The Experts below are selected from a list of 6027 Experts worldwide ranked by ideXlab platform

Gunnar Nilsson - One of the best experts on this subject based on the ideXlab platform.

Stephen T Holgate - One of the best experts on this subject based on the ideXlab platform.

  • Pathophysiology of Asthma what has our current understanding taught us about new therapeutic approaches
    The Journal of Allergy and Clinical Immunology, 2011
    Co-Authors: Stephen T Holgate
    Abstract:

    Current Asthma therapy is based on the use of adrenergic bronchodilator and anti-inflammatory drugs the specificity, efficacy, duration of action, and safety of which have been derived through classical pharmacology and medicinal chemistry. That Asthma is a T(H)2-type inflammatory disorder frequently associated with atopy and allergic comorbidities has led to a concentrated effort to find treatments that act selectively on this pathway. A systematic literature review was undertaken, as well as a review of the Web site Clinicaltrials.gov for ongoing trials. Targets have included T cells themselves and their associated cytokines, chemokines, and receptors mostly targeted with biological agents. With the exception of anti-human IgE, none of these have met the expectations predicted from animal models and human in vitro tests. For most of these new therapies, only a very small subpopulation appears to respond. A case is made for a different approach to drug discovery based on acquiring a greater understanding of Asthma stratification, the relevant pathways involved, and the development of appropriate diagnostic tests enabling the targeting of selective treatments to those Asthmatic phenotypes most likely to respond. The recognition that Asthma is more than allergy mandates improved predictive animal models and an appreciation that many of the environmental insults that initiate, consolidate, and exacerbate Asthma operate through an epithelium functioning in a disorderly fashion. An integrated model that places the epithelium at the forefront of Asthma pathogenesis suggests that greater emphasis should be placed on therapeutics that increase the airways' resistance against the inhaled environment rather than focusing only on suppression of inflammation.

  • the role of the mast cell in the Pathophysiology of Asthma
    The Journal of Allergy and Clinical Immunology, 2006
    Co-Authors: Peter Bradding, Andrew F Walls, Stephen T Holgate
    Abstract:

    There is compelling evidence that human mast cells contribute to the Pathophysiology of Asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with Asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the Asthmatic phenotype. The mechanism of mast cell recruitment by Asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with Asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to Asthmatic airways, should offer a novel approach to the treatment of Asthma.

  • expression of the high affinity receptor for immunoglobulin e ige by dendritic cells in normals and Asthmatics
    Advances in Experimental Medicine and Biology, 1995
    Co-Authors: Amanda E Semper, Peter Bradding, Martin K. Church, Judith A Hartley, Manuel J Tunondelara, Anthony E Redington, Stephen T Holgate
    Abstract:

    Immunoglobulin E (IgE) plays an important role in the Pathophysiology of Asthma and other allergic diseases. In mucosal tissues, IgE binds to specific receptors on the surface of mast cells, eosinophils and other inflammatory cells providing an important trigger mechanism for the release of inflammatory mediators.

Tsuyoshi Oguma - One of the best experts on this subject based on the ideXlab platform.

  • possible role of il 33 in the Pathophysiology of Asthma a cross sectional study
    European Respiratory Journal, 2011
    Co-Authors: Hideki Inoue, Tsuyoshi Oguma, Akio Niimi, Hisako Matsumoto, Isao Ito, Hitoshi Nakaji, Tomoko Tajiri, Toshiyuki Iwata, Tadao Nagasaki, Michiaki Mishima
    Abstract:

    Background: IL-33 and its receptor ST2 have been recognized as key molecules in Th2 inflammation. Clinical roles of serum levels of IL-33/ST2 have not been well evaluated in Asthmatic patients. Aims: To investigate relationships between serum IL-33/ST2 levels and clinical measurements in patients with stable Asthma. Methods: Seventy-two patients with stable, mild-to-severe Asthma aged 55.0±18.4 (mean ± SD) years were analyzed cross-sectionally. Serum levels of IL-33 and ST2 were measured by ELISA. Relationships between serum levels of IL-33/ST2 and clinical measurements were evaluated. Clinical measurements include spirometric values, exhaled nitric oxide (FeNO) levels, induced sputum cell differentials, blood eosinophil count and serum total and specific IgE results. Results: Forty-nine patients were positive for at least one IgE CAP RAST. Serum levels of IL-33 were positively correlated with disease duration (r = 0.34, p Conclusions: Serum levels of IL-33 may reflect atopic status as represented by serum total IgE levels as well as degree of airway inflammation as assessed by peripheral blood eosinophilia and FeNO levels.

