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Molecule That Decreases Airway Inflammation Could Lead To New Asthma …
RedOrbit Researchers at the Brigham and Women's Hospital (BWH) in Boston have discovered a molecule that controls cells responsible for decreasing airway inflammation in asthma patients, and their discovery could lead to new treatments for the millions of … |
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SHP-1 Regulation of Mast Cell Function in Allergic Inflammation and Anaphylaxis.
PLoS One. 2013;8(2):e55763
Authors: Zhou L, Oh SY, Zhou Y, Yuan B, Wu F, Oh MH, Wang Y, Takemoto C, Van Rooijen N, Zheng T, Zhu Z
Abstract
Allergic inflammation and severe allergic reactions (anaphylaxis) are important in allergen induced diseases. Bacterial products such as lipopolysaccharide (LPS) are ubiquitous and can facilitate allergen induced Th2 immune responses. Phosphatase SHP-1 is critical in regulating immunological homeostasis and in allergen induced Th2 immune responses in the lung. However, the mechanisms underlying the initiation of allergic inflammation and allergen induced anaphylaxis are still not completely elucidated and it is unclear whether SHP-1 plays any role in LPS-induced airway inflammation and in allergen-induced anaphylaxis. In this study we tested the hypothesis that phosphatase SHP-1 plays an important role in allergic inflammation and anaphylaxis and determined whether its effects are through regulation of mast cell functions. SHP-1 deficient (mev/+ and mev/mev) and mast cell deficient (Kit(W-sh)) mice were examined in their responses to LPS airway stimulation and to ovalbumin (OVA) allergen induced systemic anaphylaxis. Compared to wild type mice, mev/+ mice had significantly enhanced LPS induced airway inflammation and OVA induced anaphylactic responses, including hypothermia and clinical symptoms. These changes were mast cell dependent as Kit(W-sh) mice had reduced responses whereas adoptive transfer of mast cells restored the responses. However, T and B cells were not involved and macrophages did not play a significant role in LPS induced airway inflammation. Interestingly, basophil differentiation from SHP-1 deficient bone marrow cells was significantly reduced. These findings provided evidence that through regulation of mast cell functions SHP-1 plays a critical role as a negative regulator in allergic inflammation and in allergen induced anaphylaxis. In addition, SHP-1 seems to be required for normal basophil development.
PMID: 23390550 [PubMed – in process]
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Inflammation signals airway smooth muscle cell proliferation in asthma …
7thSpace Interactive (press release) It is now well recognized that chronic inflammation, as well as airway hyper-responsiveness and remodeling of airway during inflammation, are crucial to asthma. ASM is caused by increased cell proliferation or by hypertrophy of ASM cells depending on … |
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Alveolar Macrophages Play a Key Role in Cockroach-Induced Allergic Inflammation via TNF-? Pathway.
PLoS One. 2012;7(10):e47971
Authors: Kim JY, Sohn JH, Choi JM, Lee JH, Hong CS, Lee JS, Park JW
Abstract
The activity of the serine protease in the German cockroach allergen is important to the development of allergic disease. The protease-activated receptor (PAR)-2, which is expressed in numerous cell types in lung tissue, is known to mediate the cellular events caused by inhaled serine protease. Alveolar macrophages express PAR-2 and produce considerable amounts of tumor necrosis factor (TNF)-?. We determined whether the serine protease in German cockroach extract (GCE) enhances TNF-? production by alveolar macrophages through the PAR-2 pathway and whether the TNF-? production affects GCE-induced pulmonary inflammation. Effects of GCE on alveolar macrophages and TNF-? production were evaluated using in vitro MH-S and RAW264.6 cells and in vivo GCE-induced asthma models of BALB/c mice. GCE contained a large amount of serine protease. In the MH-S and RAW264.7 cells, GCE activated PAR-2 and thereby produced TNF-?. In the GCE-induced asthma model, intranasal administration of GCE increased airway hyperresponsiveness (AHR), inflammatory cell infiltration, productions of serum immunoglobulin E, interleukin (IL)-5, IL-13 and TNF-? production in alveolar macrophages. Blockade of serine proteases prevented the development of GCE induced allergic pathologies. TNF-? blockade also prevented the development of such asthma-like lesions. Depletion of alveolar macrophages reduced AHR and intracellular TNF-? level in pulmonary cell populations in the GCE-induced asthma model. These results suggest that serine protease from GCE affects asthma through an alveolar macrophage and TNF-? dependent manner, reflecting the close relation of innate and adaptive immune response in allergic asthma model.
PMID: 23094102 [PubMed – in process]
View full post on pubmed: asthma
Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation.
Pharmacology. 2012;90(3-4):223-32
Authors: Kobayashi M, Kubo S, Shiraki K, Iwata M, Hirano Y, Ohtsu Y, Takahashi K, Shimizu Y
Abstract
We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-? production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an ?(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with ?(2) – adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.
