cyclase besides PACAP, dramatically decreased [3H]thymidine incorporation. The results showed that, during regeneration of peripheral nerves, PACAP expression increases and the peptide is transported into the regenerating nerve, where it is released. The functional significance of this release is unknown, but it does not seem to be directly related to the initiation of proliferation of Schwann cells or initial axonal outgrowth.

Animals↗
PubMed1999

Antisera against rat recombinant histidine decarboxylase: immunocytochemical studies in different species.

Histamine is involved in many important biological processes such as allergic reactions, gastric acid secretion and neurotransmission. The formation of histamine is catalysed by the enzyme histidine decarboxylase. In order to understand the role of histamine in different tissues, information about the cellular localisation of the decarboxylase is important. However, the availability of antisera against the enzyme, which can be used in immunocytochemical techniques, has so far been limited, mainly due to the difficulties in purifying sufficient amounts of histidine decarboxylase from various tissues. In the present study we describe the use of antisera raised against rat recombinant histidine decarboxylase to localise the enzyme immunocytochemically in the gastric mucosa of different mammals and submammalian vertebrates. The antisera specifically stained histidine decarboxylase-immunoreactive cells in the gastric mucosa of not only rat, but also of species like frog, chicken, mouse and dog. This is the first report describing the immunocytochemical distribution of the decarboxylase in the gastric mucosa of species other than rat. These antisera are likely to become valuable tools for further studies of the immunocytochemical localisation of histidine decarboxylase.

Animals↗
PubMed1999

Neuropeptide-containing C-fibres and wound healing in rat skin. Neither capsaicin nor peripheral neurotomy affect the rate of healing.

Wound healing in rat skin was studied in standardized wounds inflicted on both hind legs after unilateral sciatic nerve sectioning and/or capsaicin-induced depletion of sensory nerve (C-fibre) neuropeptide content. Daily visual inspection, histological examination and immunohistochemistry with antibodies against substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide, neuropeptide Y and a pan-neuronal marker, protein gene product 9.5 (PGP 9.5) were used to assess wound healing and determine the distribution of dermal nerve fibres. In controls, nerve fibre density in the wound tissue was low during the first few days after wound infliction, but started to increase on day 4, reaching a peak on day 7 when 25% of medial wounds and 70% of lateral wounds were healed. All wounds were healed on day 11, a scar appearing on day 14 followed by a decrease in nerve fibre density. Capsaicin treatment and/or sciatic nerve sectioning reduced the density of CGRP-immunoreactive nerve fibres by 70% and that of PGP 9.5-immunoreactive fibres by 50%. The capsaicin-induced reduction in PGP 9.5-immunoreactive nerve fibre density is attributable to partial destruction of peripheral nerve fibres. CGRP-immunoreactive and PGP 9.5-immunoreactive nerve fibre density was restored both in capsaicin-treated and denervated groups, reaching a maximum, corresponding to the original level, by days 4-10. Neither the reduction in nerve fibre density following sciatic nerve sectioning nor the impairment of sensory nerve functional capacity following capsaicin treatment affected the rate of wound healing, all wounds being closed on day 11. The study shows that it is difficult to knock out all cutaneous sensory innervation. Thirty per cent of C-fibre innervation seems enough to ensure a normal wound healing.

Animals↗
PubMed1999

Islet perturbations in rats fed a high-fat diet.

The islet response to a high-fat diet, which induces insulin resistance, was investigated in Sprague-Dawley rats. It was found that the insulin response to glucose (15 or 25 mg/min, i.v.) was not different between rats given a high-fat diet and control rats after 2 weeks but was significantly reduced in rats fed high-fat diets after 4 (by 46+/-9%; p<0.001) and 8 weeks (by 68+/-12%; p<0.001). However, after 2 weeks of a high-fat diet, stimulated insulin secretion from isolated islets incubated for 60 min in 5.6, 8.3, and 11.1 mM glucose was impaired. When islets isolated from rats given a high-fat diet for 2 weeks were perifused, it was evident that the first-phase insulin secretion was impaired (seen during the first 6 min after increase of glucose from 3.3 to 8.3 mM). Insulin gene expression, examined by quantitative in situ hybridization, was impaired after 2 weeks of high-fat diet (52% decrease in mRNA-labeling; p<0.001). Islet hypertrophy was not evident in rats given high-fat diet, as determined by areas of either islet profiles in dark-field images or isolated islets. Islet innervation, as revealed by immunostaining for vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), was increased after 2, 4, and 8 weeks of high-fat diet. Thus induction of insulin resistance by high-fat diet in Sprague-Dawley rats results after 2 weeks in impaired glucose-stimulated insulin secretion in vitro, impaired insulin gene expression, and hyperinnervation of the islets without any sign of islet hypertrophy, whereas the in vivo insulin response to glucose, although normal after 2 weeks, is impaired after 4 weeks.

