| 1. |
- Åbrink, Magnus, et al.
(författare)
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Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice
- 2011
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 121, s. 4180-4191
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Tidskriftsartikel (refereegranskat)abstract
- Mast cell degranulation is important in the pathogenesis of anaphylaxis and allergic disorders. Many animal venoms contain components that can induce mast cell degranulation, and this has been thought to contribute to the pathology and mortality caused by envenomation. However, we recently reported evidence that mast cells can enhance the resistance of mice to the venoms of certain snakes and that mouse mast cell-derived carboxypeptidase A3 (CPA3) can contribute to this effect. Here, we investigated whether mast cells can enhance resistance to the venom of the Gila monster, a toxic component of that venom (helodermin), and the structurally similar mammalian peptide, vasoactive intestinal polypeptide (VIP). Using 2 types of mast cell-deficient mice, as well as mice selectively lacking CPA3 activity or the chymase mouse mast cell protease-4 (MCPT4), we found that mast cells and MCPT4, which can degrade helodermin, can enhance host resistance to the toxicity of Gila monster venom. Mast cells and MCPT4 also can limit the toxicity associated with high concentrations of VIP and can reduce the morbidity and mortality induced by venoms from 2 species of scorpions. Our findings support the notion that mast cells can enhance innate defense by degradation of diverse animal toxins and that release of MCPT4, in addition to CPA3, can contribute to this mast cell function.
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| 2. |
- Åbrink, Magnus
(författare)
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The alpha v beta 6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells
- 2012
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 122, s. 748-758
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Tidskriftsartikel (refereegranskat)abstract
- Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking alpha v beta 6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in beta 6-deficient mice. These findings were most likely explained by loss of TGF-beta activation, since the epithelial integrin alpha v beta 6 is a critical activator of latent TGF-beta, and in vitro-differentiated mast cells showed TGF-beta-dependent expression of mMCP-1 and suppression of mMCP-4 and -6. In vitro, mMCP-1 increased contractility of murine tracheal rings, an effect that depended on intact airway epithelium, whereas mMCP-4 inhibited IL-beta-induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-beta by the alpha v beta 6 integrin regulates airway responsiveness by modulating mast cell protease expression and that these proteases and their proteolytic substrates could be novel targets for improved treatment of allergic asthma.
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