|
1
|
Landucci E, Laurino A, Cinci L, Gencarelli M, Raimondi L. Thyroid Hormone, Thyroid Hormone Metabolites and Mast Cells: A Less Explored Issue. Front Cell Neurosci 2019; 13:79. [PMID: 30983971 PMCID: PMC6449760 DOI: 10.3389/fncel.2019.00079] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 02/15/2019] [Indexed: 12/24/2022] Open
Abstract
Mast cells are primary players in immune and inflammatory diseases. In the brain, mast cells are located at the brain side of the blood brain barrier (BBB) exerting a crucial role in protecting the brain from xenobiotic invasion. Furthermore, recent advances in neuroscience indicate mast cells may play an important role in glial cell-neuron communication through the release of mediators, including histamine. Interestingly, brain mast cells contain not only 50% of the brain histamine but also hormones, proteases and lipids or amine mediators; and cell degranulation may be triggered by different stimuli activating membrane bound receptors including the four types of histaminergic receptors. Among hormones, mast cells can store thyroid hormone (T3) and express membrane-bound thyroid stimulating hormone receptors (TSHRs), thus suggesting from one side that thyroid function may affect mast cells function, from the other that mast cell degranulation may impact on thyroid function. In this respect, the research on hormones in mast cells is scarce. Recent pharmacological evidence indicates the existence of a non-genomic portion of the thyroid secretion including thyroid hormone metabolites. Among which the 3,5 diiodothyronine (3,5-T2), 3-iodothyroanamine (T1AM) and 3-iodothyroacetic acid (TA1) are the most studied. All these compounds are endogenously occurring and found to be increased in inflammatory-based diseases involving mast cells. T1AM and TA1 induce, as T3, neuroprotective effects and itch but also hyperalgesia in rodents with a mechanism largely unknown but mediated by the release of histamine. Due to the rapid onset of their effectiveness they may trigger histamine release from a cell where it is “ready-to-be released,” i.e., mast cells. Following a very thin path which passes through old experimental and clinical evidence, at the light of novel acquisitions on endogenous T3 metabolites, we aim to stimulate the attention on the possibility that mast cell histamine may be the connector of a novel (neuro) endocrine pathway linking the thyroid with mast cells.
Collapse
Affiliation(s)
- Elisa Landucci
- Section of Pharmacology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Annunziatina Laurino
- Section of Pharmacology, Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence, Florence, Italy
| | - Lorenzo Cinci
- Section of Pharmacology, Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence, Florence, Italy
| | - Manuela Gencarelli
- Section of Pharmacology, Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence, Florence, Italy
| | - Laura Raimondi
- Section of Pharmacology, Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence, Florence, Italy
| |
Collapse
|
|
2
|
Meyer N, Zenclussen AC. Mast cells-Good guys with a bad image? Am J Reprod Immunol 2018; 80:e13002. [DOI: 10.1111/aji.13002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/04/2018] [Indexed: 12/12/2022] Open
Affiliation(s)
- Nicole Meyer
- Experimental Obstetrics and Gynecology; Medical Faculty; Otto-von-Guericke University; Magdeburg Germany
| | - Ana Claudia Zenclussen
- Experimental Obstetrics and Gynecology; Medical Faculty; Otto-von-Guericke University; Magdeburg Germany
| |
Collapse
|
|
3
|
Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth. Sci Rep 2017; 7:45106. [PMID: 28327604 PMCID: PMC5361184 DOI: 10.1038/srep45106] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 02/16/2017] [Indexed: 01/22/2023] Open
Abstract
Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5+ cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling.
