Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asthma is characterized by reversible bronchial hyper-responsiveness and airway inflammation, and encompasses a wide variety of patients with different clinical phenotypes that display variable responses to therapy. The definition of genomic variation presented in the Human Genome Project has facilitated the development of genetic-guided therapy in various diseases, including asthma. Tailored therapy is a reality in many types of malignancies where specific gene mutations or molecular profiles are identified and used to make critical therapeutic decisions. Despite the identification of beta-adrenergic receptor polymorphisms by Liggett and colleagues during the 1990s, the pharmacogenetics of asthma is still in its infancy. There have been great advances in asthma pharmacogenetics and pharmacotherapy with the completion of several large trials highlighting the effects of genotype on response to asthma therapy. This review focuses on research articles that serve to emphasize the potential role of using genotyping as a tool to develop individualized patient treatment regimens for asthma, thus improving outcomes and limiting adverse effects of certain therapies.
Curr Opin Mol Ther 2007 Dec
PMID:Genetic profiling and tailored therapy in asthma: are we there yet? 1804 63

Asthma is a multifactorial disease, in which the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Using a genome-wide scan for linkage in a population comprising of Danish families, we identified a novel linked locus on chromosome 1qter (LOD 3.6, asthma) and supporting evidence for this locus was identified for both asthma and atopic-asthma phenotypes in the GAIN (Genetics of Asthma International Network) families. The putative susceptibility gene was progressively localized to a 4.5 Mb region on chromosome 1q adjacent to the telomere, through a series of genotyping screens. Further screening using the pedigree-based association test (PBAT) identified polymorphisms in the OPN3 and CHML genes as being associated with asthma and atopic asthma after correcting for multiple comparisons. We observed that polymorphisms flanking the OPN3 and CHML genes wholly accounted for the original linkage in the Danish population and the genetic association was also confirmed in two separate studies involving the GAIN families. OPN3 and CHML are unique genes with no known function that are related to the pathophysiology of asthma. Significantly, analysis of gene expression at both RNA and protein levels, clearly demonstrated OPN3 expression in lung bronchial epithelia as well as immune cells, while CHML expression appeared minimal. Moreover, OPN3 down-regulation by siRNA knock-down in Jurkat cells suggested a possible role for OPN3 in modulation of T-cell responses. Collectively, these data suggest that OPN3 is an asthma susceptibility gene on 1qter, which unexpectedly may play a role in immune modulation.
Hum Mol Genet 2008 Jul 01
PMID:Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation. 1834 58

Asthma is a common disease characterized by airway inflammation and bronchorestriction. There are several common categories of medications for treating asthma; however, not all asthmatics have the same response to these medications, some of which are adverse responses that are potentially life threatening. Because interindividual responses to asthma medications can vary considerably, the potential for genetic contributions to variable drug responses is significant. This chapter reviews the most common biological pathways targeted by asthma therapy and briefly discusses the genetic contribution to varied responses to asthma therapy for four common types of asthma medications: beta-agonists, anticholinergics, leukotriene modifiers, and corticosteroids.
Methods Mol Biol 2008
PMID:Pharmacogenetics of asthma. 1837 Feb 37

Asthma is a chronic inflammatory disease of the airways, involving recurrent episodes of airway obstruction and wheezing. A common pathological feature in asthma is the presence of a characteristic allergic airway inflammatory response involving extensive leukocyte infiltration, mucus overproduction and airway hyper-reactivity. The pathogenesis of allergic airway inflammation is complex, involving multiple cell types such as T helper 2 cells, regulatory T cells, eosinophils, dendritic cells, mast cells, and parenchymal cells of the lung. The cellular response in allergic airway inflammation is controlled by a broad range of bioactive mediators, including IgE, cytokines and chemokines. The asthmatic allergic inflammatory response has been a particular focus of efforts to develop novel therapeutic agents. Animal models are widely used to investigate inflammatory mechanisms. Although these models are not perfect replicas of clinical asthma, such studies have led to the development of numerous novel therapeutic agents, of which some have already been successful in clinical trials.
Expert Rev Mol Med 2008 May 27
PMID:Mechanisms in allergic airway inflammation - lessons from studies in the mouse. 1850 27