Animals↗
PubMed1999

Modulatory role of adrenergic nerves on dexamethasone-induced islet cell NPY expression in the rat: evidence from chemical sympathectomy.

We previously demonstrated induction of neuropeptide Y (NPY) in rat islet beta-cells by the glucocorticoid dexamethasone (DEX). Because noradrenergic nerves appear to regulate NPY expression in the central nervous system (CNS), we investigated whether DEX-induced islet cell expression of NPY could be modulated by catecholaminergic nerves. Therefore rats were treated with DEX (2 mg/kg, i.p., for 12 days) and received injections of 6-hydroxydopamine (6-OHDA; 80 mg/kg, i.v., at day 1 or 10). 6-OHDA treatment eliminated islet adrenergic nerves. The frequency of NPY-immunoreactive islet cells and the levels of islet cell NPY messenger RNA (mRNA) were markedly lower in rats given 6-OHDA at day 1 of the DEX-treatment period. In contrast, the frequency of NPY-immunoreactive cells and levels of islet cell NPY mRNA in DEX-treated rats receiving 6-OHDA at day 10 did not differ from those treated with DEX alone. The findings suggest that DEX-induced islet cell expression of NPY is partially dependent on adrenergic nerves and that the effect of sympathectomy is exerted at an early stage of the NPY induction.

Adrenergic Agents↗
PubMed1999

Local downregulation of enterochromaffin-like cell histamine formation in ulcer healing: a study in rats.

BACKGROUND AND AIMS: Although enterochromaffin-like (ECL) cells are the major source of histamine for the regulation of gastric acid secretion, their role in ulcer healing has not been fully investigated. The present study aimed to investigate changes in ECL cell components as well as markers for somatostatin cells, parietal cells and macrophages during the healing of experimental ulcers in rats. METHODS: Standardised ulcer was induced directly in the rat gastric mucosa by brief application of acetic acid. At different time intervals following ulcer induction (1-15 days), histamine, histidine decarboxylase (HDC), chromogranin A, pancreastatin, vesicular monoamine transporter 2 (VMAT-2), H-K-ATPase, somatostatin as well as ED1 and ED2 (macrophage markers) were localised by immunocytochemistry. ED1- and histamine-immunoreactive cells were counted at different time points. HDC- and VMAT-2-immunoreactive cells were demonstrated by double staining and counted. The mRNA of HDC, chromogranin A and somatostatin was demonstrated by in situ hybridisation and quantitated by computerised image analysis. RESULTS: HDC immunoreactivity and mRNA were markedly reduced in the ECL cells at the ulcer margin from day 1 following ulcer induction and onwards; after day 5 HDC immunoreactivity and mRNA rose gradually and had almost normalised by day 15. This local and transient downregulation of HDC was accompanied by a similar decrease in ECL cell histamine. In contrast to HDC and histamine, other ECL cell components (chromogranin A, pancreastatin, VMAT-2) as well as somatostatin and H-K ATPase were still demonstrable at the ulcer margin and displayed no major changes at any time point studied. Of the macrophage markers, ED1, but not ED2, could be identified at the ulcer margin, and the number of ED1-immunoreactive cells was high in the ulcer margin from day 1 to day 5 after ulcer induction. The increase in ED1-positive cells and the decrease in HDC-expressing cells were coincident in time and localisation. CONCLUSION: The present results revealed a local and transient downregulation of HDC in the ECL cells at the ulcer margin. This may account for the decrease in ECL cell histamine observed. The local infiltration of macrophages into the ulcer margin suggests that inflammatory mediators are involved in the local suppression of ECL cell activity during ulcer healing.

Acetic Acid↗
PubMed1999

Lack of systemic anaphylaxis and aeroallergen-induced airway plasma extravasation in allergic immunoglobulin-deficient mice.