Collapse
|
|
4
|
Visciano C, Prevete N, Liotti F, Marone G. Tumor-Associated Mast Cells in Thyroid Cancer. Int J Endocrinol 2015; 2015:705169. [PMID: 26379707 PMCID: PMC4563106 DOI: 10.1155/2015/705169] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/16/2015] [Accepted: 07/15/2015] [Indexed: 12/26/2022] Open
Abstract
There is compelling evidence that the tumor microenvironment plays a major role in mediating aggressive features of cancer cells, including invasive capacity and resistance to conventional and novel therapies. Among the different cell populations that infiltrate cancer stroma, mast cells (MCs) can influence several aspects of tumor biology, including tumor development and progression, angiogenesis, lymphangiogenesis, and tissue remodelling. Thyroid cancer (TC), the most frequent neoplasia of the endocrine system, is characterized by a MC infiltrate, whose density correlates with extrathyroidal extension and invasiveness. Recent evidence suggests the occurrence of epithelial-to-mesenchymal transition (EMT) and stemness in human TC. The precise role of immune cells and their mediators responsible for these features in TC remains unknown. Here, we review the relevance of MC-derived mediators (e.g., the chemokines CXCL1/GRO-α, CXCL10/IP-10, and CXCL8/IL-8) in the context of TC. CXCL1/GRO-α and CXCL10/IP-10 appear to be involved in the stimulation of cell proliferation, while CXCL8/IL-8 participates in the acquisition of TC malignant traits through its ability to induce/enhance the EMT and stem-like features of TC cells. The inhibition of chemokine signaling may offer novel therapeutic approaches for the treatment of refractory forms of TC.
Collapse
Affiliation(s)
- Carla Visciano
- Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples Federico II, 80131 Naples, Italy
- Institute of Endocrinology and Experimental Oncology (IEOS), CNR, “G. Salvatore”, 80131 Naples, Italy
| | - Nella Prevete
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80131 Naples, Italy
- Center for Basic and Clinical Immunologic Research (CISI), University of Naples Federico II, 80131 Naples, Italy
| | - Federica Liotti
- Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples Federico II, 80131 Naples, Italy
- Institute of Endocrinology and Experimental Oncology (IEOS), CNR, “G. Salvatore”, 80131 Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80131 Naples, Italy
- Center for Basic and Clinical Immunologic Research (CISI), University of Naples Federico II, 80131 Naples, Italy
| |
Collapse
|
|
5
|
Uehara Y, Fujimi K, Yahiro E, Abe S, Devarajan S, Saku K, Urata H. Induction of tissue angiotensin II-forming activity in two-kidney, one-clip hypertensive hamster model. World J Hypertens 2013; 3:9. [DOI: 10.5494/wjh.v3.i2.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 08/09/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
|
|
6
|
Abstract
Mast cells (MCs) are traditionally thought of as a nuisance for its host, for example, by causing many of the symptoms associated with allergic reactions. In addition, recent research has put focus on MCs for displaying harmful effects during various autoimmune disorders. On the other hand, MCs can also be beneficial for its host, for example, by contributing to the defense against insults such as bacteria, parasites, and snake venom toxins. When the MC is challenged by an external stimulus, it may respond by degranulation. In this process, a number of powerful preformed inflammatory "mediators" are released, including cytokines, histamine, serglycin proteoglycans, and several MC-specific proteases: chymases, tryptases, and carboxypeptidase A. Although the exact effector mechanism(s) by which MCs carry out their either beneficial or harmful effects in vivo are in large parts unknown, it is reasonable to assume that these mediators may contribute in profound ways. Among the various MC mediators, the exact biological function of the MC proteases has for a long time been relatively obscure. However, recent progress involving successful genetic targeting of several MC protease genes has generated powerful tools, which will enable us to unravel the role of the MC proteases both in normal physiology as well as in pathological settings. This chapter summarizes the current knowledge of the biology of the MC proteases.
Collapse
Affiliation(s)
- Gunnar Pejler
- Department of Anatomy, Physiology and Biochemistry, The Biomedical Centre, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | | | | | | |
Collapse
|
|
7
|
Abstract
The past decade has confronted us with a striking abundance of novel findings regarding the roles of mast cells in immune responses in health and disease. Newly developed models and techniques have enabled clear-cut dissection of the mast cell contribution in these settings. We now understand that mast cells possess critical effector functions not only within the traditional context of allergic reactions. It is likely that mast cells played pivotal roles in primitive immune systems, yet these functions have been masked in the recent eras by newer immune functions, such as adaptive immunity. Conceivably, mast cells should be refocused on so as to obtain new insights about diverse pathologic conditions, ultimately leading to novel therapeutic approaches targeting these fascinating cells.