PMID: 23038661 [PubMed – in process]
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A2B Adenosine Receptor Expression by Myeloid Cells Is Proinflammatory in Murine Allergic-Airway Inflammation.
J Immunol. 2012 Sep 5;
Authors: Belikoff BG, Vaickus LJ, Sitkovsky M, Remick DG
Abstract
Asthma is a chronic condition with high morbidity and healthcare costs, and cockroach allergens are an established cause of urban pediatric asthma. A better understanding of cell types involved in promoting lung inflammation could provide new targets for the treatment of chronic pulmonary disease. Because of its role in regulating myeloid cell-dependent inflammatory processes, we examined A(2B) R expression by myeloid cells in a cockroach allergen model of murine asthma-like pulmonary inflammation. Both systemic and myeloid tissue-specific A(2B) R deletion significantly decreased pulmonary inflammatory cell recruitment, airway mucin production, and proinflammatory cytokine secretion after final allergen challenge in sensitized mice. A(2B) R deficiency resulted in a dramatic reduction on Th2-type airways responses with decreased pulmonary eosinophilia without augmenting neutrophilia, and decreased lung IL-4, IL-5, and IL-13 production. Chemokine analysis demonstrated that eotaxin 1 and 2 secretion in response to repeated allergen challenge is myeloid cell A(2B) R dependent. In contrast, there were no differences in the levels of the CXC chemokines keratinocyte-derived chemokine and MIP-2 in the myeloid cell A(2B) R-deficient mice, strengthening A(2B) R involvement in the development of Th2-type airways inflammation. Proinflammatory TNF-?, IFN-?, and IL-17 secretion were also reduced in systemic and myeloid tissue-specific A(2B) R deletion mouse lines. Our results demonstrate Th2-type predominance for A(2B) R expression by myeloid cells as a mechanism of development of asthma-like pulmonary inflammation.
PMID: 22956582 [PubMed – as supplied by publisher]
View full post on pubmed: asthma
Anti-inflammatory and antinociceptive effects of salbutamol on acute and chronic models of inflammation in rats: involvement of an antioxidant mechanism.
Mediators Inflamm. 2012;2012:438912
Authors: Uzkeser H, Cadirci E, Halici Z, Odabasoglu F, Polat B, Yuksel TN, Ozaltin S, Atalay F
Abstract
The possible role of ?-2 adrenergic receptors in modulation of inflammatory and nociceptive conditions suggests that the ?-2 adrenergic receptor agonist, salbutamol, may have beneficial anti-inflammatory and analgesic effects. Therefore, in this study, we induced inflammatory and nociceptive responses with carrageenan-induced paw edema or cotton-pellet-induced granuloma models, both of which result in oxidative stress. We hypothesized that salbutamol would prevent inflammatory and nociceptive responses by stimulating ?-2 adrenergic receptors and the prevention of generation of ROS during the acute inflammation process in rats. Both doses of salbutamol used in the study (1 and 2?mg/kg) effectively blocked the acute inflammation and inflammatory nociception induced by carrageenan. In the cotton-pellet-induced granuloma test, both doses of salbutamol also significantly decreased the weight of granuloma tissue on the cotton pellets when compared to the control. Anti-inflammatory and analgesic effects of salbutamol were found to be comparable with those of indomethacin. Salbutamol decreased myeloperoxidase (MPO) activity and lipid peroxidation (LPO) level and increased the activity of superoxide dismutase (SOD) and level of glutathione (GSH) during the acute phase of inflammation. In conclusion, salbutamol can decrease acute and chronic inflammation, possibly through the stimulation of ?-2 adrenergic receptors. This anti-inflammatory effect may be of significance in asthma treatment, where inflammation also takes part in the etiopathology. This study reveals that salbutamol has significant antioxidative effects, which at least partially explain its anti-inflammatory capabilities. These findings presented here may also shed light on the roles of ?-2 adrenergic receptors in inflammatory and hyperalgesic conditions.
PMID: 22665951 [PubMed – in process]
View full post on pubmed: asthma
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Airway inflammation linked with asthma-related mortality rates in older adults
News-Medical.net Higher mortality rates among older adult asthma patients compared to their younger counterparts may be due, at least in part, to an increase in airway inflammation, according to a study conducted by researchers in Canada, who note that their results … |
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Inflammation and Mortality in Older Asthma Patients
Newswise (press release) Newswise — ATS 2012, SAN FRANCISCO – Higher mortality rates among older adult asthma patients compared to their younger counterparts may be due, at least in part, to an increase in airway inflammation, according to a study conducted by researchers in … |
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Inflammation a possible cause of higher mortality rates in older asthma patients
Medical Xpress Higher mortality rates among older adult asthma patients compared to their younger counterparts may be due, at least in part, to an increase in airway inflammation, according to a study conducted by researchers in Canada, who note that their results … |
View full post on asthma – Google News