  • relationship between small airway function and health status dyspnea and disease control in Asthma
    Respiration, 2010
    Co-Authors: Tomoshi Takeda, Toru Oga, Akio Niimi, Hisako Matsumoto, Isao Ito, Masafumi Yamaguchi, Hirofumi Matsuoka, Makiko Jinnai, Kojiro Otsuka, Tsuyoshi Oguma
    Abstract:

    Background: Small airways play important roles in the Pathophysiology of Asthma. However, relationships between small airway involvement and health status and dyspnea have not been

  • Role of Prostaglandin D2 and Its Receptors in the Pathophysiology of Asthma
    Allergology International, 2008
    Co-Authors: Tsuyoshi Oguma, Koichiro Asano, Akitoshi Ishizaka
    Abstract:

    Prostaglandin D2 (PGD2) is one of the most abundant lipid mediators present in the airways of Asthmatics. However, little was known of the role it plays in the Pathophysiology of Asthma, until the identification of DP (DP1, PTGDR) and CRTH2 (DP2), two PGD2-specific transmembrane receptors with different distribution and intracellular signaling. Pharmacological tools, such as receptor-specific agonists and antagonists, and genetically-engineered mice, which lack either DP or CRTH2, have helped understand the complex effects of PGD2 in allergic inflammation of the airways. Furthermore, genetic association studies have shown a positive linkage of the genetic polymorphisms in DP and CRTH2, with Asthma phenotypes from specific ethnic backgrounds, further highlighting the importance of PGD2 and its receptors in the Pathophysiology of Asthma.

Reinoud Gosens - One of the best experts on this subject based on the ideXlab platform.

  • airway structural components drive airway smooth muscle remodeling in Asthma
    Proceedings of the American Thoracic Society, 2009
    Co-Authors: Bart G J Dekkers, Herman Meurs, Harm Maarsingh, Reinoud Gosens
    Abstract:

    Chronic Asthma is an inflammatory airways disease characterized by pathological changes in the airway smooth muscle (ASM) bundle that contribute to airway obstruction and hyperresponsiveness. Remodeling of the ASM is associated with an increased smooth muscle mass, involving components of cellular hypertrophy and hyperplasia, and changes in the phenotype of the muscle that facilitate proliferative, synthetic and contractile functions. These changes are considered major contributing factors to the Pathophysiology of Asthma, because of their role in exaggerated airway narrowing. The mechanisms that regulate changes in ASM mass and phenotype are incompletely understood, but likely involve the regulatory role of mediators and growth factors secreted from inflammatory cells on ASM cell proliferation and phenotype. An alternative hypothesis is that cellular and structural components that together constitute the airway wall, such as the airway epithelium, airway nerves, and the extracellular matrix, interact wit...

  • airway structural components drive airway smooth muscle remodeling in Asthma
    Proceedings of the American Thoracic Society, 2009
    Co-Authors: Bart G J Dekkers, Herman Meurs, Harm Maarsingh, Reinoud Gosens
    Abstract:

    Chronic Asthma is an inflammatory airways disease characterized by pathological changes in the airway smooth muscle (ASM) bundle that contribute to airway obstruction and hyperresponsiveness. Remodeling of the ASM is associated with an increased smooth muscle mass, involving components of cellular hypertrophy and hyperplasia, and changes in the phenotype of the muscle that facilitate proliferative, synthetic and contractile functions. These changes are considered major contributing factors to the Pathophysiology of Asthma, because of their role in exaggerated airway narrowing. The mechanisms that regulate changes in ASM mass and phenotype are incompletely understood, but likely involve the regulatory role of mediators and growth factors secreted from inflammatory cells on ASM cell proliferation and phenotype. An alternative hypothesis is that cellular and structural components that together constitute the airway wall, such as the airway epithelium, airway nerves, and the extracellular matrix, interact with the ASM bundle to facilitate changes in smooth muscle phenotype and function that drive remodeling under inflammatory conditions. This review discusses the mechanisms by which structural components of the airway wall communicate with the ASM bundle to regulate remodeling and discusses these mechanisms in the context of the Pathophysiology of Asthma.

