|
1
|
Rahman MM, Afroz S, Arthur S, Sundaram U. Mast Cell Mediated Regulation of Small Intestinal Chloride Malabsorption in SAMP1/YitFc Mouse Model of Spontaneous Chronic Ileitis. Cells 2021; 10:cells10030697. [PMID: 33801010 PMCID: PMC8004028 DOI: 10.3390/cells10030697] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/13/2021] [Accepted: 03/18/2021] [Indexed: 12/19/2022] Open
Abstract
In Inflammatory Bowel Disease (IBD), malabsorption of electrolytes (NaCl) results in diarrhea. Inhibition of coupled NaCl absorption, mediated by the dual operation of Na:H and Cl:HCO3 exchangers on the brush border membrane (BBM) of the intestinal villus cells has been reported in IBD. In the SAMP1/YitFcs (SAMP1) mice model of spontaneous ileitis, representing Crohn’s disease, DRA (Downregulated in Adenoma) mediated Cl:HCO3 exchange was shown to be inhibited secondary to diminished affinity of the exchanger for Cl. However, NHE3 mediated Na:H exchange remained unaffected. Mast cells and their secreted mediators are known to be increased in the IBD mucosa and can affect intestinal electrolyte absorption. However, how mast cell mediators may regulate Cl:HCO3 exchange in SAMP1 mice is unknown. Therefore, the aim of this study was to determine the effect of mast cell mediators on the downregulation of DRA in SAMP1 mice. Mast cell numbers and their degranulation marker enzyme (β-hexosaminidase) levels were significantly increased in SAMP1 mice compared to control AKR mice. However, treatment of SAMP1 mice with a mast cell stabilizer, ketotifen, restored the β-hexosaminidase enzyme levels to normal in the intestine, demonstrating stabilization of mast cells by ketotifen. Moreover, downregulation of Cl:HCO3 exchange activity was restored in ketotifen treated SAMP1 mice. Kinetic studies showed that ketotifen restored the altered affinity of Cl:HCO3 exchange in SAMP1 mice villus cells thus reinstating its activity to normal. Further, RT-qPCR, Western blot and immunofluorescence studies showed that the expression levels of DRA mRNA and BBM protein, respectively remained unaltered in all experimental conditions, supporting the kinetic data. Thus, inhibition of Cl:HCO3 exchange resulting in chloride malabsorption leading to diarrhea in IBD is likely mediated by mast cell mediators.
Collapse
|
|
2
|
Abstract
Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer.
Collapse
Affiliation(s)
- Kalpna Gupta
- Vascular Biology Center, Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Ilkka T Harvima
- Department of Dermatology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| |
Collapse
|
|
3
|
Governa P, Marchi M, Cocetta V, De Leo B, Saunders PTK, Catanzaro D, Miraldi E, Montopoli M, Biagi M. Effects of Boswellia Serrata Roxb. and Curcuma longa L. in an In Vitro Intestinal Inflammation Model Using Immune Cells and Caco-2. Pharmaceuticals (Basel) 2018; 11:ph11040126. [PMID: 30463367 PMCID: PMC6316569 DOI: 10.3390/ph11040126] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased because of their effectiveness and favourable safety profile, compared to conventional drugs. Boswellia serrata Roxb. and Curcuma longa L. are amongst the most promising herbal drugs, however, their clinical use in inflammatory bowel diseases is limited and little is known on their mechanism of action. The aim of this work was to investigate the effects of two phytochemically characterized extracts of B. serrata and C. longa in an in vitro model of intestinal inflammation. Their impact on cytokine release and reactive oxygen species production, as well as the maintenance of the intestinal barrier function and on intestinal mucosa immune cells infiltration, has been evaluated. The extracts showed a good protective effect on the intestinal epithelium at 1 µg/mL, with TEER values increasing by approximately 1.5 fold, compared to LPS-stimulated cells. C. longa showed an anti-inflammatory mechanism of action, reducing IL-8, TNF-α and IL-6 production by approximately 30%, 25% and 40%, respectively, compared to the inflammatory stimuli. B. serrata action was linked to its antioxidant effect, with ROS production being reduced by 25%, compared to H2O2-stimulated Caco-2 cells. C. longa and B. serrata resulted to be promising agents for the management of inflammatory bowel diseases by modulating in vitro parameters which have been identified in the clinical conditions.
Collapse
Affiliation(s)
- Paolo Governa
- Department of Physical Sciences, Hearth and Environment, University of Siena, Via Laterina 8, 53100 Siena, Italy.
- Department of Biotechnology, Chemistry and Pharmacy⁻Department of Excellence 2018⁻2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
| | - Maddalena Marchi
- Department of Physical Sciences, Hearth and Environment, University of Siena, Via Laterina 8, 53100 Siena, Italy.
| | - Veronica Cocetta
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo Egidio Meneghetti 2, 35131 Padua, Italy.
| | - Bianca De Leo
- MRC Centres for Inflammation Research and Reproductive Health, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
| | - Philippa T K Saunders
- MRC Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
| | - Daniela Catanzaro
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo Egidio Meneghetti 2, 35131 Padua, Italy.
| | - Elisabetta Miraldi
- Department of Physical Sciences, Hearth and Environment, University of Siena, Via Laterina 8, 53100 Siena, Italy.
| | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo Egidio Meneghetti 2, 35131 Padua, Italy.
- Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padua, Italy.
| | - Marco Biagi
- Department of Physical Sciences, Hearth and Environment, University of Siena, Via Laterina 8, 53100 Siena, Italy.
| |
Collapse
|
|
4
|
A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis. Sci Rep 2017; 7:10180. [PMID: 28860510 PMCID: PMC5579262 DOI: 10.1038/s41598-017-10465-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 08/10/2017] [Indexed: 02/07/2023] Open
Abstract
The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti-inflammatory properties. In UC patients, sST2 is further increased by corticosteroid treatment; however, the glucocorticoid-mediated molecular regulation remains unknown. We therefore tested whether genetic variants in the IL1RL1 distal promoter are involved in UC and affect glucocorticoid-mediated ST2 expression. Serum ST2 levels and genetic variants in the IL1RL1 distal promoter were examined by ELISA and PCR sequencing in UC patients receiving corticosteroids. Glucocorticoid-mediated ST2 production was evaluated in intestinal mucosa cultures. Molecular regulation of glucocorticoid-mediated ST2 was assessed by RT-qPCR, ChIP assay and luciferase reporter assay. Dexamethasone effect on ST2 transcript expression was analyzed in leukocytes and related to IL1RL1 variants. Sequencing of a distal IL1RL1 promoter region demonstrated that SNPs rs6543115(C) and rs6543116(A) are associated with increased sST2 in UC patients on corticosteroids. Dexamethasone up-regulated sST2 transcription through interaction with the glucocorticoid-response element (GRE) carrying rs6543115(C) variant. Our data indicate that IL1RL1 SNPs rs6543115(C) confer susceptibility to UC and is contained in the GRE, which may modulate glucocorticoid-induced sST2 expression.
Collapse
|
|
5
|
Malik F, Ali N, Jafri SIM, Ghani A, Hamid M, Boigon M, Fidler C. Continuous diphenhydramine infusion and imatinib for KIT-D816V-negative mast cell activation syndrome: a case report. J Med Case Rep 2017; 11:119. [PMID: 28438191 PMCID: PMC5402659 DOI: 10.1186/s13256-017-1278-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/25/2017] [Indexed: 12/01/2022] Open
Abstract
Background We present the first full case report of the treatment of mast cell activation syndrome with continuous diphenhydramine infusion, which resulted in the improvement of anaphylactic reactions and a decrease in hospital readmission. Furthermore, the patient received imatinib in the absence of the KIT-D816V mutation, which led to further improvement of quality of life. Currently, we are trying to wean this patient off diphenhydramine; if successful, this attempt will represent the first reported case. Case presentation An 18-year-old white girl presented with a flare of mast cell activation syndrome and received epinephrine and steroids. She had failed multiple previous therapies, and her quality of life was affected due to two to three flares/week. She was started on continuous diphenhydramine infusion and imatinib, which led to a decrease in hospital admissions and marked improvement in her quality of life. Conclusions Continuous diphenhydramine infusion can provide promising outcomes following the failure of intermittent antihistamine dosing in patients with severe mast cell activation syndrome. Initiating continuous diphenhydramine infusion may be helpful in an intensive care setting when the patient is particularly prone to anaphylaxis and/or the resources needed to manage anaphylaxis are not available outside the intensive care unit. Furthermore, imatinib provides benefits in KIT-D816V-negative mast cell disorders due to other unknown mutations.