Collapse
Affiliation(s)
- Ido Bachelet
- Department of Pharmacology, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Ein-Kerem, Jerusalem 91120, Israel
| | | | | |
Collapse
|
|
8
|
Shiota N, Kakizoe E, Shimoura K, Tanaka T, Okunishi H. Effect of mast cell chymase inhibitor on the development of scleroderma in tight-skin mice. Br J Pharmacol 2005; 145:424-31. [PMID: 15806109 PMCID: PMC1576161 DOI: 10.1038/sj.bjp.0706209] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
1 Although the pathogenesis of scleroderma is not fully understood, activation of connective-tissue-type mast cells (CTMCs) has been implicated in various fibrotic diseases. 2 Our previous study showed that the number of CTMCs was markedly increased during fibrous proliferation in the skin of a scleroderma model, namely tight-skin (Tsk) mice. Because mast cells express numerous bioactive factors, such as cytokines, growth factors, proteases, and others, it is crucial to identify the primary factors that may be involved in the pathogenesis of scleroderma. Our previous study also showed that a CTMC-specific protease, chymase-4, was selectively upregulated in accordance with the development of skin fibrosis in Tsk mice. 3 To further elucidate the role of chymase secreted from CTMCs, we evaluated the therapeutic effects of a synthetic chymase-specific inhibitor, SUN-C8257, on the development of skin fibrosis in Tsk mice. SUN-C8257 (50 mg kg-1 day-1) was administered via intraperitoneal injection in 13-week-old Tsk mice for a period of 2 weeks. 4 Treatment with SUN-C8257 significantly reduced chymase activity by 43% and the chymase-4 mRNA level by 47%, and also decreased the thickness of the subcutaneous fibrous layer of Tsk mice by 42% compared with that of Tsk mice injected with vehicle. 5 Furthermore, immunohistochemical analysis revealed that transforming growth factor (TGF)-beta1 staining in the fibrous layer of Tsk skin was markedly reduced by the treatment with SUN-C8257. This chymase inhibitor may prevent the chymase-dependent pathway that activates the latent TGF-beta1 in fibrous tissue, and may exhibit beneficial effects that inhibit the development of fibrosis. 6 In conclusion, our results strongly support the assumption that CTMC-derived chymase may play a key role in the pathogenesis of scleroderma.
Collapse
Affiliation(s)
- Naotaka Shiota
- Department of Pharmacology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan.
| | | | | | | | | |
Collapse
|
|
9
|
Rajkovic V, Matavulj M, Lazetic B. Stereological analysis of thyroid mast cells in rats after exposure to extremely low frequency electromagnetic field and the following "off" field period. ACTA BIOLOGICA HUNGARICA 2005; 56:43-51. [PMID: 15813213 DOI: 10.1556/abiol.56.2005.1-2.5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Influence of extremely low frequency electromagnetic field (ELF-EMF) on thyroid gland mast cells was investigated on male Mill Hill rats. Animals were exposed to EMF (50 Hz, 50 microT to 500 microT, 10 V/m) from 24 hours after birth, 7 hours/day, 5 days/week for three months when a part of animals (group I) was sacrificed, while the rest of them were subjected to recovery evaluation and sacrificed after one (group II), two (group II) and three (group IV) weeks following the exposure. Stereological analysis on toluidine blue-stained paraffin sections showed increased volume density of degranulated mast cells in all groups and, except in group III, and numerical density as well, implicating the sensitivity of thyroidal mast cells to power frequency EMFs. Since in our previous investigations, morphofunctional alterations of thyroid gland in rats exposed to ELF-EMF were found the contribution of released mast cell mediators to these changes could be presumed.
