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)

Although their precise mechanisms of action are undefined, the usefulness of CCS in the treatment of asthma is unquestioned. It is clear that they act at multiple sites. Among the general actions of CCS felt to be applicable to asthma are their ability to facilitate beta-adrenergic responsiveness and to suppress inflammation. More specific actions relevant to asthma are their inhibition of eicosanoid formation (e.g., reduction in leukotriene formation), prevention and reversal of LPR (probably through CCS anti-inflammatory effects), and reduction in mucus secretion. Actions that have not yet been clarified but that may be useful include possible reductions in airway hyperreactivity (or at least the prevention of increases in reactivity superimposed upon overreactive airways) and suppression of basophil (but not mast cell) mediator release.
 ...
PMID:Mechanisms of glucocorticosteroid action in bronchial asthma. 241 Apr 76

The role of human basophils and mast cells in the pathogenesis of allergic diseases has been analyzed. Purified human basophils and mast cells release several known mediators of allergic reactions, including histamine, sulfidopeptide leukotrienes, kinin-forming enzymes, and, in the case of the mast cell, PGD2. These same mediators are released in vivo after experimental challenge in the upper airways with either allergen or cold, dry air, a stimulus used to simulate exercise-induced bronchospasm. The appearance of mast cell mediators in vivo after such challenges further implicates mast cells in the pathogenesis of allergic diseases of the airways that occur as a result of exposure to allergen or physical stimuli. During the LPR after experimental challenge of the upper airways, the pattern of mediators released (i.e., histamine, leukotrienes, and others, but no PGD2) suggests that basophils may contribute to the LPR. Antiallergic drugs that prevent mediator release in vitro, such as antihistamines, also prevent the appearance of mediators in vivo, strengthening both the validity of the in vitro test as a model of the disease and the hypothesis that mediator release is an essential element of the disease process. A model discussing the pathogenetic mechanism is presented.
 ...
PMID:Role of human basophils and mast cells in the pathogenesis of allergic diseases. 241 Apr 78

Our current understanding of LPR has evolved over the past 10-12 years, and there are still many areas where our information is still incomplete and cannot provide solid support for several of the hypotheses presented herein. Each suggestion presented is testable, however, and answers to many of the questions raised should eventually be available. The hypotheses presented provide a framework for understanding how airway inflammation contributes to airway reactivity and how certain irritant exposures can cause delayed-onset asthma. More importantly, they provide a rationale for the use of many of the specific drugs used to treat allergies and asthma. Indeed, if LPR and airway inflammation are as important in asthma (and other allergic diseases) as these hypotheses suggest, the use of agents specifically designed to prevent or treat LPR should increase. Thus, mast cell stabilizing compounds such as cromoglycate, ketotifen, and tranilast and anti-inflammatory agents like GCS might be viewed as specific therapy for asthma (and other allergic diseases), while bronchodilators (like antihistamines, decongestants and antipruritic drugs in other allergic diseases) might be considered as supportive agents. These concepts therefore suggest the early and aggressive use of specific agents in asthma while employing supportive drugs to help maintain lung function.
 ...
PMID:Late phase reactions. 330 57

Biphasic skin reactions, with peaks at 1 and 24 h after epicutaneous challenge with antigen (immediate phase response: IPR and late phase response: LPR, respectively), were induced in ddY, ICR, Balb/c and Balb/c-nu/nu mice passively sensitized with monoclonal IgE antibody 24 h before. In WBB6F1-W/Wv mice, which lack mast cells, only the LPR was observed. The IPR was characterized by a rapid increase in capillary permeability and the LPR by skin thickening with significant infiltration of eosinophils and other inflammatory cells in Balb/c mice. Histamine H1 receptor antagonists, including diphenhydramine and homochlorcyclizine, and the allergic histamine release inhibitors, tranilast and amlexanox, clearly inhibited the IPR, but not the LPR. Prednisolone and dexamethasone, however, inhibited both. Prednisolone also inhibited the LPR in WBB6F1-W/Wv mice. These results indicate that IgE antibody-dependent biphasic skin reactions consist of a mast cell- and histamine-dependent IPR and a mast cell-independent LPR.
 ...
PMID:An immunopharmacological study of the biphasic allergic skin reaction in mice. 774 91

Epicutaneous antigen challenge in passively sensitized mice with IgE produces a biphasic cutaneous response which peaks 1 h (immediate-phase reaction) and 24 h (late-phase reaction; LPR) after the antigen challenge. In this model, anaphylactic degranulation and interleukin 6 (IL-6) expression between 4 and 8 h are observed in resident mast cells as the preceding stage of LPR. Prednisolone at a dose of 3 mg kg(-1) clearly inhibited the LPR when administered 2 h before and 4 h after antigen challenge. Slight or no inhibition of LPR was observed by prednisolone administered 6-12 h after challenge. Histologically, prednisolone treatment 2 h before antigen challenge completely inhibited edema and inflammatory cell infiltration, while treatment at 6 h did not at all. In order to investigate the relationship between inhibition of LPR by prednisolone and mast cell activation, the effects of prednisolone on degranulation of mast cells and IL-6 expression in mast cells were investigated. 8 h after antigen challenge, prednisolone clearly inhibited the increase in the number of anaphylactic degranulated and IL-6-positive mast cells by administration 2 h before challenge, but did not affect it by administration 6 h after challenge. These data indicate that the inhibitory mechanism of prednisolone on LPR, at least, involves the inhibition of mast cell activation before LPR.
 ...
PMID:Prednisolone inhibits an IgE-mediated late-phase allergic cutaneous reactionby interfering with the activation of mast cells in mice. 1115 Sep 18

Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 A resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase--zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.
 ...
PMID:Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. 1254 Aug 54

Allergic conjunctivitis (AC) is a common allergic eye disease characterized by clinical symptoms such as itchiness, conjunctival congestion, elevated Ag-specific IgE, mast cell activation, and local eosinophil infiltration. In this study we established a murine model for Ag-induced AC to understand the pathogenesis of the disease. Cell transfer experiments indicated that AC can be divided into early and late phase responses (EPR and LPR). EPR was associated with IgE responses, leading to itchiness, whereas LPR was characterized by local eosinophil infiltration. Both EPR and LPR were significantly inhibited in STAT6-deficient mice, and adoptive transfer of Th2 cells reconstituted LPR. Furthermore, SOCS3 was highly expressed at the disease site, and T cell-specific expression of SOCS3 deteriorated clinical and pathological features of AC, indicating that Th2-mediated SOCS3 expression controls the development and persistence of AC. Reduction of the expression level in SOCS3 heterozygous mice or inhibition of function in dominant-negative SOCS3 transgenic mice clearly reduced the severity of AC. In contrast, constitutive expression of SOCS5, a specific inhibitor of IL-4 signaling, resulted in reduced eosinophil infiltration. These results suggest that negative regulation of the Th2-mediated response by dominant-negative SOCS3 and SOCS5 could be a target for therapeutic intervention in allergic disease.
 ...
PMID:The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model. 1621 Jun 57