Collapse
Affiliation(s)
- Faizan Malik
- Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA.
| | - Naveed Ali
- Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA
| | - Syed Imran Mustafa Jafri
- Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA
| | - Ali Ghani
- Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA
| | - Mohsin Hamid
- Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA
| | - Margot Boigon
- Department of Internal Medicine, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA
| | - Christian Fidler
- Rosenfeld Cancer Center, Abington Jefferson Health, 1200 Old York Road, Abington, PA, 19001, USA
| |
Collapse
|
|
6
|
Photobiomodulation laser and pulsed electrical field increase the viability of the musculocutaneous flap in diabetic rats. Lasers Med Sci 2017; 32:641-648. [DOI: 10.1007/s10103-017-2160-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/25/2017] [Indexed: 01/09/2023]
|
|
7
|
Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
Collapse
|
|
8
|
Mori T, Abe N, Saito K, Toyama H, Endo Y, Ejima Y, Yamauchi M, Goto M, Mushiake H, Kazama I. Hydrocortisone and dexamethasone dose-dependently stabilize mast cells derived from rat peritoneum. Pharmacol Rep 2016; 68:1358-1365. [PMID: 27710865 DOI: 10.1016/j.pharep.2016.09.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/24/2016] [Accepted: 09/03/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Besides their anti-inflammatory properties, corticosteroid drugs exert anti-allergic effects. Exocytosis of mast cells is electrophysiologically detected as the increase in the whole-cell membrane capacitance (Cm). Therefore, the lack of such increase after exposure to the drugs suggests their mast cell-stabilizing effects. METHODS We examined the effects of 1, 10, 100 and 200μM hydrocortisone or dexamethasone on the degranulation from rat peritoneal mast cells. Employing the whole-cell patch-clamp recording technique, we also tested their effects on the Cm during exocytosis. RESULTS At relatively lower concentrations (1, 10μM), both hydrocortisone and dexamethasone did not significantly affect the degranulation from mast cells and the increase in the Cm induced by GTP-γ-S. Nevertheless, at higher doses (100, 200μM), these drugs inhibited the degranulation from mast cells and markedly suppressed the GTP-γ-S-induced increase in the Cm. CONCLUSIONS Our results provided electrophysiological evidence for the first time that corticosteroid drugs, such as hydrocortisone and dexamethasone, inhibited the exocytotic process of mast cells in a dose-dependent manner. The mast cell-stabilizing effects of these drugs may be attributable to their "non-genomic" action, by which they exert rapid anti-allergic effects.
Collapse
Affiliation(s)
- Tomohiro Mori
- Department of Physiology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Nozomu Abe
- Department of Anesthesiology, Tohoku University Hospital Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Kazutomo Saito
- Department of Anesthesiology, Tohoku University Hospital Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Hiroaki Toyama
- Department of Anesthesiology, Tohoku University Hospital Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Yasuhiro Endo
- Department of Anesthesiology, Tohoku University Hospital Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Yutaka Ejima
- Department of Anesthesiology, Tohoku University Hospital Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Masanori Yamauchi
- Department of Anesthesiology, Tohoku University Hospital Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Mariko Goto
- Department of Physiology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Hajime Mushiake
- Department of Physiology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan
| | - Itsuro Kazama
- Department of Physiology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan.
| |
Collapse
|
|
9
|
Abstract
Mast cells (MCs) are tissue-resident immune cells that carry out protective roles against pathogens. In disease states, such as inflammatory bowel disease, these granulocytes release a diverse array of mediators that contribute to inflammatory processes. They also participate in wound repair and tissue remodeling. In this review, the composition of MCs and how their phenotypes can be altered during inflammation of the gastrointestinal tract is detailed. Animal and human clinical studies that have implicated the participation of MCs in inflammatory bowel disease are reviewed, including the contribution of the cell's mediators to clinical symptoms, stress-triggered inflammation, and fistula and strictures. Studies that have focused on negating the proinflammatory roles of MCs and their mediators in animal models suggest new targets for therapies for patients with inflammatory bowel disease.
Collapse
|
|
10
|
Borriello F, Granata F, Varricchi G, Genovese A, Triggiani M, Marone G. Immunopharmacological modulation of mast cells. Curr Opin Pharmacol 2014; 17:45-57. [PMID: 25063971 DOI: 10.1016/j.coph.2014.07.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 07/02/2014] [Accepted: 07/04/2014] [Indexed: 12/31/2022]
Abstract
Mast cells produce a wide spectrum of mediators and they have been implicated in several physiopathological conditions (e.g. allergic reactions and certain tumors). Pharmacologic agents that modulate the release of mediators from mast cells has helped to elucidate the biochemical mechanisms by which immunological and non-immunological stimuli activate these cells. Furthermore, the study of surface receptors and signaling pathways associated with mast cell activation revealed novel pharmacologic targets. Thus, the development of pharmacologic agents based on this new wave of knowledge holds promise for the treatment of several mast cell-mediated disorders.
Collapse
Affiliation(s)
- Francesco Borriello
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, Via Pansini 5, 80131 Naples, Italy
| | - Francescopaolo Granata
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, Via Pansini 5, 80131 Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, Via Pansini 5, 80131 Naples, Italy
| | - Arturo Genovese
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, Via Pansini 5, 80131 Naples, Italy
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, School of Medicine, Salerno, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, School of Medicine, Via Pansini 5, 80131 Naples, Italy.
| |
Collapse
|
|
11
|
Oppong E, Flink N, Cato ACB. Molecular mechanisms of glucocorticoid action in mast cells. Mol Cell Endocrinol 2013; 380:119-26. [PMID: 23707629 DOI: 10.1016/j.mce.2013.05.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 05/13/2013] [Indexed: 01/07/2023]
Abstract
Glucocorticoids are compounds that have successfully been used over the years in the treatment of inflammatory disorders. They are known to exhibit their effects through the glucocorticoid receptor (GR) that acts to downregulate the action of proinflammatory transcription factors such as AP-1 and NF-κB. The GR also exerts anti-inflammatory effects through activation of distinct genes. In addition to their anti-inflammatory actions, glucocorticoids are also potent antiallergic compounds that are widely used in conditions such as asthma and anaphylaxis. Nevertheless the mechanism of action of this hormone in these disorders is not known. In this article, we have reviewed reports on the effects of glucocorticoids in mast cells, one of the important immune cells in allergy. Building on the knowledge of the molecular action of glucocorticoids and the GR in the treatment of inflammation in other cell types, we have made suggestions as to the likely mechanisms of action of glucocorticoids in mast cells. We have further identified some important questions and research directions that need to be addressed in future studies to improve the treatment of allergic disorders.
