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Asthma belongs to the category of classical allergic diseases which generally arise due to IgE mediated hypersensitivity to environmental triggers. Since its prevalence is very high in developed or urbanized societies it is also referred to as "disease of civilizations". Due to its increased prevalence among related individuals, it was understood quite long back that it is a genetic disorder. Well designed epidemiological studies reinforced these views. The advent of modern biological technology saw further refinements in our understanding of genetics of asthma and led to the realization that asthma is not a disorder with simple Mendelian mode of inheritance but a multifactorial disorder of the airways brought about by complex interaction between genetic and environmental factors. Current asthma research has witnessed evidences that are compelling researchers to redefine asthma altogether. Although no consensus exists among workers regarding its definition, it seems obvious that several pathologies, all affecting the airways, have been clubbed into one common category called asthma. Needless to say, genetic studies have led from the front in bringing about these transformations. Genomics, molecular biology, immunology and other interrelated disciplines have unearthed data that has changed the way we think about asthma now. In this review, we center our discussions on genetic basis of asthma; the molecular mechanisms involved in its pathogenesis. Taking cue from the existing data we would briefly ponder over the future directions that should improve our understanding of asthma pathogenesis.
Clin Mol Allergy 2009 May 06
PMID:Genetics of asthma: a molecular biologist perspective. 1941 42

15-Lipoxygenase-1 (15-LOX-1) has been proposed to be involved in various physiological and pathophysiological activities such as inflammation, atherosclerosis, cell maturation, and tumorigenesis. Asthma and chronic obstructive pulmonary disease are associated with increased expression of 15-LOX-1 in bronchial epithelial cells, but the potential functions of 15-LOX-1 in airway epithelial cells have not been well clarified. To study the function of 15-LOX-1 in bronchial epithelial cells, we ectopically expressed 15-LOX-1 in the human lung epithelial cell line A549. We found that overexpression of 15-LOX-1 in A549 cells leads to increased release of the chemokines MIP-1alpha, RANTES, and IP-10, and thereby to increased recruitment of immature dendritic cells, mast cells, and activated T cells. These results suggest that an increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders.
Am J Physiol Lung Cell Mol Physiol 2009 Jul
PMID:15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells. 1942 75

Asthma is a common chronic condition in children, where the response to treatment can be heterogeneous within a population. Genetic variations may partly explain the inconsistent response to asthma treatment between individuals. There is a relatively small but consistent body of literature linking genetic variations to improved response to different classes of asthma treatment, including short- and long-acting beta-agonists, corticosteroids, and leukotriene modifiers. In most cases, the advantage conferred by a single genetic mutation for treatment response is relatively small; the Arg16Gly single nucleotide polymorphism of the beta2-adrenoceptor is the exception to this rule and is associated with a marked difference in response to short-acting beta-agonists. Pharmacogenetic studies have only recently been undertaken in asthmatic individuals, and much more work is required before clinical applications arise. Future genome-wide association (GWA) studies and randomized controlled trials in genetically susceptible populations will determine whether asthma treatment can be tailored to an individual based on their DNA. The aim of the present paper is to review pharmacogenetic studies concerning asthma medications, with a primary focus on studies involving children.
Mol Diagn Ther 2009
PMID:Genetic predictors of response to therapy in childhood asthma. 1953 47

Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th(1))/Th(2) immune response. Increased Th(2) cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through transforming growth factor-beta(1) (TGF-beta(1)) and lead to subepithelial fibrosis, which is a crucial component of airway remodeling. Synthetic antimalarials have been reported to have immunomodulatory properties. Mepacrine is known for its reduction of airway inflammation in short-term allergen challenge model by reducing Th(2) cytokines and cysteinyl leukotrienes, which has an important role in the development of airway remodeling features. Therefore, we hypothesized that mepacrine may reduce airway remodeling. For this, extended subacute ovalbumin mice model of asthma was developed; these mice showed an increased expression of profibrotic mediators, subepithelial fibrosis, and goblet cell metaplasia along with airway inflammation, increased Th(2) cytokines, allergen-specific IgE, IgG(1), increased cytosolic PLA(2) (cPLA(2)), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-beta(1) expression in subepithelial mesenchymal regions by repeated allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of asthma. However, mepacrine treatment decreased Th(2) cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by mepacrine were associated with a decrease in levels and expression of TGF-beta(1) and the reduction in activity, expression of arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that mepacrine might reduce the development of subepithelial fibrosis by reducing the arginase and TGF-beta(1). These effects of mepacrine likely underlie its antiairway remodeling action in asthma.
Am J Physiol Lung Cell Mol Physiol 2009 Sep
PMID:Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and TGF-beta1 in an extended subacute mouse model of allergic asthma. 1954 46

Asthma needs continuous treatment often for years. In humans, some drugs are administered via aerosol, therefore they come in contact with both respiratory and olfactory mucosa. We explored the possibility that antiasthma corticosteroid treatment could influence the olfactory function by passage through the nose. A group of mice was exposed twice daily for 42 days to fluticasone propionate aerosol and was compared with a control group. Olfactory behavior, respiratory mechanics, histology, and immunoreactivity in the olfactory system were assessed. Fluticasone-treated mice were slower in retrieving a piece of hidden food, but both groups were similarly fast when the food was visible. When a clearly detectable odor was present in the environment, all mice behaved in a similar way. Respiratory mechanics indices were similar in all mice except for the viscose resistance, which was reduced in fluticasone-treated mice. Olfactory mucosa of fluticasone-treated mice was thicker than that of controls. Slight but consistent differences in staining were present for Olfactory Marker Protein but not for other proteins. A mild impairment of olfactory function is present in mice chronically treated with fluticasone aerosol, apparently accompanied by slight modifications of the olfactory receptor cells, and suggests monitoring of olfactory function modifications in long-term steroid users.
Am J Physiol Lung Cell Mol Physiol 2009 Dec
PMID:The olfactory system is affected by steroid aerosol treatment in mice. 1980 53

Asthma and allergic rhinitis are almost invariable accompanied by elevated levels of immunoglobin E (IgE), and more importantly a genetic link between IgE levels and airway hyper-responsiveness has been established. We hypothesized that expression of soluble receptors directed against interleukin (IL)-13 and IL-17e would prevent the cytokines from engaging the cell-bound receptors and therefore help to attenuate allergic responses in a Cftr(-/-)-dependent mouse model of exaggerated-IgE responses. Cftr(-/-) mice were injected with recombinant adeno-associated virus 1 (rAAV1) intramuscularly expressing soluble receptors to IL-17e (IL-17Rh1fc) or IL-13 (IL-13Ralpha2Fc). Total IgE levels, in mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapy, were lower than in the control group. Interestingly Aspergillus fumigatus (Af)-specific IgE levels were undetectable in both the mice receiving the IL-17Rh1fc and IL-13Ralpha2Fc therapies. Further flow cytometry analysis of intracellular gene expression suggests that blocking IL-17e may be interfering with signaling upstream of CD4+ and CD11b+ cells and reducing IgE levels by affecting signaling on these cell populations. In contrast it appears that IL-13 blockade acts downstream to reduce IgE levels probably by directly affecting B-cell maturation. These studies demonstrate the feasibility of targeting T helper 2 (Th2) cytokines with rAAV-delivered fusion proteins as a means to treat aberrant immune responses.
Mol Ther 2010 Mar
PMID:Modulation of exaggerated-IgE allergic responses by gene transfer-mediated antagonism of IL-13 and IL-17e. 1993 81

Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemokine receptor-3 (CCR3) play a primary role in the recruitment of eosinophils in allergic asthma. Development of novel and potent CCR3 antagonists could provide a novel mechanism for inhibition of this recruitment process, thereby preventing asthma. With the intention of designing new ligands with enhanced inhibitor potencies against CCR3, a 3D-QSAR CoMFA study was carried out on 41 4-benzylpiperidinealkylureas and amide derivatives. The best statistics of the developed CoMFA model were r (2) = 0.960, r(2)cv, n = 32 for the training set and r(2)pred, n = 9 for the test set. The generated 3D-QSAR contribution maps shed some light on the effects of the substitution pattern related to CCR3 antagonist activity.
J Mol Model 2010 Apr
PMID:Ligand-based molecular design of 4-benzylpiperidinealkylureas and amides as CCR3 antagonists. 1996 Mar 58

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.
Am J Physiol Lung Cell Mol Physiol 2010 Mar
PMID:Intelectin is required for IL-13-induced monocyte chemotactic protein-1 and -3 expression in lung epithelial cells and promotes allergic airway inflammation. 2006 38

Regulatory T cells (Tregs) play an essential role in maintaining the homeostatic balance of immune responses. Asthma is an inflammatory condition of the airways that is driven by dysregulated immune responses toward normally innocuous antigens. Individuals with asthma have fewer and less functional Tregs, which may lead to uncontrolled effector cell responses and promote proasthmatic responses of T helper type 2, T helper 17, natural killer T, antigen-presenting, and B cells. Tregs have the capacity to either directly or indirectly suppress these responses. Hence, the induced expansion of functional Tregs in predisposed or individuals with asthma is a potential approach for the prevention and treatment of asthma. Infection by a number of micro-organisms has been associated with reduced prevalence of asthma, and many infectious agents have been shown to induce Tregs and reduce allergic airways disease in mouse models. The translation of the regulatory and therapeutic properties of infectious agents for use in asthma requires the identification of key modulatory components and the development and trial of effective immunoregulatory therapies. Further translational and clinical research is required for the induction of Tregs to be harnessed as a therapeutic strategy for asthma.
Am J Respir Cell Mol Biol 2010 Nov
PMID:Harnessing regulatory T cells to suppress asthma: from potential to therapy. 2009 30

Asthma is the leading serious pediatric chronic illness in the United States, affecting 7.1 million children. The prevalence of asthma in children under 4 years of age has increased dramatically in the last 2 decades. Existing evidence suggests that this increase in prevalence derives from early environmental exposures acting on a pre-existing asthma-susceptible genotype. We studied the origins of asthma susceptibility in developing lung in rat strains that model the distinct phenotypes of airway hyperresponsiveness (Fisher rats) and atopy (brown Norway [BN] rats). Postnatal BN rat lungs showed increased epithelial proliferation and tracheal goblet cell hyperplasia. Fisher pups showed increased lung resistance at age 2 weeks, with elevated neutrophils throughout the postnatal period. Diverse transcriptomic signatures characterized the distinct respiratory phenotypes of developing lung in both rat models. Linear regression across age and strain identified developmental variation in expression of 1,376 genes, and confirmed both strain and temporal regulation of lung gene expression. Biological processes that were heavily represented included growth and development (including the T Box 1 transcription factor [Tbx5], the epidermal growth factor receptor [Egfr], the transforming growth factor beta-1-induced transcript 1 [Tgfbr1i1]), extracellular matrix and cell adhesion (including collagen and integrin genes), and immune function (including lymphocyte antigen 6 (Ly6) subunits, IL-17b, Toll-interacting protein, and Ficolin B). Genes validated by quantitative RT-PCR and protein analysis included collagen III alpha 1 Col3a1, Ly6b, glucocorticoid receptor and Importin-13 (specific to the BN rat lung), and Serpina1 and Ficolin B (specific to the Fisher lung). Innate differences in patterns of gene expression in developing lung that contribute to individual variation in respiratory phenotype are likely to contribute to the pathogenesis of asthma.
Am J Respir Cell Mol Biol 2010 Dec
PMID:Genetic influences on asthma susceptibility in the developing lung. 2011 17


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