Asthma is characterized by the presence of increased numbers of inflammatory cells in the airway in particular eosinophils and Th2 lymphocytes. In addition to the presence of inflammatory cells, the airways of patients with asthma exhibit varying levels of structural changes termed airway remodeling. These structural changes include subepithelial fibrosis, smooth muscle hypertrophy/hyperplasia, epithelial cell mucus metaplasia, and increased angiogenesis. This review focuses on the potential role of the eosinophil in promoting features of airway remodeling including fibrosis and neovascularization in chronic asthma. Eosinophils may potentially contribute to airway remodeling through release of eosinophil derived mediators such as TGFbeta which act directly upon target fibroblasts to promote fibrosis. In addition to the potential importance of the eosinophil to remodeling in asthma, eosinophilic esophagitis (EE) is another eosinophil associated disease that is associated with increased levels of esophageal eosinophils, increased levels of TGFbeta expression, and increased levels of fibrosis, suggesting that a similar mechanism of remodeling may contribute to both of these eosinophil associated diseases. However, remodeling in both asthma and EE is likely complex involving both eosinophil dependent and eosinophil independent pathways. Further studies in both humans and animal models will help to increase our knowledge of the contribution of the eosinophil to remodeling in asthma as well as EE.
Curr Mol Med 2008 Aug
PMID:Airway fibrosis and angiogenesis due to eosinophil trafficking in chronic asthma. 1869 Oct 61

Asthma, chronic obstructive pulmonary disorder (COPD), and cystic fibrosis (CF), chronic diseases of the airways, are characterized by symptoms such as inflammation of the lung tissue, mucus hypersecretion, constriction of the airways, and excessive fibrosis of airway tissue. Transforming growth factor (TGF)-beta, a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of these chronic airway diseases, especially with respect to airway remodeling. Eosinophils can be activated by and are a major source of TGF-beta in asthma. The action of TGF-beta also shows associations with other cell types, such as T cells and neutrophils, which are involved in the pathogenesis of asthma. TGF-beta can perpetuate the pathogenesis of COPD and CF, as well, through its induction of inflammation via release from and action on different cells. The intracellular signaling induced by TGF-beta in various cell types has been elucidated and may point to mechanisms of action by TGF-beta on different structural or immune cells in these airway diseases. Some possible treatments, especially that prevent the deleterious airway changes induced by the action of either eosinophils or TGF-beta in asthma, have been investigated. TGF-beta-induced signaling pathways, especially those in different cell types in asthma, COPD, or CF, may provide potential therapeutic targets for the treatment of some of the most devastating airway diseases.
Curr Mol Med 2008 Aug
PMID:Interaction of tgf-beta with immune cells in airway disease. 1869 Oct 70

Asthma is a chronic inflammatory disorder of the airways. Type 2 T helper (Th) cell-dominated inflammation in the lung is a hallmark of asthma. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is a negative regulator in the signaling pathways of many growth factor and cytokine receptors. However, a direct role of SHP-1 in the IL-4/IL-13 signaling pathway has not been established. In this study, we sought to define the function of SHP-1 in the lung by characterizing the pulmonary inflammation of viable motheaten (mev) mice, and to investigate the molecular mechanisms involved. Pulmonary histology, physiology, and cytokine expression of mev mice were analyzed to define the nature of the inflammation, and the gene-deletion approach was used to identify critical molecules involved. In mev mice, we observed spontaneous Th2-like inflammatory responses in the lung, including eosinophilia, mucus metaplasia, airway epithelial hypertrophy, pulmonary fibrosis, and increased airway resistance and airway hyperresponsiveness. The pulmonary phenotype was accompanied by up-regulation of Th2 cytokines and chemokines. Selective deletion of IL-13 or signal transducer and activator of transcription 6, key genes in the Th2 signaling pathway, significantly reduced, but did not completely eliminate, the inflammation in the lung. These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis.
Am J Respir Cell Mol Biol 2009 May
PMID:A critical role of SHP-1 in regulation of type 2 inflammation in the lung. 1895 67