Collapse
Affiliation(s)
- Emmanuel Oppong
- Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
| | | | | |
Collapse
|
|
12
|
Behera JP, Mohanty B, Ramani YR, Rath B, Pradhan S. Effect of aqueous extract of Aegle marmelos unripe fruit on inflammatory bowel disease. Indian J Pharmacol 2013; 44:614-8. [PMID: 23112424 PMCID: PMC3480795 DOI: 10.4103/0253-7613.100389] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 06/12/2012] [Accepted: 07/01/2012] [Indexed: 01/26/2023] Open
Abstract
Objective: The present study was designed to evaluate the effect of Aegle marmelos unripe fruit extract (AMFE) on inflammatory bowel disease (IBD) in Wistar albino rats. Materials and Methods: Effect of AMFE was studied on acetic acid induced ulcerative colitis (1 ml of 4% acetic acid solution, transrectal) and indomethacin-induced enterocolitis (10 mg/kg, single dose, p.o) in Wistar albino rats. The extract was administered orally at different dose of 150, 200 and 250 mg/kg body weight. Disease pathogenesis was assessed by measuring disease activity index (DAI), macroscopic score, microscopic score, mesenteric mast cell protection, superoxide dismutase (SOD), and malonaldehyde (MDA) levels in the above two models. Results: The results showed a dose dependent decrease in intestinal inflammation following treatment with AMFE. Significant protection in mast cell degranulation was observed in acetic acid and indomethacin-induced IBD models. Treatment with AMFE significantly decreased the MDA levels and increased SOD activity. Conclusion: In our study, AMFE produced anti-inflammatory, antioxidant, and mast cell stabilizing effects demonstrating protective effect in inflammatory bowel disease.
Collapse
Affiliation(s)
- Jayanti P Behera
- Department of Pharmacology, MKCG Medical College, Berhampur, Odisha, India
| | | | | | | | | |
Collapse
|
|
13
|
Blandino P, Hueston CM, Barnum CJ, Bishop C, Deak T. The impact of ventral noradrenergic bundle lesions on increased IL-1 in the PVN and hormonal responses to stress in male sprague dawley rats. Endocrinology 2013; 154:2489-500. [PMID: 23671261 DOI: 10.1210/en.2013-1075] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The impact of acute stress on inflammatory signaling within the central nervous system is of interest because these factors influence neuroendocrine function both directly and indirectly. Exposure to certain stressors increases expression of the proinflammatory cytokine, Il-1β in the hypothalamus. Increased IL-1 is reciprocally regulated by norepinephrine (stimulatory) and corticosterone (inhibitory), yet neural pathways underlying increased IL-1 have not been clarified. These experiments explored the impact of bilateral lesions of the ventral noradrenergic bundle (VNAB) on IL-1 expression in the paraventricular nucleus of the hypothalamus (PVN) after foot shock. Adult male Sprague Dawley rats received bilateral 6-hydroxydopamine lesions of the VNAB (VNABx) and were exposed to intermittent foot shock. VNABx depleted approximately 64% of norepinephrine in the PVN and attenuated the IL-1 response produced by foot shock. However, characterization of the hypothalamic-pituitary-adrenal response, a crucial prerequisite for interpreting the effect of VNABx on IL-1 expression, revealed a profound dissociation between ACTH and corticosterone. Specifically, VNABx blocked the intronic CRH response in the PVN and the increase in plasma ACTH, whereas corticosterone was unaffected at all time points examined. Additionally, foot shock led to a rapid and profound increase in cyclooxygenase-2 and IL-1 expression within the adrenal glands, whereas more subtle effects were observed in the pituitary gland. Together the findings were the 1) demonstration that exposure to acute stress increased expression of inflammatory factors more broadly throughout the hypothalamic-pituitary-adrenal axis; 2) implication of a modest role for norepinephrine-containing fibers of the VNAB as an upstream regulator of PVN IL-1; and 3) suggestion of an ACTH-independent mechanism controlling the release of corticosterone in VNABx rats.
Collapse
Affiliation(s)
- Peter Blandino
- Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, USA
| | | | | | | | | |
Collapse
|
|
14
|
Abstract
Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions. This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression. A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor. However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production. The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.
Collapse
|
|
15
|
Shi MA, Shi GP. Different roles of mast cells in obesity and diabetes: lessons from experimental animals and humans. Front Immunol 2012; 3:7. [PMID: 22566893 PMCID: PMC3341969 DOI: 10.3389/fimmu.2012.00007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 01/09/2012] [Indexed: 12/18/2022] Open
Abstract
Mast cells (MCs) play an important role in allergic hyperresponsiveness and in defending microorganism infections. Recent studies of experimental animals and humans have suggested that MCs participate in obesity and diabetes. MC distribution and activities in adipose tissues may vary, depending on the locations of different adipose tissues. In addition to releasing inflammatory mediators to affect adipose tissue extracellular matrix remodeling and to promote inflammatory cell recruitment and proliferation, MCs directly and indirectly interact and activate adipose tissue cells, including adipocytes and recruited inflammatory cells. Plasma MC protease levels are significantly higher in obese patients than in lean subjects. Experimental obese animals lose body weight after MC inactivation. MC functions in diabetes are even more complicated, and depend on the type of diabetes and on different diabetic complications. Both plasma MC proteases and MC activation essential immunoglobulin E levels are significant risk factors for human pre-diabetes and diabetes mellitus. MC stabilization prevents diet-induced diabetes and improves pre-established diabetes in experimental animals. MC depletion or inactivation can improve diet-induced type 2 diabetes and some forms of type 1 diabetes, but also can worsen other forms of type 1 diabetes, at least in experimental animals. Observations from animal and human studies have suggested beneficial effects of treating diabetic patients with MC stabilizers. Some diabetic patients may benefit from enhancing MC survival and proliferation – hypotheses that merit detailed basic researches and clinical studies.
Collapse
Affiliation(s)
- Michael A Shi
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School Boston, MA, USA
| | | |
Collapse
|
|
16
|
Dietary α-eleostearic acid ameliorates experimental inflammatory bowel disease in mice by activating peroxisome proliferator-activated receptor-γ. PLoS One 2011; 6:e24031. [PMID: 21904603 PMCID: PMC3164124 DOI: 10.1371/journal.pone.0024031] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 08/01/2011] [Indexed: 11/23/2022] Open
Abstract
Background Treatments for inflammatory bowel disease (IBD) are modestly effective and associated with side effects from prolonged use. As there is no known cure for IBD, alternative therapeutic options are needed. Peroxisome proliferator-activated receptor-gamma (PPARγ) has been identified as a potential target for novel therapeutics against IBD. For this project, compounds were screened to identify naturally occurring PPARγ agonists as a means to identify novel anti-inflammatory therapeutics for experimental assessment of efficacy. Methodology/Principal Findings Here we provide complementary computational and experimental methods to efficiently screen for PPARγ agonists and demonstrate amelioration of experimental IBD in mice, respectively. Computational docking as part of virtual screening (VS) was used to test binding between a total of eighty-one compounds and PPARγ. The test compounds included known agonists, known inactive compounds, derivatives and stereoisomers of known agonists with unknown activity, and conjugated trienes. The compound identified through VS as possessing the most favorable docked pose was used as the test compound for experimental work. With our combined methods, we have identified α-eleostearic acid (ESA) as a natural PPARγ agonist. Results of ligand-binding assays complemented the screening prediction. In addition, ESA decreased macrophage infiltration and significantly impeded the progression of IBD-related phenotypes through both PPARγ-dependent and –independent mechanisms in mice with experimental IBD. Conclusions/Significance This study serves as the first significant step toward a large-scale VS protocol for natural PPARγ agonist screening that includes a massively diverse ligand library and structures that represent multiple known target pharmacophores.
