Platelet-Activating Factor Receptor Develops Airway Hyperresponsiveness Independently of Airway Inflammation in a Murine Asthma Model

Ishii, Satoshi; Nagase, Takahide; Shindou, Hideo; Takizawa, Hajime; Ouchi, Yasuyoshi; Shimizu, Takao

doi:10.4049/jimmunol.172.11.7095

Cited by 45 publications

(27 citation statements)

References 69 publications

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“…Several reports have used PAFR-KO mice to elucidate the role of PAF in various pathophysiologies. The PAFR-KO mice exhibited attenuation in animal models in which inflammatory injuries were crucial: chemical lung injury, 18 bronchial asthma, 19 and sponge-induced subcutaneous granuloma formation. 20 On the other hand, PAFR-KO mice showed exacerbation of infection models such as pulmonary gramnegative bacteria infection 41 and cardiac Trypanosoma infection.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16] Therefore, we have developed genetically engineered PAFR-deficient (PAFR-KO) mice to confirm the role of PAF in vivo. 17 The resultant PAFR-KO mice exhibit attenuated symptoms in several animal models such as chemical lung injury, 18 bronchial asthma, 19 and sponge-induced subcutaneous granuloma formation. 20 It has been demonstrated that infiltrating inflammatory cells play important roles in these animal models.…”

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confidence: 99%

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Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Doi

Okamoto

Negishi

et al. 2006

The American Journal of Pathology

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Platelet-activating factor (PAF), a potent lipid mediator with various biological activities, plays an important role in inflammation by recruiting leukocytes. In this study we used platelet-activating factor receptor (PAFR)-deficient mice to elucidate the role of PAF in inflammatory renal injury induced by folic acid administration. PAFR-deficient mice showed significant amelioration of renal dysfunction and pathological findings such as acute tubular damage with neutrophil infiltration, lipid peroxidation observed with antibody to 4-hydroxy-2-hexenal (day 2), and interstitial fibrosis with macrophage infiltration associated with expression of monocyte chemoattractant protein-1 and tumor necrosis factor-␣ in the kidney (day 14). Acute tubular damage was attenuated by neutrophil depletion using a monoclonal antibody (RB6-8C5), demonstrating the contribution of neutrophils to acute phase injury. Macrophage infiltration was also decreased when treatment with a PAF antagonist (WEB2086) was started after acute phase. In vitro chemotaxis assay using a Boyden chamber demonstrated that PAF exhibits a strong chemotactic activity for macrophages. These results indicate that PAF is involved in pathogenesis of folic acid-induced renal injury by activating neutrophils in acute phase and macrophages in chronic interstitial fibrosis. Inhibiting the PAF pathway might be therapeutic to kidney injury from inflammatory cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Doi

Okamoto

Negishi

et al. 2006

The American Journal of Pathology

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“…Because elevated levels of LPC are observed in Krabbe and twitcher brain, it can be postulated that LPC may, at least in part, be responsible for the inflammatory response observed in Krabbe disease and in twitcher mice. Moreover, LPC is also a precursor for platelet-activating factor, which is a well-known inflammatory mediator in the regulation of several inflammatory diseases (60)(61)(62)(63). Therefore, inhibition of LPC generation should play an important part in therapeutics against the disease process in Krabbe disease and twitcher mice brains.…”

Section: Discussionmentioning

confidence: 99%

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Giri

Khan

Rattan

et al. 2006

Journal of Lipid Research

101

122

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Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside bgalactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose-and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.-Giri, S

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“…From the paraffin-embedded right and left lobes of lung, sections of 5-m thickness were prepared from the middle position of each lobe, and stained with H&E or periodic acidSchiff (PAS). A semiquantitative scoring system was used to grade the size of lung infiltrates in the H&E-stained sections, where ϩ5 signifies widespread infiltrates around the majority of vessels and bronchioles, and ϩ1 signifies a small number of inflammatory foci (30). The goblet cell hyperplasia in the PAS-stained sections was graded by a semiquantitative scoring system (0 ϭ Ͻ5% goblet cells in airway epithelium; 1 ϭ 5-25%; 2 ϭ 25-50%; 3 ϭ 50-75%; 4 ϭ Ͼ75%) as described by McMillan et al (31).…”

Section: Calcium Mobilization In Mouse Granulocytesmentioning

confidence: 99%

Absence of Leukotriene B4 Receptor 1 Confers Resistance to Airway Hyperresponsiveness and Th2-Type Immune Responses

Terawaki

Yokomizo²,

Nagase³

et al. 2005

The Journal of Immunology

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156

147

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Bronchial asthma is an increasingly common disorder that remains poorly understood and difficult to manage. The disease is characterized by airway hyperresponsiveness, chronic inflammation, and mucus overproduction. Based on the finding that leukotriene B4 receptor 1 (BLT1) is expressed highly in Th2 lymphocytes, we analyzed the roles of BLT1 using an OVA-induced bronchial asthma model. BLT1-null mice did not develop airway hyperresponsiveness, eosinophilic inflammation, and hyperplasia of goblet cells. Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice. Peribronchial lymph node cells of sensitized BLT1-null mice showed much attenuated proliferation and production of Th2 cytokines upon re-stimulation with Ag in vitro. Thus, LTB4-BLT1 axis is required for the development of Th2-type immune response, and blockade of LTB4 functions through BLT1 would be novel and useful in the effort to ameliorate bronchial asthma and related Th2-biased immune disorders.

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Platelet-Activating Factor Receptor Develops Airway Hyperresponsiveness Independently of Airway Inflammation in a Murine Asthma Model

Cited by 45 publications

References 69 publications

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Attenuation of Folic Acid-Induced Renal Inflammatory Injury in Platelet-Activating Factor Receptor-Deficient Mice

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Absence of Leukotriene B4 Receptor 1 Confers Resistance to Airway Hyperresponsiveness and Th2-Type Immune Responses

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