Asthma frequently commences in early life during airway and immune development and exposure to new environmental challenges. Endobronchial biopsies from children with asthma are abnormal, and lung function is maximally reduced by 6 years of age. As longitudinal biopsy studies are unethical in children, the relationship between development of pathology and reduced lung function is unknown. We aimed to establish a novel neonatal mouse model of allergic airways disease to investigate the developmental sequence of the pathophysiologic features of asthma. Neonatal Balb/c mice were challenged three times weekly from Day 3 of life using intranasal house dust mite (HDM) or saline for up to 12 weeks. Weekly assessments of airway inflammation and remodeling were made. Airway hyperresponsiveness (AHR) to methacholine was assessed from Week 2 onward. Total and eosinophilic inflammation was significantly increased in the lungs of HDM-exposed neonates from Week 2 onwards, and a peak was seen at 3 weeks. Goblet cells and peribronchiolar reticulin deposition were significantly increased in HDM-exposed neonates from Week 3, and peribronchiolar collagen was significantly greater from Week 4. HDM-exposed neonates had increased AHR from Week 2 onward. Although inflammation and AHR had subsided after 4 weeks without allergen challenge, the increased reticulin and collagen deposition persisted in HDM-exposed mice. Neonatal mice exposed to intranasal HDM developed eosinophilic inflammation, airway remodeling, and AHR as reported in pediatric asthma. Importantly, all abnormalities developed in parallel, not sequentially, between 2 and 3 weeks of age.
Am J Respir Cell Mol Biol 2009 Sep
PMID:Pathophysiological features of asthma develop in parallel in house dust mite-exposed neonatal mice. 1915 16

Though not widely recognized, food hypersensitivity by inhalation can cause major morbidity in affected individuals. The exposure is usually more obvious and often substantial in occupational environments but frequently occurs in non-occupational settings, such as homes, schools, restaurants, grocery stores, and commercial flights. The exposure can be trivial, as in mere smelling or being in the vicinity of the food. The clinical manifestations can vary from a benign respiratory or cutaneous reaction to a systemic one that can be life-threatening. In addition to strict avoidance, such highly-sensitive subjects should carry self-injectable epinephrine and wear MedicAlert(R) identification. Asthma is a strong predisposing factor and should be well-controlled. It is of great significance that food inhalation can cause de novo sensitization.
Clin Mol Allergy 2009 Feb 20
PMID:Food hypersensitivity by inhalation. 1923 16

Asthma is an inflammatory disorder of the airways that has been typified by its bronchospastic component. New attention has been directed to the long-term changes in asthmatic airways as indicated by the accelerated rate of lung function decline occurring in these patients despite therapy with inhaled corticosteroids. These structural changes in the airway wall, termed airway remodeling, are now thought to be a key component in the pathophysiology of asthma. Airway remodeling is characterized by thickening of the lamina reticularis with deposition of collagen and other extracellular matrix proteins leading to subepithelial fibrosis and increased airway goblet cells causing mucus hypersecretion. Of note, there is myofibroblast proliferation and increased airway smooth muscle mass caused by both hyperplasia and hypertrophy of smooth muscle cells. While an important role for cysteinyl leukotrienes (CysLTs) in the pathogenesis of airway inflammation and bronchoconstriction in asthma has been well-established, the specific role of CysLTs in airway remodeling is less clear. This aim of this review is to summarize the data from mouse models of asthma as well as limited human studies that demonstrate a key role for CysLTs in allergen-induced mucus hypersecretion, thickening of the lamina reticularis, and subepithelial fibrosis in the lungs. We will also focus on the interaction between CysLTs and cytokines/growth factors that mediate these changes in epithelial cells, smooth muscle cells, vasculature, and other structural components of the lungs in patients with asthma.
Curr Mol Med 2009 Apr
PMID:The role of leukotrienes in airway remodeling. 1935 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>