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Journal ArticleDOI

Role of Mammalian Chitinases in Asthma

01 Jan 2009-International Archives of Allergy and Immunology (Karger Publishers)-Vol. 149, Iss: 4, pp 369-377
TL;DR: The recent studies in a mouse asthma model revealed that anti-inflammatory drugs like corticosteroid and cysteinyl leukotriene receptor antagonist were able to suppress elevated pulmonary levels of mammalian chitinases, suggesting that mammalian ch itinases may be useful as biomarkers for asthma.
Abstract: Asthma is a chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway hyperresponsiveness. Mechanisms underlying the pathogenesis of asthma are not fully understood. In recent years, there are mounting evidences demonstrating that mammalian chitinases may play a key role in mediating the T-helper 2 cell-driven inflammatory response that is commonly associated with asthma. Chitinases (e.g., chitotriosidase and acidic mammalian chitinase) are enzymes that degrade chitin, the second most abundant biopolymer that can be found in the cell walls of fungi, microfilarial sheaths of helminths, and exoskeletons of insects and crustaceans. There are also chitinase-like proteins (e.g., YKL-40, Ym1 and Ym2) that lack chitinolytic activity but retain chitin-binding ability. Therefore, chitinases were originally believed to function in host defense against parasitic infections, but the first discovery of their role in inflammatory airway diseases came as a surprise. There is ample evidence to support an association of acidic mammalian chitinase and YKL-40 with allergic bronchial asthma in patients. Our recent studies in a mouse asthma model revealed that anti-inflammatory drugs like corticosteroid and cysteinyl leukotriene receptor antagonist were able to suppress elevated pulmonary levels of mammalian chitinases. Taken together, mammalian chitinases may be useful as biomarkers for asthma. Notwithstanding, large-scale multi-center association studies are required to confirm this hypothesis. Besides, substantially more works using knockout mice, recombinant chitinases and siRNA technology are required to investigate a potential role of chitinases in the pathogenesis of asthma.

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Citations
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Journal ArticleDOI
TL;DR: The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment.
Abstract: Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain T(H)2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.

390 citations

Journal ArticleDOI
TL;DR: The fact that chitin depresses the development of adaptive type 2 allergic responses is supported, which supports the use of chitosans as biomaterials, and more specifically as drug carriers for a variety of applications.
Abstract: Due to the fact that some individuals are allergic to crustaceans, the presumed relationship between allergy and the presence of chitin in crustaceans has been investigated. In vivo, chitin is part of complex structures with other organic and inorganic compounds: in arthropods chitin is covalently linked to proteins and tanned by quinones, in fungi it is covalently linked to glucans, while in bacteria chitin is diversely combined according to Gram(+/-) classification. On the other hand, isolated, purified chitin is a plain polysaccharide that, at the nano level, presents itself as a highly associated structure, recently refined in terms of regularity, nature of bonds, crystallinity degree and unusual colloidal behavior. Chitins and modified chitins exert a number of beneficial actions, i.e., (i) they stimulate macrophages by interacting with receptors on the macrophage surface that mediate the internalization of chitin particles to be degraded by lysozyme and N-acetyl-beta-glucosaminidase (such as Nod-like, Toll-like, lectin, Dectin-1, leukotriene 134 and mannose receptors); (ii) the macrophages produce cytokines and other compounds that confer non-specific host resistance against bacterial and viral infections, and anti-tumor activity; (iii) chitin is a strong Th1 adjuvant that up-regulates Th1 immunity induced by heat-killed Mycobacterium bovis, while down- regulating Th2 immunity induced by mycobacterial protein; (iv) direct intranasal application of chitin microparticles into the lung was also able to significantly down-regulate allergic response to Dermatophagoids pteronyssinus and Aspergillus fumigatus in a murine model of allergy; (v) chitin microparticles had a beneficial effect in preventing and treating histopathologic changes in the airways of asthmatic mice; (vi) authors support the fact that chitin depresses the development of adaptive type 2 allergic responses. Since the expression of chitinases, chitrotriosidase and chitinase-like proteins is greatly amplified during many infections and diseases, the common feature of chitinase-like proteins and chitinase activity in all organisms appears to be the biochemical defense of the host. Unfortunately, conceptual and methodological errors are present in certain recent articles dealing with chitin and allergy, i.e., (1) omitted consideration of mammalian chitinase and/or chitotriosidase secretion, accompanied by inactive chitinase-like proteins, as an ancestral defensive means against invasion, capable to prevent the insurgence of allergy; (2) omitted consideration of the fact that the mammalian organism recognizes more promptly the secreted water soluble chitinase produced by a pathogen, rather than the insoluble and well protected chitin within the pathogen itself; (3) superficial and incomplete reports and investigations on chitin as an allergen, without mentioning the potent allergen from crustacean flesh, tropomyosine; (4) limited perception of the importance of the chemical/biochemical characteristics of the isolated chitin or chitosan for the replication of experiments and optimization of results; and (5) lack of interdisciplinarity. There is quite a large body of knowledge today on the use of chitosans as biomaterials, and more specifically as drug carriers for a variety of applications: the delivery routes being the same as those adopted for the immunological studies. Said articles, that devote attention to the safety and biocompatibility aspects, never reported intolerance or allergy in individuals and animals, even when the quantities of chitosan used in single experiments were quite large. Therefore, it is concluded that crab, shrimp, prawn and lobster chitins, as well as chitosans of all grades, once purified, should not be considered as "crustacean derivatives", because the isolation procedures have removed proteins, fats and other contaminants to such an extent as to allow them to be classified as chemicals regardless of their origin.