Collapse
|
|
17
|
Patel MA, Patel PK, Patel MB. Effects of ethanol extract of Ficus bengalensis (bark) on inflammatory bowel disease. Indian J Pharmacol 2011; 42:214-8. [PMID: 20927245 PMCID: PMC2941610 DOI: 10.4103/0253-7613.68420] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 03/30/2010] [Accepted: 06/21/2010] [Indexed: 11/12/2022] Open
Abstract
Objective: The present study was designed to evaluate the effects of ethanol extract of Ficus bengalensis Linn. bark (AEFB) on inflammatory bowel disease (IBD). Materials and Methods: Effects of AEFB were studied on 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol intrarectally, on first day only) induced IBD in rats. The effects of co-administration of prednisolone (2 mg/kg) and AEFB (250, 500 mg/kg) for 21 days were evaluated. Animals sacrificed at end of the experiment and various histopathological parameters like colon mucosal damage index (CMDI) and disease activity index (DAI) were assessed. In the colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and nitric oxide (NO) levels and in mesentery % mast cell protection was also measured. Results: Rats treated with only TNBS showed more score of CMDI and DAI, higher MDA, NO, MPO, and lower SOD activity as compared to the control group. Treatment with AEFB significantly declined both indices scores and decreased the MPO, MDA, NO, and increased the SOD activity. AEFB also increased the % mast cell protection compared to alone TNBS-treated animals. Conclusion: In our study, we found that AEFB has a significant protective effect in the IBD in rats that is comparable to that of prednisolone and may be because of the presence of flavonoids, terpenoids, and phenolic compounds.
Collapse
Affiliation(s)
- Manish Amerutlal Patel
- Department of Pharmacology, C.K. Pithawala Institute of Pharmaceutical Sciences and Research, Surat - 395 007, Gujarat, India
| | | | | |
Collapse
|
|
18
|
Patel M, Patel M, Shah G. Investigation of Possible Role of the PAR-2 Receptor in Intestinal Inflammation. J Young Pharm 2011; 2:54-8. [PMID: 21331192 PMCID: PMC3035886 DOI: 10.4103/0975-1483.62214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The present study was undertaken to study the role of PAR-2 receptor activation in pathophysiology of intestinal inflammation. Inflammatory bowel disease was induced in Wistar albino rats by intrarectal administration of 2, 4, 6 trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol intrarectally, on 1st day only). Trypsin (500 μg/kg, 1 mg/kg, 5 mg/kg, intrarectal) was given from the same day up to 20 days. Various physical parameters including body weight, food and water intake were measured on 1st and 20th days. At end of the experiment, colon weight and various histopathological indexes were assessed. The colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), and superoxide dismutase (SOD) and % mast cell protection in mesentery were also measured. Trypsin at higher dose (5 mg/kg) showed the higher level of oxidative enzymes and lower level of protective enzymes as compared to the animals treated with only TNBS. Trypsin treatment produced significantly more mast cell degranulation. Finally in the histopathology, there was increased in severity of the disease in trypsin-treated animals. The role of PAR-2 (protease activated receptor-2) receptor in gut is pro-inflammatory and thus appears as a new potential therapeutic target for inflammatory bowel disease treatments.
Collapse
Affiliation(s)
- Mb Patel
- Department of Pharmacology, Shree Sarvajanik Pharmacy College, Mahesana, India
| | | | | |
Collapse
|
|
19
|
De Winter BY, van den Wijngaard RM, de Jonge WJ. Intestinal mast cells in gut inflammation and motility disturbances. Biochim Biophys Acta Mol Basis Dis 2011; 1822:66-73. [PMID: 21497195 DOI: 10.1016/j.bbadis.2011.03.016] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 03/20/2011] [Accepted: 03/25/2011] [Indexed: 12/12/2022]
Abstract
Mast cells may be regarded as prototypes of innate immune cells that can be controlled by neuronal mediators. Their activation has been implicated in many types of neuro-inflammatory responses, and related disturbances of gut motility, via direct or indirect mechanisms that involve several mechanisms relevant to disease pathogenesis such as changes in epithelial barrier function or activation of adaptive or innate immune responses. Here we review the evidence for the involvement of mast cells in the inflammation of the bowel wall caused by bowel manipulation that leads to motility disturbances such as postoperative gastroparesis and ileus. Also in IBD there is substantial evidence for the involvement of mast cells and a mast cell-mediated neuroimmune interaction showing an increased number and an increased degranulation of mast cells. We discuss the potential of mast cell inhibition as a bona fide drug target to relief postoperative ileus. Further research on mast cell-related therapy either by stabilizing the mast cells or by blocking specific mast cell mediators as adjunctive therapy in IBD is encouraged, bearing in mind that several drugs currently used in the treatment of IBD possess properties affecting mast cell activities. This article is part of a Special Issue entitled: Mast cells in inflammation.
Collapse
Affiliation(s)
- Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Department of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | | | | |
Collapse
|
|
20
|
Carvalho VDF, Barreto EDO, Farias-Filho FA, Gomes LHF, Mendonça LDL, Cordeiro RSB, Martins MA, Rodrigues e Silva PM. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int J Exp Pathol 2009; 90:148-55. [PMID: 19335553 DOI: 10.1111/j.1365-2613.2008.00620.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Rats turned diabetic by alloxan treatment are refractory to systemic anaphylactic shock, in a direct association with reduced intestinal haemorrhage and tissue response to antigen challenge. As diabetic rats show reduction in mast cell numbers in different body compartments, this study was undertaken to investigate the influence of alloxan diabetes on mast cell population as well as the expression of the mast cell growth factor interleukin (IL)-3 in the small intestine of rats. We also analysed the putative involvement of endogenous insulin and glucocorticoid hormones in this phenomenon. There was a significant decrease in the number of mast cells present in the small intestine (ileum segment) of diabetic rats. Likewise, the immunohistochemical analysis revealed that IL-3 labelling was markedly attenuated in diabetic rats, as compared with normal animals, a phenomenon which paralleled with a decreased mRNA expression as attested by Reverse transcriptase-polymerase chain reaction technique. Treatment with insulin and with the steroid receptor antagonist RU 486 restored basal mast cell numbers, normal levels of IL-3 labelling and mRNA expression for IL-3 in the ileum of diabetic rats. In conclusion, our findings show that there is a causative relationship between down-regulation of mast cell numbers and the expression of IL-3 associated with diabetic state. In addition, as both parameters were suppressed by administration of insulin and RU 486, it indicates that an imbalance between the systemic levels of insulin and glucocorticoid hormones seems to be implicated in the reduction in intestinal mast cell population and refractoriness to antigen provocation in alloxan diabetes.
Collapse
Affiliation(s)
- Vinicius de Frias Carvalho
- Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, RJ, Brazil
| | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Kashiwase Y, Inamura H, Morioka J, Igarashi Y, Kawai-Kowase K, Kurosawa M. Quantitative analysis of mast cells in benign and malignant colonic lesions: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Allergol Immunopathol (Madr) 2009; 36:271-6. [PMID: 19080799 DOI: 10.1016/s0301-0546(08)75222-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Comparison of the number of mast cells in the active stage and that in remission in the same patients with ulcerative colitis with immunohistochemical staining remains to be elucidated, and analysis of the number of mast cells in benign and malignant colonic lesions is insufficient. METHODS Using immunohistochemical methods, morphological examinations of mast cells were undertaken in colonic tissues from 8 patients with ulcerative colitis and 10 patients with colonic primary cancer, which were formalin-fixed and paraffin-embedded. Changes in the number of mast cells in the active stage and in remission in the same patients with ulcerative colitis were investigated. Then, the number of mast cells in malignant tissues and adjacent healthy tissues obtained from the same patients with colonic primary cancer were compared, and finally the number of mast cells was compared among the samples from benign and malignant colonic lesions. RESULTS Accumulation of mast cells was found to be significant in the active stage of ulcerative colitis compared with remission in the same patients. The number of mast cells in colonic primary cancer was significantly increased compared with that in adjacent healthy tissues. The number of mast cells in ulcerative colitis was significantly greater than that in adjacent healthy tissues from patients with colonic primary cancer, irrespective of the stages of ulcerative colitis. CONCLUSIONS We were the first to analyse mast cells in the active stage and in remission in the same patients with ulcerative colitis using immunohisto-chemical methods, and compared the number of mast cells between benign and malignant colonic lesions.