Collapse
Affiliation(s)
- Vesna Rajkovic
- Department of Biology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 2, 21000 Novi Sad, Serbia and Montenegro.
| | | | | |
Collapse
|
|
10
|
Leskinen MJ, Lindstedt KA, Wang Y, Kovanen PT. Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol 2003; 23:238-43. [PMID: 12588765 DOI: 10.1161/01.atv.0000051405.68811.4d] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Chymase released from activated mast cells has been shown to induce apoptosis of vascular smooth muscle cells (SMCs) in vitro. The proteolytic activity of chymase is essential for the proapoptotic effect, but the mechanism of chymase-induced apoptosis has remained unknown. METHODS AND RESULTS Here we show by means of FACS analysis, immunohistochemistry, and Western blotting that mast cell-derived chymase induces SMC apoptosis by a mechanism involving degradation of an extracellular matrix component, fibronectin (FN), with subsequent disruption of focal adhesions. The FN degradation products induced SMC apoptosis of similar magnitude and with similar changes in outside-in signaling, as did chymase. Sodium orthovanadate, an inhibitor of tyrosine phosphatases, inhibited the chymase-induced SMC apoptosis. Focal adhesion kinase (FAK), one of the key mediators of integrin-extracellular matrix interactions and cell survival, was rapidly degraded in the presence of chymase or FN degradation products. Loss of phosphorylated FAK (p-FAK) resulted in a rapid dephosphorylation of the p-FAK-dependent downstream mediator Akt. CONCLUSIONS The results suggest that chymase-secreting mast cells can mediate apoptosis of neighboring SMCs through a mechanism involving degradation of pericellular FN and disruption of the p-FAK-dependent cell-survival signaling cascade.
Collapse
|
|
11
|
Kunori Y, Koizumi M, Masegi T, Kasai H, Kawabata H, Yamazaki Y, Fukamizu A. Rodent alpha-chymases are elastase-like proteases. EUROPEAN JOURNAL OF BIOCHEMISTRY 2002; 269:5921-30. [PMID: 12444981 DOI: 10.1046/j.1432-1033.2002.03316.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Although the alpha-chymases of primates and dogs are known as chymotrypsin-like proteases, the enzymatic properties of rodent alpha-chymases (rat mast cell protease 5/rMCP-5 and mouse mast cell protease 5/mMCP-5) have not been fully understood. We report that recombinant rMCP-5 and mMCP-5 are elastase-like proteases, not chymotrypsin-like proteases. An enzyme assay using chromogenic peptidyl substrates showed that mast cell protease-5s (MCP-5s) have a clear preference for small aliphatic amino acids (e.g. alanine, isoleucine, valine) in the P1 site of substrates. We used site-directed mutagenesis and computer modeling approaches to define the determinant residue for the substrate specificity of mMCP-5, and found that the mutant possessing a Gly substitution of the Val at position 216 (V216G) lost elastase-like activity but acquired chymase activity, suggesting that the Val216 dominantly restricts the substrate specificity of mMCP-5. Structural models of mMCP-5 and the V216G mutant based on the crystal structures of serine proteases (rMCP-2, human cathepsin G, and human chymase) revealed the active site differences that can account for the marked differences in substrate specificity of the two enzymes between elastase and chymase. These findings suggest that rodent alpha-chymases have unique biological activity different from the chymases of other species.
Collapse
Affiliation(s)
- Yuichi Kunori
- TEIJIN Institute for Biomedical Research, Hino, Tokyo, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
12
|
Imada T, Komorita N, Kobayashi F, Naito K, Yoshikawa T, Miyazaki M, Nakamura N, Kondo T. Therapeutic potential of a specific chymase inhibitor in atopic dermatitis. JAPANESE JOURNAL OF PHARMACOLOGY 2002; 90:214-7. [PMID: 12499574 DOI: 10.1254/jjp.90.214] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613 (2-[5-amino-2-(4-fluorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-[1-[(5-methoxycarbonyl-2-benzoxazolyl)carbonyl]-2-phenylethyl]acetamide) dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation.