372 citations


Cites background from "Role of Mammalian Chitinases in Ast..."

  • ...Several authors sustained these views and concluded that more works using knockout mice, recombinant chitinases and siRNA technology are required to investigate a potential role of chitinases in the pathogenesis of asthma [68]....

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Journal ArticleDOI
TL;DR: This review will address current knowledge of the origins and functions of macrophages during the progression of tissue repair, with emphasis on skin and skeletal muscle.
Abstract: Macrophages are essential for the efficient healing of numerous tissues, and they contribute to impaired healing and fibrosis. Tissue repair proceeds through overlapping phases of inflammation, proliferation, and remodeling, and macrophages are present throughout this progression. Macrophages exhibit transitions in phenotype and function as tissue repair progresses, although the precise factors regulating these transitions remain poorly defined. In efficiently healing injuries, macrophages present during a given stage of repair appear to orchestrate transition into the next phase and, in turn, can promote debridement of the injury site, cell proliferation and angiogenesis, collagen deposition, and matrix remodeling. However, dysregulated macrophage function can contribute to failure to heal or fibrosis in several pathological situations. This review will address current knowledge of the origins and functions of macrophages during the progression of tissue repair, with emphasis on skin and skeletal muscle. Dysregulation of macrophages in disease states and therapies targeting macrophage activation to promote tissue repair are also discussed.

282 citations

Journal ArticleDOI
TL;DR: Different aspects of chitinases and chi-lectins from bacteria, fungi, insects, plants and mammals are discussed.

172 citations

Journal ArticleDOI
TL;DR: A review on properties and applications of chitinases starting from bacteria, followed by fungi, insects, plants, and vertebrates is presented in this paper, where a rational approach for improved catalytic activity for cost-effective field applications has also been explored.
Abstract: Chitin is the second most plenteous polysaccharide in nature after cellulose, present in cell walls of several fungi, exoskeletons of insects, and crustacean shells. Chitin does not accumulate in the environment due to presence of bacterial chitinases, despite its abundance. These enzymes are able to degrade chitin present in the cell walls of fungi as well as the exoskeletons of insect. They have shown being the potential agents for biological control of the plant diseases caused by various pathogenic fungi and insect pests and thus can be used as an alternative to chemical pesticides. There has been steady increase in demand of chitin derivatives, obtained by action of chitinases on chitin polymer for various industrial, clinical, and pharmaceutical purposes. Hence, this review focuses on properties and applications of chitinases starting from bacteria, followed by fungi, insects, plants, and vertebrates. Designing of chitinase by applying directed laboratory evolution and rational approaches for improved catalytic activity for cost-effective field applications has also been explored.

143 citations


Cites background from "Role of Mammalian Chitinases in Ast..."

  • ...Therefore, mammalian chitinases can be used as a biomarkers for asthma and hence inhibition of AMCase with chitinase inhibitors such as allosamidin reduces inflammation and can be used as potential target for asthma therapy [42]....

