Prostaglandin modulation of airway inflammation and hyperresponsiveness in mice sensitized without adjuvant
The National Institute of Environmental Medicine, Division of Physiology, Karolinska Institutet, Stockholm, Sweden. Prostaglandins & other lipid mediators
(Impact Factor: 2.38).
03/2010; 92(1-4):44-53. DOI: 10.1016/j.prostaglandins.2010.02.004
As adjuvant during sensitization may cause unspecific immune reactions, the aim of the present study was to define the role of cyclooxygenase (COX) activity on airway inflammation and airway hyperresponsiveness (AHR) in an adjuvant-free allergic mouse model. Administration of diclofenac and indomethacin (non-selective COX inhibitors), FR122047 (COX-1 inhibitor) and lumiracoxib (selective COX-2 inhibitor) enhanced AHR. Only diclofenac and lumiracoxib reduced the inflammatory cell content of bronchoalveolar lavage (BAL). Moreover, levels of prostaglandins in BAL were reduced by indomethacin and FR122047 but were unaffected by lumiracoxib. However, compared with antigen controls, none of the COX inhibitors displayed major effects on the production of cytokines, smooth muscle mass, number of goblet cells and eosinophils, or collagen deposition in the airways. These data in mice sensitized without adjuvant support the fact that COX products have a general bronchoprotective role in allergic airway inflammation. Furthermore, the data suggest that COX-1 activity predominantly generates prostanoids in BAL, whereas COX-2 activity is associated with the accumulation of inflammatory cells in BAL. This study further supports that AHR on the one hand, and the inflammatory response and generation of prostanoids on the other, are dissociated and, at least in part, uncoupled events.
Available from: jpet.aspetjournals.org
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ABSTRACT: A deep inspiration (DI) produces bronchodilation in healthy individuals. Conversely, in asthmatics, DIs are less effective in producing bronchodilation and can cause more rapid airway renarrowing and even bronchoconstriction in moderate to severe asthmatics. It is noteworthy that the manner by which a DI is able to cause bronchoconstriction via a stretch-activated contraction (R(stretch)) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A(2) (TxA(2)) and subsequent thromboxane prostanoid (TP) receptor activation, causing the heightened contractility of airway smooth muscle. In this study, we sought to investigate the effect of TxA(2) on airway R(stretch) by using bovine bronchial segments. In brief, these intact bronchial segments (2 mm in diameter) were dissected, side branches were ligated, and the tissues were mounted horizontally in an organ bath. R(stretch) was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced R(stretch) response in tissues pretreated with indomethacin, a cyclooxygenase inhibitor, a result mimicked by pretreatment with the TP-selective receptor antagonist 4-(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid (ICI 192605) and the selective p42/p44 mitogen-activated protein kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD 95089) and by airway epithelial denudation. 9,11-Dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), a TP receptor agonist, elicited enhanced R(stretch) responses in a dose-dependent manner. Pretreatment with 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a prostaglandin E (EP) receptor 1/prostaglandin D2 (DP)-selective receptor antagonist, and 9α,15R-dihydroxy-11.β-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid (AL 8810), a prostaglandin F (FP)-selective receptor antagonist, had no effect, suggesting EP, DP, and FP receptor activation is not involved in amplifying airway smooth muscle R(stretch). These data suggest a role for TP receptor activation and epithelial release of TxA(2) in amplifying airway R(stretch), thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics.
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ABSTRACT: Mast cells play a key role in the pathogenesis of asthma and are a promising target for therapeutic intervention in asthma. This study investigated the effects of polydatin (PD), a resveratrol glucoside, on mast cell degranulation upon cross-linking of the high-affinity IgE receptors (FcεRI), as well as the anti-allergic activity of PD in vivo. Herein, we demonstrated that PD treatment for 30min suppressed FcεRI-mediated mast cell degranulation in a dose-dependent manner. Concomitantly, PD significantly decreased FcεRI-mediated Ca(2+) increase in mast cells. The suppressive effects of PD on FcεRI-mediated Ca(2+) increase were largely inhibited by using LaCl(3) to block the Ca(2+) release-activated Ca(2+) channels (CRACs). Furthermore, PD significantly inhibited Ca(2+) entry through CRACs evoked by thapsigargin (TG). Knocking down protein expression of Orai1, the pore-forming subunit of CRACs, significantly decreased PD suppression of FcεRI-induced intracellular Ca(2+) influx and mast cell degranulation. In a mouse model of mast cell-dependent passive cutaneous anaphylaxis (PCA), in vivo PD administration suppressed mast cell degranulation and inhibited anaphylaxis. Taken together, our data indicate that PD stabilizes mast cells by suppressing FcεRI-induced Ca(2+) mobilization mainly through inhibiting Ca(2+) entry via CRACs, thus exerting a protective effect against PCA.
Available from: Gunnar Nilsson
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ABSTRACT: Allergic asthma is a chronic inflammatory disease, characterized by airway hyperresponsiveness (AHR), inflammation and tissue remodelling, in which mast cells play a central role. In the present study, we analyzed how mast cell numbers and localization influence the AHR in a chronic murine model of asthma. C57BL/6 (wild-type) and mast cell-deficient B6.Cg-Kit(W-sh) mice without (Wsh) and with (Wsh+MC) mast cell-engraftment were sensitized to and subsequently challenged with ovalbumin for a 91 days period. In wild-type mice, pulmonary mast cells were localized in the submucosa of the central airways whereas the more abundant mast cells in Wsh+MC mice were found mainly in the alveolar parenchyma. In Wsh+MC, OVA challenge induced a relocation of mast cells from the perivascular space and central airways to the parenchyma. Allergen challenge caused a similar AHR in wild-type and Wsh mice in the resistance of the airways and the pulmonary tissue. In Wsh+MC mice the AHR was more pronounced. The elevated functional responses were partly related to the numbers and localization of connective tissue-type mast cells in the peripheral pulmonary compartments. A mast cell-dependent increase in IgE and IL-33 together with impairment of the IL-23/IL-17 axis was evoked in Wsh and Wsh+MC mice by allergen challenge. This study shows that within the same chronic murine asthma model the development of AHR can be both dependent and independent of mast cells. Moreover, the spatial distribution and number of pulmonary mast cells determine severity and localisation of the AHR.
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