Collapse
Affiliation(s)
- Teruaki Imada
- Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Abstract
Snake envenomation employs three well integrated strategies: prey immobilization via hypotension, prey immobilization via paralysis, and prey digestion. Purines (adenosine, guanosine and inosine) evidently play a central role in the envenomation strategies of most advanced snakes. Purines constitute the perfect multifunctional toxins, participating simultaneously in all three envenomation strategies. Because they are endogenous regulatory compounds in all vertebrates, it is impossible for any prey organism to develop resistance to them. Purine generation from endogenous precursors in the prey explains the presence of many hitherto unexplained enzyme activities in snake venoms: 5'-nucleotidase, endonucleases (including ribonuclease), phosphodiesterase, ATPase, ADPase, phosphomonoesterase, and NADase. Phospholipases A(2), cytotoxins, myotoxins, and heparinase also participate in purine liberation, in addition to their better known functions. Adenosine contributes to prey immobilization by activation of neuronal adenosine A(1) receptors, suppressing acetylcholine release from motor neurons and excitatory neurotransmitters from central sites. It also exacerbates venom-induced hypotension by activating A(2) receptors in the vasculature. Adenosine and inosine both activate mast cell A(3) receptors, liberating vasoactive substances and increasing vascular permeability. Guanosine probably contributes to hypotension, by augmenting vascular endothelial cGMP levels via an unknown mechanism. Novel functions are suggested for toxins that act upon blood coagulation factors, including nitric oxide production, using the prey's carboxypeptidases. Leucine aminopeptidase may link venom hemorrhagic metalloproteases and endogenous chymotrypsin-like proteases with venom L-amino acid oxidase (LAO), accelerating the latter. The primary function of LAO is probably to promote prey hypotension by activating soluble guanylate cyclase in the presence of superoxide dismutase. LAO's apoptotic activity, too slow to be relevant to prey capture, is undoubtedly secondary and probably serves principally a digestive function. It is concluded that the principal function of L-type Ca(2+) channel antagonists and muscarinic toxins, in Dendroaspis venoms, and acetylcholinesterase in other elapid venoms, is to promote hypotension. Venom dipeptidyl peptidase IV-like enzymes probably also contribute to hypotension by destroying vasoconstrictive peptides such as Peptide YY, neuropeptide Y and substance P. Purines apparently bind to other toxins which then serve as molecular chaperones to deposit the bound purines at specific subsets of purine receptors. The assignment of pharmacological activities such as transient neurotransmitter suppression, histamine release and antinociception, to a variety of proteinaceous toxins, is probably erroneous. Such effects are probably due instead to purines bound to these toxins, and/or to free venom purines.
Collapse
Affiliation(s)
- Steven D Aird
- Laboratório de Toxinas Naturais, Universidade Estadual do Ceará, Avenida Paranjana, 1700, Itaperí, 60740-000, Fortaleza, CE, Brazil.
| |
Collapse
|
|
14
|
Abstract
The renin angiotensin system is implicated in the development of vein graft disease after coronary artery bypass surgery. Components of this system have been shown to play important roles in determining the short-term and long-term performance of coronary artery bypass grafts. Significant differences exist in the commonly used arterial and venous grafts in angiotensin converting enzyme activity and angiotensin responses. The existence of a dual enzyme pathway in angiotensin II formation has also been demonstrated. Such findings have implications for the use of AT1-receptor antagonists over enzyme inhibitors to improve graft performance and prevent the development of coronary artery bypass graft disease.
Collapse
Affiliation(s)
- J A Borland
- Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Heart Science Centre, Harefield Hospital, United Kingdom
| | | | | |
Collapse
|
|
15
|
Toda S, Tokuda Y, Koike N, Yonemitsu N, Watanabe K, Koike K, Fujitani N, Hiromatsu Y, Sugihara H. Growth factor-expressing mast cells accumulate at the thyroid tissue-regenerative site of subacute thyroiditis. Thyroid 2000; 10:381-6. [PMID: 10884184 DOI: 10.1089/thy.2000.10.381] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The localization and biological roles of the multifunctional cell type mast cells remain unclear in subacute thyroiditis that is characterized by both epithelioid granuloma formation and thyroid tissue repair. We examined their immunolocalization with tryptase of a mast cell marker, using the biopsy specimens from 12 cases. In the epithelioid granuloma, no mast cells were detected in any of the cases, although a small number of them (4.6 +/- 2.4) were seen at the fibrous stroma around the granuloma in all cases. By contrast, in all cases, increased mast cells (28 +/- 7.2) localized at the thyroid tissue-regenerative site where both thyroid folliculogenesis and angiogenesis take place. To elucidate possible roles of mast cells in the disease, we also examined their immunoexpressions of vascular endothelial cell growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF), transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF), which affect thyroid folliculogenesis and angiogenesis. In all 12 cases, mast cells displayed all of these growth factors in a manner not specific to the infiltrating site. The data suggest that growth factor-expressing mast cells may play crucial roles in the thyroid tissue repair of subacute thyroiditis, modulating thyroid folliculogenesis and angiogenesis; and that the multifunctionality of the cells may be partly dependent on their expressions of various growth factors.