  • Muscarinic receptor signaling in the Pathophysiology of Asthma and COPD
    Respiratory Research, 2006
    Co-Authors: Reinoud Gosens, Herman Meurs, Johan Zaagsma, Andrew J Halayko
    Abstract:

    Anticholinergics are widely used for the treatment of COPD, and to a lesser extent for Asthma. Primarily used as bronchodilators, they reverse the action of vagally derived acetylcholine on airway smooth muscle contraction. Recent novel studies suggest that the effects of anticholinergics likely extend far beyond inducing bronchodilation, as the novel anticholinergic drug tiotropium bromide can effectively inhibit accelerated decline of lung function in COPD patients. Vagal tone is increased in airway inflammation associated with Asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle. Vagally derived acetylcholine also regulates mucus production in the airways. A number of recent research papers also indicate that acetylcholine, acting through muscarinic receptors, may in part regulate pathological changes associated with airway remodeling. Muscarinic receptor signalling regulates airway smooth muscle thickening and differentiation, both in vitro and in vivo. Furthermore, acetylcholine and its synthesizing enzyme, choline acetyl transferase (ChAT), are ubiquitously expressed throughout the airways. Most notably epithelial cells and inflammatory cells generate acetylcholine, and express functional muscarinic receptors. Interestingly, recent work indicates the expression and function of muscarinic receptors on neutrophils is increased in COPD. Considering the potential broad role for endogenous acetylcholine in airway biology, this review summarizes established and novel aspects of muscarinic receptor signaling in relation to the Pathophysiology and treatment of Asthma and COPD.

  • growth factor induced contraction of human bronchial smooth muscle is rho kinase dependent
    European Journal of Pharmacology, 2004
    Co-Authors: Reinoud Gosens, Herman Meurs, Johan Zaagsma, Dedmer Schaafsma, Mechteld Grootte M Bromhaar, Bart Vrugt, Adriaan S Nelemans
    Abstract:

    Growth factors have been implicated in the Pathophysiology of Asthma. However, the putative effects of these growth factors on human airway smooth muscle tone are still largely unknown. We performed contraction experiments using human bronchial smooth muscle ring preparations. The growth factor insulin-like growth factor-1 (IGF-1) induced a slowly developing sustained contraction, which was dependent on Rho-kinase, since contraction was almost completely inhibited by (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide (Y-27632; 1 muM). Angiotensin II, a G(q)-coupled receptor agonist which can act as a growth factor as well, induced a biphasic contraction, the sustained phase of which was also almost completely inhibited by Y-27632. We conclude that angiotensin II and IGF-1 induce a Rho-kinase-dependent sustained contraction of human bronchial smooth muscle. Since growth factors are associated with pathophysiologiocal conditions such as Asthma, inhibition of Rho-kinase could be effective under these conditions. (C) 2004 Elsevier B.V. All rights reserved.

Pablo Altman - One of the best experts on this subject based on the ideXlab platform.

  • The impact of the prostaglandin D2 receptor 2 and its downstream effects on the Pathophysiology of Asthma.
    Allergy, 2019
    Co-Authors: Christopher E. Brightling, Guy Brusselle, Pablo Altman
    Abstract:

    Current research suggests that the prostaglandin D-2 (PGD(2)) receptor 2 (DP2) is a principal regulator in the Pathophysiology of Asthma, because it stimulates and amplifies the inflammatory response in this condition. The DP2 receptor can be activated by both allergic and nonallergic stimuli, leading to several pro-inflammatory events, including eosinophil activation and migration, release of the type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 from T helper 2 (Th2) cells and innate lymphoid cells type 2 (ILCs), and increased airway smooth muscle mass via recruitment of mesenchymal progenitors to the airway smooth muscle bundle. Activation of the DP2 receptor pathway has potential downstream effects on Asthma Pathophysiology, including on airway epithelial cells, mucus hypersecretion, and airway remodelling, and consequently might impact Asthma symptoms and exacerbations. Given the broad distribution of DP2 receptors on immune and structural cells involved in Asthma, this receptor is being explored as a novel therapeutic target.

  • the prostaglandin d 2 receptor 2 pathway in Asthma a key player in airway inflammation
    Respiratory Research, 2018
    Co-Authors: Christian Domingo, Oscar Palomares, David Andrew Sandham, Veit J Erpenbeck, Pablo Altman
    Abstract:

    Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in Asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response. Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the Pathophysiology of Asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for Asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in Asthma.