Collapse
|
|
22
|
Villanacci V, Bassotti G, Nascimbeni R, Antonelli E, Cadei M, Fisogni S, Salerni B, Geboes K. Enteric nervous system abnormalities in inflammatory bowel diseases. Neurogastroenterol Motil 2008; 20:1009-16. [PMID: 18492026 DOI: 10.1111/j.1365-2982.2008.01146.x] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Various studies have described abnormalities of the enteric nervous system (ENS) in tissue samples from patients with chronic idiopathic inflammatory bowel diseases (IBD). The distribution of density of the different cell types of the ENS was however not studied in a systematic way. The aim of this study was to examine the density of neurons, enteroglial cells and interstitial cells of Cajal (ICC) in the different plexuses of the ENS in samples from patients with Crohn's disease (CD), ulcerative colitis (UC) and controls. Tissue samples from 16 patients with CD (ileum) and 16 patients with UC obtained in involved and non-involved areas were studied using immunohistochemistry with antibodies directed against neuron-specific enolase, S100, C-Kit and CD3. Sections were analysed blindly by two pathologists and the number of positive cells was counted for each type. Overall, an increase was noted for neuronal cell bodies, enteroglia and ICC in the deep muscular plexus in CD. In uninvolved areas of CD patients, the number of enteroglial cells was decreased. In UC, an increase of ICC in the muscularis propria and enteroglial cells was observed in diseased tissue. The study confirms the presence of abnormalities of the different cells of the ENS in IBD. The presence of lesions in samples from uninvolved areas, such as a reduction of enteroglia, supports a pathogenetic role of the ENS.
Collapse
Affiliation(s)
- V Villanacci
- 2nd Department of Pathology, Spedali Civili and University of Brescia, Brescia, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Rijnierse A, Nijkamp FP, Kraneveld AD. Mast cells and nerves tickle in the tummy: implications for inflammatory bowel disease and irritable bowel syndrome. Pharmacol Ther 2007; 116:207-35. [PMID: 17719089 DOI: 10.1016/j.pharmthera.2007.06.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Accepted: 06/20/2007] [Indexed: 12/12/2022]
Abstract
Mast cells are well known as versatile cells capable of releasing and producing a variety of inflammatory mediators upon activation and are often found in close proximity of neurons. In addition, inflammation leads to local activation of neurons resulting in the release neuropeptides, which also play an important immune modulatory role by stimulation of immune cells. In intestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), the number of mast cells is known to be much higher than in the normal intestine. Moreover, both these disorders are also reported to be associated with alterations in neuropeptide content and in neural innervation. Mutual association between mast cells and enteric nerves has been demonstrated to be increased in pathophysiological conditions and contribute to spreading and amplification of the response in IBD and IBS. In this review the focus lies on studies appointed to the direct interaction between mast cells and nerves in IBD, IBS, and animal models for these disorders so far.
Collapse
Affiliation(s)
- Anneke Rijnierse
- Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
| | | | | |
Collapse
|
|
24
|
Étude des effets deMorinda morindoides (Back) sur le système immunitaire de l’homme. ACTA ACUST UNITED AC 2006. [DOI: 10.1007/s10298-006-0154-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
25
|
Carvalho VF, Barreto EO, Cordeiro RSB, Lagente V, Martins MA, e Silva PMR. Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem Inst Oswaldo Cruz 2005; 100 Suppl 1:121-5. [PMID: 15962110 DOI: 10.1590/s0074-02762005000900021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The prevalence of atopic diseases and diabetes is increasing worldwide though the concurrence of these pathologies in individual patients is found less frequent than it would be predicted. Moreover, co-existence of diabetes and allergy is generally marked by attenuation of their respective symptoms, and effective treatment of one disease exacerbates the other. This review gives an update of the state-of-the-art concerning the intercurrence of allergy and diabetes, particularly focusing on the consequences to the allergen-evoked vascular and cellular changes. It is proposed that the reduction in mast cell numbers and reactivity may be a pivotal mechanism behind the mutual exclusion phenomenon.
Collapse
Affiliation(s)
- Vinicius F Carvalho
- Laboratório de Inflamação, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ 21040-900, Brasil
| | | | | | | | | | | |
Collapse
|
|
26
|
Barreto EO, Carvalho VF, Lagente V, Lugnier C, Cordeiro RSB, Martins MA, E Silva PMR. Increased levels of cyclic adenosine monophosphate contribute to the hyporesponsiveness of mast cells in alloxan diabetes. Int Immunopharmacol 2004; 4:755-62. [PMID: 15135317 DOI: 10.1016/j.intimp.2004.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2003] [Revised: 12/30/2003] [Accepted: 03/01/2004] [Indexed: 11/21/2022]
Abstract
In this study, we investigated the influence of intracellular cyclic adenosine monophosphate (cAMP) changes on the rat mast cell hyporesponsiveness following immunological and non-immunological stimuli. Compared with mast cells from normal rats, those recovered from 21-day diabetic animals showed a significant augmentation in the intracellular levels of cAMP, in directly correlated with secretion of lower amounts of histamine after stimulation with antigen, bradykinin and compound 48/80 in vitro. Incubation of normal mast cells with selective inhibitors of phosphodiesterase type 4 (PDE 4) rolipram, NCS 613 and RP 73401, or the cell permeable analogue N6-2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (db cAMP), led to a decrease of histamine secretion in vitro. However, the effectiveness of either NCS 613 or db cAMP in inhibiting antigen-induced degranulation is comparable in both normal and diabetic mast cells. We suggest that (a) there is a close correlation between higher levels of intracellular cAMP and hyporesponsiveness of diabetic mast cells, phenomena probably associated with a reduction in the expression and/or activity of PDE 4 and that (b) the mechanism of cAMP-mediated down-regulation of mast cell function is saturated in diabetic rats.
Collapse
Affiliation(s)
- Emiliano O Barreto
- Laboratory of Inflammation, Physiology and Pharmacodynamics Department, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brasil, no 4365, Manguinhos, Rio de Janeiro, CEP 21045-900, Brazil
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Abstract
Historically, mast cells were known as a key cell type involved in type I hypersensitivity. Until last two decades, this cell type was recognized to be widely involved in a number of non-allergic diseases including inflammatory bowel disease (IBD). Markedly increased numbers of mast cells were observed in the mucosa of the ileum and colon of patients with IBD, which was accompanied by great changes of the content in mast cells such as dramatically increased expression of TNF-α, IL-16 and substance P. The evidence of mast cell degranulation was found in the wall of intestine from patients with IBD with immunohistochemistry technique. The highly elevated histamine and tryptase levels were detected in mucosa of patients with IBD, strongly suggesting that mast cell degranulation is involved in the pathogenesis of IBD. However, little is known of the actions of histamine, tryptase, chymase and carboxypeptidase in IBD. Over the last decade, heparin has been used to treat IBD in clinical practice. The low molecular weight heparin (LMWH) was effective as adjuvant therapy, and the patients showed good clinical and laboratory response with no serious adverse effects. The roles of PGD2, LTC4, PAF and mast cell cytokines in IBD were also discussed. Recently, a series of experiments with dispersed colon mast cells suggested there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. The hypothesis is that mast cell secretogogues induce mast cell degranulation, release histamine, then stimulate the adjacent mast cells or positively feedback to further stimulate its host mast cells through H1 receptor. Whereas released tryptase acts similarly to histamine, but activates mast cells through its receptor PAR-2. The connections between current anti-IBD therapies or potential therapies for IBD with mast cells were discussed, implicating further that mast cell is a key cell type that is involved in the pathogenesis of IBD. In conclusion, while pathogenesis of IBD remains unclear, the key role of mast cells in this group of diseases demonstrated in the current review implicates strongly that IBD is a mast cell associated disease. Therefore, close attentions should be paid to the role of mast cells in IBD.