Collapse
Affiliation(s)
- S Toda
- Department of Pathology, Saga Medical School, Japan.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Akasu M, Urata H, Kinoshita A, Sasaguri M, Ideishi M, Arakawa K. Differences in tissue angiotensin II-forming pathways by species and organs in vitro. Hypertension 1998; 32:514-20. [PMID: 9740619 DOI: 10.1161/01.hyp.32.3.514] [Citation(s) in RCA: 95] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Angiotensin (Ang) II plays an important role in cardiovascular homeostasis, not only in the systemic circulation but also at the tissue level, and is involved in the remodeling of the heart and vasculature under pathological conditions. Although alternative Ang II-forming pathways are known to exist in various tissues, the details of such pathways remain unclear. The aim of this study was to examine tissue Ang II-forming activities and to identify the responsible enzyme in several organs (lung, heart, and aorta) in various species (human, hamster, rat, rabbit, dog, pig, and marmoset). Among the organs examined, the lung contained the highest Ang II-forming activity. The responsible enzyme for pulmonary Ang II formation was angiotensin I-converting enzyme (ACE) in all of the species except the human lung, in which a chymaselike enzyme was dominant. In the heart, the highest total Ang II-forming activity was observed in humans, and a chymaselike enzyme was dominant in all of the species except rabbit and pig. Aorta exhibited a relatively high total Ang II-forming activity, with a predominance of chymaselike activity in all of the species except rabbit and pig, in which ACE was dominant. Our results indicate that there were remarkable differences in Ang II-forming pathways among the species and organs we examined. To study the pathophysiological roles of ACE-independent Ang II formation, one should choose species and/or organs that have Ang II-forming pathways similar to those in humans.
Collapse
Affiliation(s)
- M Akasu
- From Fukuoka University, School of Medicine, Department of Internal Medicine, Fukuoka City, Japan
| | | | | | | | | | | |
Collapse
|
|
17
|
Shiota N, Fukamizu A, Okunishi H, Takai S, Murakami K, Miyazaki M. Cloning of the gene and cDNA for hamster chymase 2, and expression of chymase 1, chymase 2 and angiotensin-converting enzyme in the terminal stage of cardiomyopathic hearts. Biochem J 1998; 333 ( Pt 2):417-24. [PMID: 9657983 PMCID: PMC1219600 DOI: 10.1042/bj3330417] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Chymase is responsible for the formation of angiotensin II, which plays crucial roles in the pathogenesis of cardiovascular diseases. In the present study we determined the gene organization of a novel hamster chymase (hamster chymase 2) and analysed the expression of chymase 1, chymase 2 and angiotensin-converting enzyme (ACE) in hamster hearts at the terminal stage of cardiomyopathy. The gene encoding hamster chymase 2 is 3.2 kb in length and has five exons and four intervening sequences. The overall organization of this gene is similar to that of several other serine proteases. The deduced amino acid sequence revealed the existence of a preproenzyme composed of a signal peptide with 19 amino acids, a propeptide with two amino acids and a catalytic domain with 226 amino acids. The predicted full sequence of the catalytic domain was revealed to be very similar to the sequences of mouse mast-cell protease 5 (86%), rat mast-cell protease III (85%) and human chymase (70%) and less similar to hamster chymase 1 (56%). The expression of chymase 1 in heart was higher than that of chymase 2. The cardiac chymase-like activity, as well as the mRNA levels of chymase 1 and 2 of BIO 14.6 cardiomyopathic hamsters at the age of 60 weeks were increased 3.4-, 2.8- and 5.1-fold respectively compared with age-matched BIO F1B control hamsters. The cardiac ACE activity and the ACE mRNA level of cardiomyopathic hamsters were also increased 4.1- and 2.4-fold compared with those of age-matched controls. These results suggest that up-regulation of both ACE and chymases participates in the pathophysiology of the terminal stage of cardiomyopathy.