BACKGROUND: In Ig-deficient mice allergen challenge-induced pulmonary late phase inflammation is at least as pronounced as in wild-type animals. This study investigates immediate hypersensitivity responses in these mice. METHODS: To examine the acute plasma extravasation response in airway tissue, immunized Ig-deficient and wild-type mice and sham-immunized wild-type controls were subjected to 15 min ovalbumin aerosol challenge. 125I-albumin was injected (i.v.) 1 min prior to challenge. Immediately after challenge 131I-albumin was injected and the experiment was terminated. Plasma and trachea were analyzed for 125I and 131I, and the amount of extravasated plasma in the trachea was calculated. To study the development of systemic anaphylaxis immunized Ig-deficient and wild-type animals received intravenous allergen challenge followed by determination of mast cell responses and plasma histamine levels. RESULTS: Allergen aerosol-exposed immunized wild-type mice exhibited marked plasma extravasation in the trachea (pd0.01 vs. wild-type controls), but in the corresponding Ig-deficient mice there was no increased extravasation. Immunized Ig-deficient mice receiving intravenous allergen challenge were resistant to anaphylactic shock. By contrast, the wild-type animals developed systemic anaphylaxis, accompanied by plasma extravasation, mast cell degranulation, elevated plasma histamine and rapid death. CONCLUSION: The present data are evidence that immunoglobulins are crucial for the development of immediate (type 1) responses. These findings together with our previous observations on late-phase pulmonary responses suggest that immediate hypersensitivity processes are unimportant for development of the late phase inflammation in the respiratory tract of mice.

Acute-Phase Reaction↗
PubMed1999

Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells.

Triglycerides in the beta-cell may be important for stimulus-secretion coupling, through provision of a lipid-derived signal, and for pathogenetic events in NIDDM, where lipids may adversely affect beta-cell function. In adipose tissues, hormone-sensitive lipase (HSL) is rate-limiting in triglyceride hydrolysis. Here, we investigated whether this enzyme is also expressed and active in beta-cells. Northern blot analysis and reverse transcription-polymerase chain reaction demonstrated that HSL is expressed in rat islets and in the clonal beta-cell lines INS-1, RINm5F, and HIT-T15. Western blot analysis identified HSL in mouse and rat islets and the clonal beta-cells. In mouse and rat, immunocytochemistry showed a predominant occurrence of HSL in beta-cells, with a presumed cytoplasmic localization. Lipase activity in homogenates of the rodent islets and clonal beta-cells constituted 2.1 +/- 0.6% of that in adipocytes; this activity was immunoinhibited by use of antibodies to HSL. The established HSL expression and activity in beta-cells offer a mechanism whereby lipids are mobilized from intracellular stores. Because HSL in adipocytes is activated by cAMP-dependent protein kinase (PKA), PKA-regulated triglyceride hydrolysis in beta-cells may participate in the regulation of insulin secretion, possibly by providing a lipid-derived signal, e.g., long-chain acyl-CoA and diacylglycerol.

Adipocytes↗
PubMed1998

Reduced nociceptive behavior in islet amyloid polypeptide (amylin) knockout mice.

Islet amyloid polypeptide (IAPP or amylin) is predominantly expressed by insulin cells, but occurs also in primary sensory neurons in the rat. Here, using mice targeted for a null mutation in the IAPP gene, we establish murine expression of IAPP in sensory neurons; its distribution in a population of calcitonin gene-related peptide-containing neurons in the spinal cord and dorsal root ganglion is similar to that previously described in the rat. We also report the IAPP mutant mice display a reduced pain response in the paw formalin test. Adjuvant-induced joint inflammation was not altered in IAPP mutants, arguing against a peripheral inflammatory abnormality. These findings lead us to suggest that IAPP has a pro-nociceptive function in primary sensory neurons.

Amyloid↗
PubMed1998

CCK receptor subtype in insulin-producing cells: a combined functional and in situ hybridization study in rat islets and a rat insulinoma cell line.

Cholecystokinin (CCK) stimulates insulin secretion. It is, however, not established whether CCK receptors are expressed in insulin-producing cells. We therefore investigated, by in situ hybridization, whether CCK-A or CCK-B receptor mRNA could be detected in normal rat pancreatic islets and in the rat insulinoma cell line, RINm5F. The CCK-A, but not the CCK-B, receptor transcript was detected in both islets and RINm5F cells. Islet CCK-A receptors were mostly confined to the center of the islets corresponding to the distribution of the B cells. In RINm5F cells, insulin release was not significantly affected by cholecystokinin (CCK)-8-S (10(-13) to 10(-7) M), which is in contrast to the insulinotropic effect of CCK-8-S in normal rat islets. Similarly, in FURA-2AM-loaded cells, CCK-8-S (10(-11) to 10(-7) M) was without effect on the intracellular Ca2+ concentration ([Ca2+]ic) in RINm5F cells, whereas CCK-8-S (10(-7) M) markedly increased [Ca2+]ic (by 366+/-2 nM (P < 0.001) in normal rat islet cells. We conclude that the CCK-A, but not the CCK-B, receptor subtype is expressed in both normal rat islets and in the rat insulinoma-derived cell line RINmS5F. There is, however, a functional difference between normal islets and the RINm5F cells with respect to effects of CCK-8-S on insulin release and [Ca2+]ic.