Collapse
Affiliation(s)
- Shao-Heng He
- Allergy and Inflammation Research Institute, Medical College, Shantou University, Shantou 515031, Guangdong Province, China.
| |
Collapse
|
|
28
|
Jeong HJ, Na HJ, Hong SH, Kim HM. Inhibition of the stem cell factor-induced migration of mast cells by dexamethasone. Endocrinology 2003; 144:4080-6. [PMID: 12933682 DOI: 10.1210/en.2003-0115] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Mast cell accumulation can be causally related to several allergic inflammations. Previous work has demonstrated that glucocorticoids decreased tissue mast cell number, and stem cell factor (SCF)-induced migration of mast cells required p38 MAPK activation. In the present study we investigated the effects of dexamethasone on SCF-induced migration of rat peritoneal mast cells (RPMCs). SCF significantly induced the migration of RPMCs at 4 h. Dexamethasone dose-dependently inhibited SCF-induced migration of RPMCs (approximately 90.1% at 100 nM; P < 0.05). The MAPK p38 inhibitor SB203580 (20 microM) also inhibited the SCF-induced migration. The ability of SCF to enhance morphological alteration and filamentous actin formation was also abolished by treatment with dexamethasone. Dexamethasone inhibited SCF-induced p38 MAPK activation to near-basal levels and induced MAPK phosphatase-1 expression. In addition, SCF-induced inflammatory cytokine production was significantly inhibited by treatment with dexamethasone or SB203580 (P < 0.01). Our results show that dexamethasone potently regulates SCF-induced migration, p38 MAPK activation, and inflammatory cytokine production through the expression of MKP-1 protein in RPMCs. Such modulation may have functional consequences during dexamethasone treatment, especially mast cell-mediated allergic inflammation disorders.
Collapse
Affiliation(s)
- Hyun-Ja Jeong
- Department of Pharmacology, Kyung Hee University College of Oriental Medicine, 130-701 Seoul, South Korea
| | | | | | | |
Collapse
|
|
29
|
Shin EH, Kim TH, Hong SJ, Park JH, Guk SM, Chai JY. Effects of anti-allergic drugs on intestinal mastocytosis and worm expulsion of rats infected with Neodiplostomum seoulense. THE KOREAN JOURNAL OF PARASITOLOGY 2003; 41:81-7. [PMID: 12815318 PMCID: PMC2717495 DOI: 10.3347/kjp.2003.41.2.81] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The effects of anti-allergic drugs on intestinal mastocytosis and the expulsion of Neodiplostomum seoulense were observed in Sprague-Dawley rats, after oral infection with 500 metacercariae. The drugs used were hydroxyzine (a histamine receptor H1 blocker), cimetidine (a H2 blocker), cyclosporin-A (a helper T-cell suppressant), and prednisolone (a T- and B-cell suppressant). Infected, but untreated controls, and uninfected controls, were prepared. Worm recovery rate and intestinal mastocytosis were measured on weeks 1, 2, 3, 5, and 7 post-infection. Compared with the infected controls, worm expulsion was significantly (P < 0.05) delayed in hydroxyzine- and cimetidine-treated rats, despite mastocytosis being equally marked in the duodenum of all three groups. In the cyclosporin-A- and prednisolone-treated groups, mastocytosis was suppressed, but worm expulsion was only slightly delayed, without statistical significance. Our results suggest that binding of histamine to its receptors on intestinal smooth muscles is more important in terms of the expulsion of N. seoulense from rats than the levels of histamine alone, or mastocytosis.
Collapse
Affiliation(s)
- Eun-Hee Shin
- Department of Parasitology and Tropical Medicine, College of Medicine and Institute of Endemic Diseases, Medical Research Center, Seoul National University, Seoul 110-799, Korea
| | | | | | | | | | | |
Collapse
|
|
30
|
Akhavan A, Rudikoff D. The treatment of atopic dermatitis with systemic immunosuppressive agents. Clin Dermatol 2003; 21:225-40. [PMID: 12781440 DOI: 10.1016/s0738-081x(02)00362-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Arash Akhavan
- Department of Dermatology, Mount Sinai School of Medicine, New York, New York 10029, USA
| | | |
Collapse
|
|
31
|
Abstract
Solitary mastocytoma is an uncommon disease characterized by monotonous infiltrations of mast cells that extend from papillary dermis to subcutaneous fat. They usually resolve by adulthood, and there is no satisfactory treatment other than waiting. A two-month-old Korean male infant with deep solitary mastocytoma was treated intralesionally with triamcinolone acetonide. His mastocytoma in medial malleolus was very distressing because it was very sensitive to friction, and he was just reaching the crawling stage. After three injections, his skin lesion flattened with marked decrease of erythema and subjective symptoms. His skin lesion has continued to have a good clinical response for 9 months after the last treatment.
Collapse
Affiliation(s)
- Nam-Gyu Kang
- Department of Dermatology, College of Medicine, Gyeongsang National University, Chinju, Korea
| | | |
Collapse
|
|
32
|
Sasaki Y, Tanaka M, Kudo H. Differentiation between ulcerative colitis and Crohn's disease by a quantitative immunohistochemical evaluation of T lymphocytes, neutrophils, histiocytes and mast cells. Pathol Int 2002; 52:277-85. [PMID: 12031083 DOI: 10.1046/j.1440-1827.2002.01354.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mucosal biopsy criteria has limited validity in terms of discrimination between ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to set up quantitative immunohistochemical criteria, with a special focus on inflammatory cell distribution within individual specimens and throughout the large bowel. Quantitative evaluation was performed for the density of CD8+, CD45RO+, neutrophil elastase+, CD68+ and mast cell tryptase+ cells in affected and unaffected mucosa taken from 41 patients with UC and 61 patients with CD. Each slide was examined at the highest and lowest density fields, which were further divided into the upper and deeper half of mucosa. Multiple logistic regression analysis using 51 features as independent variables constructed a predictive equation finding the probability of UC (PUC), and the diagnostic categories were subsequently defined based on a receiver-operating characteristic curve. The analysis disclosed five significant features suggesting UC; these implied intense infiltration of CD8+ and mast cell tryptase+ cells, diffuse infiltration of neutrophil elastase+ and CD68+ cells, and continuous infiltration of CD45RO+ cells. The criteria consisted of three diagnostic categories, 'suggestive of UC (PUC > or = 0.7)', 'indeterminate (0.3 < PUC < 0.7)', and 'suggestive of CD (PUC < or = 0.3)'; the criteria had values for sensitivity and specificity exceeding 95%. The immunohistochemical criteria distinguishing UC from CD may help to confirm the diagnosis in patients with ambiguous endoscopic and histological diagnosis.
Collapse
Affiliation(s)
- Yoshio Sasaki
- Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan
| | | | | |
Collapse
|
|
33
|
Tremaine WJ, Brzezinski A, Katz JA, Wolf DC, Fleming TJ, Mordenti J, Strenkoski-Nix LC, Kurth MC. Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study. Aliment Pharmacol Ther 2002; 16:407-13. [PMID: 11876693 DOI: 10.1046/j.1365-2036.2002.01194.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase. AIM To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis. METHODS This was an open-label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6-9 on a 12-point scale. Fifty-six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end-point was response, defined as a final disease activity index of < or = 3. Supplementary analyses were also performed. RESULTS Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty-seven (49%) improved, with a final disease activity index of < or = 3 or a four-point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%). CONCLUSIONS In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.
Collapse
|
|
34
|
Scarampella F, Abramo F, Noli C. Clinical and histological evaluation of an analogue of palmitoylethanolamide, PLR 120 (comicronized Palmidrol INN) in cats with eosinophilic granuloma and eosinophilic plaque: a pilot study. Vet Dermatol 2001; 12:29-39. [PMID: 11301536 DOI: 10.1046/j.1365-3164.2001.00214.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Fifteen cats with eosinophilic granuloma or eosinophilic plaque were given PLR 120 at the dosage of 10 mg kg-1 twice daily for one month. PLR-120 down-modulates mast cell degranulation via a receptor-mediated mechanism. No other drugs were permitted and cats were kept free of parasites throughout the study. A clinical evaluation and skin biopsies were performed before and after the treatment. Clinical improvement was assessed at 15 and 30 days. Mast cell numbers were counted and their granular content was assessed by densitometric analysis on toluidine blue-stained sections before and after the treatment. Ten of 15 (67%) cats showed clinical improvement of signs and lesions. There was no significant difference between mast cell numbers in skin biopsies taken before and after the trial, whereas the number of granules was significantly increased (P < 0.009). This pilot study suggests that PLR-120 might be a useful drug for the treatment of eosinophilic granuloma and eosinophilic plaque.
