Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nothwithstanding difficulties associated with the limitations of survey techniques and methodology employed to define asthma, the evidence accumulated to date suggests that the reported differences in the prevalence rates of this disease from country to country and within local populations of the one country are real. It is accepted that allergy is not the sole cause of asthma but nonetheless hypersensitivity to environmental allergens is a significant triggering factor in most countries of the world. Comparisons between countries might therefore be influenced by the time of the year when the survey is taken since the prevalence of seasonal asthma would be higher in the period of pollinosis. Environmental factors, and in particular the relative atmospheric concentrations of pollens and the density of house dust mite (D. pteronyssinus and D. farinae) in dwellings, must therefore be considered when accumulating prevalence data. The prevalence rate for childhood asthma is high in Australia, United Kingdom, United States of America and New Zealand, and medium to low in the Scandinavian countries and Switzerland. It is not clear what factors contribute toward these differences since several studies indicate that racial characteristics per se are not pre-eminent in defining susceptibility to asthma. Most surveys indicate that the prevalence of childhood asthma is low to very low among low-income populations living in tropical areas. While it is possible to implicate inadequate diagnosis, genetic factors, nutritional status and allergen exposure as factors contributing towards the low prevalence, it has become fashionable to attribute this observation to the influence of certain helminthic infections. Parasites stimulate the production of high levels of serum IgE, the bulk of which has as yet an undetermined specificity. The suggestion that this IgE blocks mast cell receptors leaving insufficient sites available for sensitization by allergen-specific IgE antibody is attractive. However, since the kinetics of binding to mast cell receptors is unlikely to be the same for all IgE molecules, irrespective of their specificity, this hypothesis appears to be an oversimplification of the problem. It is more likely that parasitic infections repress the synthesis of IgE antibody to environmental allergens, although the mechanism for this is unclear. Circumstantial evidence suggests that the time course of exposure to parasites versus sensitization by environmental allergens may be critical. Another possibility is that parasitic infections in some way nullify the effect of allergens at the level of the target organ, perhaps through the modulating role of eosinophils. If it is established that parasitic infections, particularly in early childhood, suppress the capacity of potentially atopic children to develop asthma and other allergic disorders, there would be some justification in attempting to circumvent allergic disorders in susceptible individuals by a harmless preparation of parasite antigens.
 ...
PMID:The conflicting role of parasitic infections in modulating the prevalence of asthma. 28 88

Asthma is a common disease of children the basis of which is a state of chronic immunological inflammation which causes bronchial hyperreactivity and renders the patient liable to develop widespread airways obstruction in response to a variety of stimuli. In many instances it is likely that the immunological inflammation results from ongoing antigenic stimuli with the release of chemical mediators responsible for short term bronchospasm and cytokines responsible for the ongoing inflammatory process. Other insults can apparently result in very similar immunological events in asthmatics, particularly viral infections and a similar process can be initiated in children without asthma, including those with chronic bacterial infections of the lungs. There are differences in the bronchial hyperreactivity of asthma and other diseases which suggest that in the asthmatic the mast cell is either different structurally or functionally and this renders the patient susceptible to exercise induced asthma in addition to the bronchial hyperreactivity to chemical mediators common to a number of diseases with hyperreactivity. There is good evidence of direct genetic control of atopy and the large majority of children with asthma are atopic but there is no direct genetic link between atopy and asthma and twin studies strongly suggest the existence of a 'permissive' asthma gene which will allow the disease to develop if there is an appropriate external trigger. The only drugs which have been shown to significantly reduce bronchial reactivity are the corticosteroids with a lesser effect noted for sodium cromoglycate and nedocromil. Inhaled corticosteroids can reverse the immunologic inflammatory process and reduce bronchial reactivity, sometimes to normal levels, but on stopping treatment the patient reverts back to the asthmatic state. At the present time it appears that controlled longterm inhaled corticosteroid therapy is the most rational treatment for significant perennial childhood asthma.
 ...
PMID:Airway inflammation, bronchial reactivity and asthma. 848 May 45

During an allergic inflammatory response in the airway, if a failure of the epithelial cell barrier occurs before the systemic immune response is triggered by allergens, more allergens can invade. Using a rat model of asthma, we previously found that mucosal mast cells, which localise to the epithelial layer of the airways, are activated to promote a pro-asthmatic immune response. In this study, we developed a neonatal rat model of allergic airway hypersensitivity that mimics some features of childhood asthma. Airway hypersensitivity was measured using unrestrained whole-body plethysmography after analysis of the serum IgE titre. Inflammatory cells and inflammatory mediators in bronchoalveolar lavage fluid samples were examined. Two mast cell-specific proteases were detected using PCR. In addition, we analysed the phenotype and the number of mast cells in the airways by immunohistochemistry, and we found that the number of mucosal mast cells and the expression level of the proteases increased 2 weeks after sensitisation. Changes in the IgE titre, airway hypersensitivity and the activation of other inflammatory cells were delayed, appearing during the 4 weeks after sensitisation. Our results indicate that the activation of mucosal mast cells contributes to the pro-asthmatic immune response. This activation may be a biomarker allowing early intervention that could help prevent allergic airway inflammation.
 ...
PMID:Early activation of mucosal mast cells during the primary immune response in a rodent model of neonatal asthma. 2066 Dec 60