Collapse
Affiliation(s)
- N Shiota
- Department of Pharmacology, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569, Japan.
| | | | | | | | | | | |
Collapse
|
|
18
|
Abstract
We have presented results that increase our understanding of the roles MC and EOS play in modulating fibrotic processes. In vitro studies have provided clear-cut evidence for the direct involvement of these two inflammatory cells in enhancing proliferation, and either enhancing or decreasing collagen synthesis in human fibroblasts isolated from different anatomical locations. In addition, we have shown that MC and EOS interactions can also take part in modulating fibrosis. In vivo studies in murine and human cGVHD showed that MC activation is detrimental, and that MC stabilization therapy may be helpful in treating the fibrotic outcome of this disease. Much is still obscure. It is, for example, important to define the MC and EOS mediators involved in the modulation of fibroblast properties, and their pattern of influence, keeping in mind the ultimate goal of defining new therapeutic targets for the treatment of fibrotic diseases.
Collapse
Affiliation(s)
- F Levi-Schaffer
- Department of Pharmacology, School of Pharmacy, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | | |
Collapse
|
|
19
|
Shiota N, Jin D, Takai S, Kawamura T, Koyama M, Nakamura N, Miyazaki M. Chymase is activated in the hamster heart following ventricular fibrosis during the chronic stage of hypertension. FEBS Lett 1997; 406:301-4. [PMID: 9136906 DOI: 10.1016/s0014-5793(97)00295-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Chronic pressure overload induces cardiac tissue remodeling. Chymase is known to regulate matrix metabolism and angiotensin II formation. In the present study, we investigated the pathophysiological functions of chymase in the pressure-overloaded hamster heart induced by a two-kidney, one-clip (2K1C) hypertension procedure. Fibrosis and apoptosis were observed in the pressure-overloaded hearts of 2K1C hamsters 32 weeks after clipping, but these histological changes were not detected at 16 weeks. Heart chymase-like activity of 2K1C hamsters at 32 weeks increased 5.2-fold compared with that at 16 weeks, while angiotensin-converting enzyme was not activated. Chymase might be involved in cardiac tissue remodeling during the chronic stage of hypertension.
Collapse
Affiliation(s)
- N Shiota
- Department of Pharmacology of Osaka Medical College, Takatsuki, Japan
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Kofford MW, Schwartz LB, Schechter NM, Yager DR, Diegelmann RF, Graham MF. Cleavage of type I procollagen by human mast cell chymase initiates collagen fibril formation and generates a unique carboxyl-terminal propeptide. J Biol Chem 1997; 272:7127-31. [PMID: 9054407 DOI: 10.1074/jbc.272.11.7127] [Citation(s) in RCA: 152] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The ability of human mast cell chymase and tryptase to process procollagen was examined. Purified human intestinal smooth muscle cell procollagen was incubated with human mast cell tryptase or human mast cell chymase. Purified chymase, but not tryptase, exhibited procollagen proteinase activity in the presence of EDTA. Addition of purified porcine heparin over a range of 0.1-100 microg/ml did not affect either the rate or the products of procollagen chymase cleavage. The cleavage site of chymase on the pro-alpha1(I) collagen carboxyl terminus was found to be in the propeptide region at Leu-1248-Ser-1249. Cleavage at this site suggested that the collagen products would form fibrils and confirmed the production of a unique carboxyl-terminal propeptide. Turbidometric fibril formation assay demonstrated de novo formation of chymase-generated collagen fibrils with characteristic lag, growth, and plateau phases. When observed by dark field microscopy, these fibrils were similar to fibrils formed by the action of procollagen proteinases. Thus, mast cell chymase, but not tryptase, exhibits procollagen peptidase-like activity as evidenced by its ability to process procollagen to fibril-forming collagen with concurrent formation of a unique carboxyl-terminal propeptide. These data demonstrate that mast cell chymase has a potential role in the regulation of collagen biosynthesis and in the pathogenesis of fibrosis.