Collapse
Affiliation(s)
- F Scarampella
- Studio Dermatologico Veterinario, Via Sismondi 62, 20133 Milan, Italy
| | | | | |
Collapse
|
|
35
|
Abstract
Mast cells are complex, multifunctional cells that have unique phenotypes and growth requirements. Regulation in vitro of human mast cell growth and function differs from regulation of rodent mast cells. Human cell yields in vitro vary depending on tissue of origin, use of mononuclear or CD34+ progenitor cells, presence of cytokines, and serum-free versus serum-containing mediums. This article presents a summary of recent advances in the understanding of cytokine regulation of mast cell numbers and function in rodents and humans.
Collapse
Affiliation(s)
- A Kirshenbaum
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| |
Collapse
|
|
36
|
Yamagata K, Tanaka M, Kudo H. A quantitative immunohistochemical evaluation of inflammatory cells at the affected and unaffected sites of inflammatory bowel disease. J Gastroenterol Hepatol 1998; 13:801-8. [PMID: 9736173 DOI: 10.1111/j.1440-1746.1998.tb00736.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Levels of T lymphocytes, histiocytes and mast cells have been reported to be increased in the affected mucosa of Crohn's disease (CD) and ulcerative colitis (UC), but the colorectal distribution of these cells is not fully understood. We hypothesized that differences in cell densities between CD and UC would be characteristic, not only in the affected, but also in the unaffected mucosa. The aims of the present study were to clarify whether there were any differences in cell densities in CD, UC and infectious colitis (IC) in the affected mucosa and between CD and UC in the unaffected mucosa. Using mouse monoclonal antibodies recognizing memory T cells (OPD4), cytotoxic/suppressor T cells (C8/144B), histiocytes (PG-M1) and mast cells (AA1), we evaluated mucosal cell densities in biopsy specimens from both endoscopically affected and unaffected sites of CD (n = 12) and UC (n = 15) and from affected sites of IC (n = 10). Ten normal controls were also examined. At affected sites, all cells were significantly more abundant in UC than in the other conditions, except that the density of PG-M1+ in CD was similar to that seen in UC. Although the densities of OPD4+ and C8/144B+ cells at unaffected sites were slightly higher in both CD and UC and in UC, respectively, there was no significant difference in cell densities between CD and UC. The ratio of OPD4+ cell density at affected sites to that at unaffected sites was appreciably higher in UC than in CD. The results suggest that a common feature of UC and CD is an increase in PG-M1+ cells at the affected mucosa but that the other inflammatory cells studied are more abundant, particularly in UC, and that the difference between UC and CD is conspicuous when comparing the OPD4+ cell density of the affected mucosa with that of the unaffected mucosa.
Collapse
Affiliation(s)
- K Yamagata
- Department of Pathology, Hirosaki University School of Medicine, Japan
| | | | | |
Collapse
|
|
37
|
Thiele J, Pecher G, Klöppel R, Pecher S, Emmert C, Schulz HG. CT-Sellink—A standardized technique in the diagnosis of chronic inflammatory bowel disease. Radiography (Lond) 1997. [DOI: 10.1016/s1078-8174(97)90017-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
38
|
Finotto S, Mekori YA, Metcalfe DD. Glucocorticoids decrease tissue mast cell number by reducing the production of the c-kit ligand, stem cell factor, by resident cells: in vitro and in vivo evidence in murine systems. J Clin Invest 1997; 99:1721-8. [PMID: 9120017 PMCID: PMC507993 DOI: 10.1172/jci119336] [Citation(s) in RCA: 107] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The local delivery of glucocorticoids to tissues significantly decreases mast cell number. This pharmacologic effect of glucocorticoids is believed to be one of the mechanisms by which glucocorticoids regulate allergic inflammation. To determine the mechanism by which glucocorticoids are able to exert this effect, we first applied the glucocorticoid fluocinonide to mouse dermis and observed that the decrease in mast cell number was associated with an increase in mast cell apoptosis. This did not appear to be due to a direct effect of the glucocorticoid on mast cells, as the addition of 0.01-1.0 microM of the glucocorticoid dexamethasone into stem cell factor (SCF)-dependent mast cell cultures did not enhance mast cell death. However, addition of dexamethasone to cultured fibroblasts did result in a downregulation of SCF mRNA and a significant decrease in SCF protein production. Similarly, immunohistochemistry performed on fluocinonide-treated mouse dermis revealed a decrease in immunoreactive SCF. Administration of SCF at sites of fluocinonide administration to the dermis abolished the mast cell-depleting effect of this glucocorticoid. Thus, glucocorticoids decrease tissue mast cell number by downregulating tissue SCF production required for the survival of local mast cells. This observation may be applicable to the design of improved strategies to treat mast cell-mediated disorders.
Collapse
Affiliation(s)
- S Finotto
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | | | | |
Collapse
|
|
39
|
Affiliation(s)
- H P McNeil
- Inflammation Research Unit, School of Pathology, University of New South Wales
| |
Collapse
|
|
40
|
Minocha A, Thomas C, Omar R. Lack of crucial role of mast cells in pathogenesis of experimental colitis in mice. Dig Dis Sci 1995; 40:1757-62. [PMID: 7648976 DOI: 10.1007/bf02212698] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Mast cell alterations have been implicated in the pathogenesis of chronic ulcerative colitis (UC). We studied the effect of mast cell deficiency of the severity of inflammation in a murine model of colitis. Colitis was induced in mice using dextran sodium sulfate (DSS). Mast-cell-deficient mice (WBB6F1/J-W/WV; N = 17) and normal littermates (WBB6F1/J-+/+; N = 17) were administered DSS 4% w/v for seven days, then water alone for one week, followed by 5% DSS for six days. Animals were sacrificed at the end of the protocol. Segments of proximal, mid-, and distal colon of each animal were processed for histopathological examination. Mortality and morbidity (diarrhea and weight loss) for each group were assessed. There was no significant difference between the two groups in either their clinical parameters (mortality and morbidity) or the severity of colitis as graded histopathologically. Our findings suggest that mast cells are not crucial for the development of DSS-induced colitis.
Collapse
Affiliation(s)
- A Minocha
- Department of Medicine, University of Louisville, Kentucky, USA
| | | | | |
Collapse
|
|
41
|
Trevethick MA, Bahl AK, Clayton NM, Strong P, Sanjar S, Harman IW. Neutrophil infiltration does not contribute to the ulcerogenic effects of indomethacin in the rat gastric antrum. AGENTS AND ACTIONS 1994; 43:39-43. [PMID: 7741039 DOI: 10.1007/bf02005762] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We have previously suggested (Trevethick et al., Gut 34, 156-160) that indomethacin-induced ulceration of the rat gastric antrum may be a neutrophil-dependent process. Accordingly, in this study we have used an anti-neutrophil serum (ANS) to investigate the effects of neutrophil depletion on this pathology. In animals pretreated with the ANS to induce a nearly total neutropaenia, indomethacin-induced increases in blood neutrophilia and cell infiltration into the gastric antrum (assessed as LTB4 release ex vivo) were eliminated. In marked contrast, however, ANS pretreatment affected neither the area of mucosa damaged nor the microscopic characteristics or distribution of the lesions. These results suggest that, in contrast to the published reports examining indomethacin-induced ulceration of the gastric fundus, neutrophil infiltration is not involved in the pathogenesis of indomethacin-induced ulceration of the rat gastric antrum.