Early life respiratory viral infections and atopic characteristics are significant risk factors for the development of childhood asthma. It is hypothesized that repeated respiratory viral infections might induce structural remodeling by interfering with the normal process of lung maturation; however, the specific molecular processes that underlie these pathological changes are not understood. To investigate the molecular basis for these changes, we used an established Sendai virus infection model in weanling rats to compare the post-infection transcriptomes of an atopic asthma susceptible strain, Brown Norway, and a non-atopic asthma resistant strain, Fischer 344. Specific to this weanling infection model and not described in adult infection models, Sendai virus in the susceptible, but not the resistant strain, results in morphological abnormalities in distal airways that persist into adulthood. Gene expression data from infected and control lungs across five time points indicated that specific features of the immune response following viral infection were heightened and prolonged in lungs from Brown Norway rats compared with Fischer 344 rats. These features included an increase in macrophage cell number and related gene expression, which then transitioned to an increase in mast cell number and related gene expression. In contrast, infected Fischer F344 lungs exhibited more efficient restoration of the airway epithelial morphology, with transient appearance of basal cell pods near distal airways. Together, these findings indicate that the pronounced macrophage and mast cell responses and abnormal re-epithelialization precede the structural defects that developed and persisted in Brown Norway, but not Fischer 344 lungs.
...
PMID:Comparison of temporal transcriptomic profiles from immature lungs of two rat strains reveals a viral response signature associated with chronic lung dysfunction. 2543 59

Childhood asthma is an umbrella of multifactorial diseases with similar clinical features such as mast cell and eosinophil infiltration causing airway hyper responsiveness, inflammation, and airway obstruction. There are various factors that are implicated in childhood asthma pathogenesis. A combined contribution of genetic predisposition, environmental insults, and epigenetic changes account for polarisation of the immune system towards T helper (Th) type 2 cell responses that include production of pro-inflammatory cytokines, IgE, and eosinophil infiltrates, shown to associate with asthma. Environmental cues in prenatal, perinatal, and early childhood seem to determine development of asthma incidence or protection against it. Mode of birth delivery, use of antibiotics, oxidative stress, exposure to tobacco smoke and an industrialised lifestyle are significant contributors to childhood asthma exacerbation. Environmental stimuli such as exposure to maternal antibodies through breast milk, and certain early infections favour Th1 cell responses, leading to the production of anti-inflammatory cytokines that protect from asthma. Aside from the Th cell responses the role of innate immunity in the context of alveolar macrophages, dendritic cells, and surfactant protein A (SP-A) and SP-D is discussed. SP-A and SP-D enhance pathogen phagocytosis and cytokine production by alveolar macrophages, bind and clear pathogens, and interact with dendritic cells to mediate adaptive immunity responses. Further study of the interactions between genetic variants of genes of interest (SP-A and SP-D) and the environment may provide valuable knowledge about the underlying mechanisms of various interactions that differentially affect asthma susceptibility, disease severity, and reveal potential points for therapeutic interventions.
...
PMID:Childhood asthma: causes, risks, and protective factors; a role of innate immunity. 2553 26

Asthma is a clinically heterogeneous disorder, whose onset and progression results from a complex interplay between genetic susceptibility, allergens, and viral triggers. Sphingolipids and altered sphingolipid metabolism have emerged as potential key contributors to the pathogenesis of asthma. Orosomucoid-like 3 gene (ORMDL3) and the asthma susceptibility locus 17q21 have been strongly and reproducibly linked to childhood asthma, but how this gene is functionally linked to asthma is incompletely understood. ORMDL proteins play an integral role in sphingolipid homeostasis and synthesis, and asthma-associated ORMDL3 polymorphisms have been associated with early viral respiratory infections and increased risk of asthma. ORMDL proteins act as inhibitors of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis, and decreased sphingolipid synthesis through SPT increases airway hyperreactivity, which is independent of allergy or inflammation. In allergic models of asthma, the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide have been shown to be important signaling molecules for airway hyperreactivity, mast cell activation, and inflammation. This review will highlight how sphingolipids and altered sphingolipid metabolism may contribute towards the underlying mechanisms of childhood asthma.
...
PMID:Airway reactivity and sphingolipids-implications for childhood asthma. 2663 47