Animals↗
PubMed1998

Expression of non-classical islet hormone-like peptides during the embryonic development of the pancreas.

Understanding of islet embryogenesis may prove to be key in the design of future therapies for diabetes directed at re-initiating islet growth, with the goal to replace and/or replenish the impaired beta-cell mass in the disease. In this context, studies of islet neurohormonal peptides, known to play a role in the local regulation of islet function, and their expression during islet embryogenesis are important. Here we review our studies on the embryonic islet expression of islet amyloid polypeptide (IAPP) and the PP-fold peptides pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY). IAPP, which is constitutively expressed in beta- and delta-cells in the adult rat, was found to occur in the assumed pluripotent islet progenitor cell, together with PYY, glucagon, and to a lesser extent with insulin. As development proceeds, the insulin/IAPP phenotype is segregated from that of PYY/glucagon; with the formation of islet-like structures, insulin/IAPP-expressing cells primarily occupy their central portions, while PYY/glucagon-expressing cells are found in their periphery. At the time of formation of islet-like structures, expression of NPY is induced in the insulin/IAPP-containing cells. Whereas NPY-expression ceases at birth, PYY is constitutively expressed in non-beta-cells in the mature rat. Expression of PP is induced just prior to birth in a separate population of islet cells, occasionally co-expressed with PYY. Although a clear role for these peptides during embryogenesis has not been identified, they conceivably could play a role in the control of insulin secretion, islet growth and islet blood flow.

Amyloid↗
PubMed1998

Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin).

Islet amyloid polypeptide (IAPP or amylin) is costored and cosecreted with insulin and may regulate insulin secretion and blood glucose handling. However, the role and importance of endogenous IAPP in the regulation of insulin release and glucose homeostasis have been controversial. Here we report on the generation and phenotypic analysis of IAPP-deficient mice. These mice have normal, or near to normal, basal levels of circulating insulin and glucose. However, following glucose administration, IAPP-deficient males presented increased insulin responses paralleled with a more rapid blood glucose elimination compared to wild-type controls. Blood glucose elimination was also found to be enhanced in IAPP-deficient females, but the insulin response in this gender did not differ from controls. In a transgenic rescue experiment, using an insulin-promoter human-IAPP fusion gene, insulin responses and blood glucose elimination were reversed in IAPP-deficient males, whereas the female phenotype appeared unaffected. Our results provide the first firm evidence of a physiological role for endogenous IAPP and indicate that IAPP, apparently in a gender-dependent manner, limits the degree of glucose-induced insulin secretion and the rate of blood glucose elimination.

Amyloid↗
PubMed1998

Protein kinase B is expressed in pancreatic beta cells and activated upon stimulation with insulin-like growth factor I.

Protein kinase B (PKB) is involved in signaling to a multitude of important cellular events and is activated by insulin and growth factors, including insulin-like growth factor I (IGF-I). We show here expression of PKB in pancreatic islets and in the beta cell lines HIT-T15, INS-1, and RINm5F. Expression of PKB mRNA and the presence of PKB isoforms (alpha, beta, and gamma) were assessed by Northern blot analysis and RT-PCR, respectively. Antibodies recognizing different parts of PKB isoforms were employed to demonstrate PKB protein expression by immunoblot analysis. By use of immunohistochemistry in rat and mouse pancreatic tissue sections, PKB was localized to predominantly beta cells. Regulation of PKB was examined in INS-1 and RINm5F cells; upon stimulation with IGF-I (5-10 min), PKB was phosphorylated and activated (approximately 3-fold) by a wortmannin-sensitive mechanism, indicating involvement of phosphatidylinositol-3 kinase. The possible participation of PKB in signal transduction pathways modulating cAMP-dependent insulin secretion and in proliferation of beta cells is discussed.

Animals↗