Collapse
Affiliation(s)
- M A Trevethick
- Biology Division, Glaxo Research and Development Ltd. Pharmacology, Ware, Herts, UK
| | | | | | | | | | | |
Collapse
|
|
42
|
Levine DS. Immune modulating therapies for idiopathic inflammatory bowel diseases. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 1994; 25:171-234. [PMID: 8204501 DOI: 10.1016/s1054-3589(08)60432-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- D S Levine
- Department of Medicine, University of Washington, Seattle 98195
| |
Collapse
|
|
43
|
Juliusson S, Holmberg K, Karlsson G, Enerbäck L, Pipkorn U. Mast cells and mediators in the nasal mucosa after allergen challenge. Effects of four weeks' treatment with topical glucocorticoid. Clin Exp Allergy 1993; 23:591-9. [PMID: 7693314 DOI: 10.1111/j.1365-2222.1993.tb00899.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The study focuses on the relationship between the tissue density of mast cells, the tissue histamine levels and the levels of markers of mast cell activation after an allergen challenge of the nasal mucosa of allergic patients. The effect of 4 weeks' treatment with a topical glucocorticoid, fluticasone propionate, was studied in a double-blind, placebo-controlled study of 25 hay fever patients. Nasal biopsies were obtained before and after the treatment period for the evaluation of mast cell density and tissue histamine levels. Nasal challenges were performed at 2-week intervals for 8 weeks using a standardized nasal lavage model. TAME-esterase was analysed in the returned lavage fluid from all the challenges (weeks 0-8), while the levels of histamine and tryptase were analysed in lavage fluids from challenges performed before and after the treatment period (weeks 0 and 4). The symptoms of nasal allergy were assessed after each challenge. Treatment with fluticasone propionate did not influence mast cell density, the tissue histamine concentration, the lavage histamine levels or the TAME-esterase activity, while a reduction in nasal symptoms and tryptase in nasal lavage fluid was revealed. Our present study again emphasizes the fact that the mast cell is an important trigger cell in the immediate nasal allergic response. The study also demonstrates the usefulness of the measurements of tryptase as an indicator of both mast cell activation and the efficacy of topical steroid treatment.
Collapse
Affiliation(s)
- S Juliusson
- Department of Otorhinolaryngology, Sahlgrenska Hospital, University of Göteborg, Sweden
| | | | | | | | | |
Collapse
|
|
44
|
King T, Biddle W, Bhatia P, Moore J, Miner PB. Colonic mucosal mast cell distribution at line of demarcation of active ulcerative colitis. Dig Dis Sci 1992; 37:490-5. [PMID: 1551335 DOI: 10.1007/bf01307568] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We examined the distribution of colonic mucosal mast cells in 25 patients with active ulcerative colitis, with a clear line of demarcation separating active inflammation from normal mucosa. Biopsies, at least one adjacent to the line of demarcation, one in inflamed mucosa, and one above were obtained during colonoscopy. Eight patients had elevated mast cells throughout the colon, and 12 had increased numbers at the line of demarcation of disease. Mean numbers of mast cells from these patients were 6.3 (+/- 2.1 SD) in active inflammation, 19.5 (+/- 7.1 SD) at the line of demarcation, and 15.8 (+/- 8.4 SD) in normal mucosa. Histologic inflammation decreased as mast cells increased. The accumulation of mast cells at the visible line of demarcation between normal and abnormal mucosa suggests mast cells play a critical role in either accelerating the process of inflammation or in suppressing continued extension of the disease.
Collapse
Affiliation(s)
- T King
- Department of Medicine, University of Kansas Medical Center, Kansas City 66103
| | | | | | | | | |
Collapse
|
|
45
|
Abstract
Once regarded as medical curiosities, ulcerative colitis and Crohn's disease have achieved a remarkable change in status recently and today are among the more compelling of all human illnesses. The cause(s) of inflammatory bowel disease (IBD) are not known. Genetic, environmental, microbial, and immunologic factors are involved, but the precise mechanisms are obscure. The incidence of ulcerative colitis is relatively stable, while Crohn's disease continues to increase in frequency. In 10% to 15% of patients, it is hard to differentiate between ulcerative colitis and Crohn's colitis, however, problems with diagnosis usually resolve with time and repeated examinations. In part I of his two-part monograph on IBD, Dr. Kirsner addressed the nature and pathogenesis of the disease. Increased study of ulcerative colitis and Crohn's disease in recent years has generated new knowledge regarding their etiology. Part I focused on microbial, immunologic, and genetic mechanisms of, and the inflammatory process involved in the disease. In this part, Dr. Kirsner deals with the clinical features, course, and management of IBD, based on the author's 55 years of experience with these problems and supplemented by critical examination of the recent (1988-1990) literature. Particular attention is directed to the symptoms and physical findings of ulcerative colitis and Crohn's disease. The laboratory, radiologic, endoscopic, and pathologic features, and the many systemic complications. IBDs are mimicked by several enterocolonic infections and other conditions making differential diagnosis necessary. Inflammatory bowel disease in children and the elderly conforms to conventional clinical patterns modified by the health circumstances of the respective age groups. Because the cause of IBD has not been established, current medical therapy is facilitative and supportive rather than curative. The principles of medical treatment are approximately the same for ulcerative colitis and Crohn's disease. Treatment emphasizes a program rather than a drug and also considers the individuality of the therapeutic response. A clearer understanding of dietary and nutritional needs, including hyperalimentation and electrolyte and fluid balance, aids treatment. Antidiarrheal and antispasmodal preparation and sedatives are prescribed for symptom relief. The bowel inflammation is controlled with sulfasalazine or the newer 5-amino-salicylic acid (5-ASA) compounds, antibacterial drugs for complications of Crohn's disease and IBD, adrenocortical steroids, and the immunosuppressive compounds 6-mercaptopurine (6MP), azathioprine, and cyclosporine, as determined in each patient. The surgical procedures available for treatment of ulcerative colitis include total proctocolectomy and ileostomy or ileoanal anastomosis.(ABSTRACT TRUNCATED AT 400 WORDS)
Collapse
Affiliation(s)
- J B Kirsner
- Department of Medicine, University of Chicago, Illinois
| |
Collapse
|
|
46
|
Miller MJ, Zhang XJ, Barkemeyer B, Sadowska-Krowicka H, Eloby-Childress S, Gu X, Clark DA. Potential role of histamine monochloramine in a rabbit model of ileitis. Scand J Gastroenterol 1991; 26:852-8. [PMID: 1663272 DOI: 10.3109/00365529109037022] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Histamine chloramines, derived from the chlorination of histamine by granulocyte-derived oxidants, are potential mediators of intestinal injury and dysfunction in states of atopy or inflammation. We assessed the ability of histamine monochloramine to increase epithelial permeability in rabbit distal small intestine and determined whether the conditions for histamine chloramine formation are favorable in a rabbit model of ileitis. Epithelial permeability, quantified by the blood-to-lumen clearance of 51Cr-labeled ethylenediaminetetraacetic acid, was enhanced by luminal perfusion with either histamine or histamine monochloramine (10 microM), although the latter was twice as effective (p less than 0.05). In a rabbit model of ileitis induced by a luminal solution of acetic acid (200 mM) and casein (10 mg/ml) there was a marked increase in epithelial permeability and in the release into the lumen of histamine, myeloperoxidase, 6-keto-prostaglandin F1 alpha and protein. These results suggest that the conditions are favorable for histamine chloramine formation and that histamine and histamine chloramine may impair the integrity of the epithelial barrier.
Collapse
Affiliation(s)
- M J Miller
- Dept. of Pediatrics, Louisiana State University Medical Center, New Orleans 70112
| | | | | | | | | | | | | |
Collapse
|