Collapse
Affiliation(s)
- M W Kofford
- Department of Pediatrics, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia 23298-0529, USA.
| | | | | | | | | | | |
Collapse
|
|
21
|
Shiota N, Saegusa Y, Nishimura K, Miyazaki M. Angiotensin II-generating system in dog and monkey ocular tissues. Clin Exp Pharmacol Physiol 1997; 24:243-8. [PMID: 9131292 DOI: 10.1111/j.1440-1681.1997.tb01814.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
1. Angiotensin II (AngII) is generated locally in several tissues, including ocular tissues. Recently, it has been suggested that in addition to angiotensin-converting enzyme (ACE), an alternative AngII-generating enzyme, chymase, is present in the present in the cardiovascular tissues of humans, monkeys and dogs and may be involved in the local production of AngII. The purpose of the present study was to determine whether chymase contributes to AngII generation in dog and monkey ocular tissues and to clarify the intraocular AngII-generating system. 2. Chymase-like and ACE activities were measured in dog and monkey ocular tissues, carotid artery, heart and lung. Their mRNA levels were quantified using the competitive reverse transcriptase-polymerase chain reaction (RT-PCR) method. 3. Chymase-like activity was detected in the anterior uveal tract, choroid and sclera in dog eyes, but not in the cornea, lens or fluid phase (vitreous body and aqueous humor). In monkey eyes, chymase-like activity was detected in the anterior uveal tract and it was higher here than in the heart. Angiotensin-converting enzyme activity was detected in the anterior uveal tract, choroid, retina, sclera and fluid phase in both dog and monkey eyes. Chymase and ACE mRNA were detected in tissues showing enzymatic activity. 4. These findings show for the first time that chymase, in addition to ACE, is expressed locally in dog and monkey ocular tissues and may be involved in local AngII generation in the eye.
Collapse
Affiliation(s)
- N Shiota
- Department of Pharmacology, Osaka Medical College, Takatsuki, Japan
| | | | | | | |
Collapse
|
|
22
|
Abstract
The extent of mast cell direct involvement in fibrosis is not defined as yet. In the present study we assessed whether long-term co-culture (up to 7 d) of functionally active rat peritoneal mast cells with 3T3 mouse fibroblasts and mass cell activation can affect fibroblast proliferation and collagen production. Co-culture of subconfluent 3T3 fibroblasts with resting mast cells or with mast cells stimulated by alpha IgE (1:35) or repeatedly activated by low concentrations of compound 48/80 (0.25-0.75 microgram/ml) did not alter fibroblast proliferation. However, fibroblast proliferation was increased significantly (100-130%) when mast cells were repeatedly activated with higher concentrations of compound 48/80 (1-3 micrograms/ml). Repeated mast cell activation by compound 48/80 (0.25 microgram/ml) caused a twofold increase in collagen production and this was reduced by 63% by the mast cell stabilizer nedocromil sodium (10(-5) M). At the same time, co-culture of 3T3 fibroblasts with unstimulated or immunologically activated mast cells did not modulate their collagen production. In conclusion, we have demonstrated that mast cell activation, under certain conditions, can enhance significantly 3T3 fibroblast proliferation and collagen production, thus indicating a direct mast cell involvement in the fibrotic processes.
Collapse
Affiliation(s)
- F Levi-Schaffer
- Department of Pharmacology, School of Pharmacy, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | | |
Collapse
|
|
23
|
Affiliation(s)
- F Levi-Schaffer
- Department of Pharmacology, Hebrew University--Hadassah Medical School, Jerusalem, Israel
| | | |
Collapse
|