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References
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Journal ArticleDOI
01 May 2004-Allergy
TL;DR: This report provides a wealth of information that will be an invaluable source of information for those who wish to explore available data on the burden of asthma by region and will be extremely useful to develop background materials for World Asthma Day activities in 2004 and well into the future.
Abstract: It is estimated that as many as 300 million people of all ages, and all ethnic backgrounds, suffer from asthma and the burden of this disease to governments, health care systems, families, and patients is increasing worldwide. In 1989 the Global Initiative for Asthma (GINA) program was initiated in an effort to raise awareness among public health and government officials, health care workers, and the general public that asthma was on the increase. The GINA program recommends a management program based on the best available scientific evidence to provide effective medical care for asthma tailored to local health care systems and resources. Working in continued collaboration with leaders in asthma care from many countries, GINA sponsors World Asthma Day (first Tuesday in May) which has been extremely successful. A vast number of people have made a commitment to bring awareness about the burden of asthma to their local health care officials, and to implement programs of effective asthma care. Beginning in 2003, the theme of World Asthma Day has been the ‘‘Global Burden of Asthma.’’ GINA commissioned Professor Richard Beasley, Wellington, New Zealand (member, GINA Dissemination Committee) to provide available data on the burden of asthma. A summary of this report is provided in this publication; the full document with data sets for 20 different regions worldwide may be obtained from the GINA website (http://www.ginasthma.com). Professor Beasley and his colleagues obtained data on the burden of asthma from literature primarily published through the International StudyofAsthmaandAllergies in Childhood (ISAAC) and the European Community Respiratory Health Survey (ECHRS). Methodologies differ in these studies, and epidemiological data on asthma are very difficult to collect, as Professor Beasley carefully describes in his segment on ‘‘Methodological Issues.’’ Nonetheless, the full report provides a wealth of information, along with a large number of scientific references. The study regions have been grouped according to geographical, political, historical, and racial considerations based on official data from WHO, the United Nations (UN), and other sources, and to some extent, the availability of asthma epidemiological data within the study region. Using the United Nations World Population Prospect Population Database (http://esa.un.org/unpp) as a source within each region, all countries were included, and in some cases territories and dependencies if specific asthma epidemiological data were available. For simplicity some data from small territories have been omitted or lumped in a larger sub-regional unit. The report will be updated as new information becomes available and following feedback from individual countries and regions. The GINA Executive Committee is indebted to Professor Beasley and his colleagues for providing this report that will be an invaluable source of information for those who wish to explore available data on the burden of asthma by region. It will be extremely useful to develop background materials for World Asthma Day activities in 2004 and well into the future. Matthew Masoli, Denise Fabian, Shaun Holt, Richard Beasley for the Global Initiative for Asthma (GINA) Program

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1,271 citations

Journal ArticleDOI
11 Jun 2004-Science
TL;DR: It is shown that acidic mammalian chitinase (AMCase) is induced via a T helper-2 (Th2)–specific, interleukin-13 (IL-13)–mediated pathway in epithelial cells and macrophages in an aeroallergen asthma model and expressed in exaggerated quantities in human asthma.
Abstract: Chitin is a surface component of parasites and insects, and chitinases are induced in lower life forms during infections with these agents. Although chitin itself does not exist in humans, chitinases are present in the human genome. We show here that acidic mammalian chitinase (AMCase) is induced via a T helper-2 (Th2)-specific, interleukin-13 (IL-13)-mediated pathway in epithelial cells and macrophages in an aeroallergen asthma model and expressed in exaggerated quantities in human asthma. AMCase neutralization ameliorated Th2 inflammation and airway hyperresponsiveness, in part by inhibiting IL-13 pathway activation and chemokine induction. AMCase may thus be an important mediator of IL-13-induced responses in Th2-dominated disorders such as asthma.

795 citations

Journal ArticleDOI
TL;DR: Although the cell wall composition varies among fungal species, chemogenomic comparative analysis have led to a better understanding of the genes and mechanisms involved in the construction of the common central core composed of branched β1,3 glucan‐chitin.
Abstract: The cell wall is composed of a polysaccharide-based three-dimensional network. Considered for a long time as an inert exoskeleton, the cell wall is now seen as a dynamic structure that is continuously changing as a result of the modification of culture conditions and environmental stresses. Although the cell wall composition varies among fungal species, chemogenomic comparative analysis have led to a better understanding of the genes and mechanisms involved in the construction of the common central core composed of branched beta1,3 glucan-chitin. Because of its essential biological role, unique biochemistry and structural organization and the absence in mammalian cells of most of its constitutive components, the cell wall is an attractive target for the development of new antifungal agents. Genomic as well as drug studies have shown that the death of the fungus can result from inhibition of cell wall polysaccharide synthases. To date, only beta1,3 glucan synthase inhibitors have been launched clinically and many more targets remain to be explored.

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TL;DR: The biology of eosinophils is summarized, focusing on transcriptional regulation of eOSinophil differentiation, characterization of the growing properties of eOsinophIL granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of Eosinophile degranulation.
Abstract: Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.

768 citations

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