A critical role for Pin1 in allergic pulmonary eosinophilia in rats
A critical role for Pin1 in allergic pulmonary eosinophilia in rats
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DOI：
10.1016/j.jaci.2007.06.024
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发表时间：
2007-11-01
影响因子：
14.2
通讯作者：
Malter, James S.
中科院分区：
文献类型：
--
作者：
Esnault, Stephane;Rosenthal, Louis A.;Malter, James S.
背景：嗜酸性粒细胞在肺内的渗透、聚集和脱颗粒是活动性过敏性哮喘的特征。肺对吸入变应原的反应触发嗜酸性粒细胞趋化因子和抗凋亡细胞因子的分泌，包括GM-CSF、IL-3、IL-4、IL-5和嗜酸性粒细胞趋化因子等。我们最近发现Pint在体外可调节GM-CSF的嗜酸性粒细胞的产生和反应。目的：我们试图确定Pint抑制对变应原激发后肺嗜酸性粒细胞增多症的影响。检测肺泡灌洗液和肺组织的炎症反应、细胞因子表达和PIN1活性。结果：胡桃仁治疗组大鼠肺泡灌洗液和肺嗜酸粒细胞数显著减少(约75%)，而淋巴细胞、单核/巨噬细胞和中性粒细胞数无明显变化。GM-CSF和IL-5的表达也显著降低，而Pin1非依赖的细胞因子，如嗜酸性粒细胞趋化素或IL-4，以及看家的mRNAs和蛋白质，包括肌动蛋白，不受胡桃仁酮的影响。结论：在体内，Pint阻滞剂可以减少GM-CSF和IL-5的产生，并且可以选择性地减少嗜酸性变态反应性炎症。临床意义：Pint阻滞剂可以选择性地减少嗜酸性粒细胞，尽管有过敏原的攻击。
Background: Infiltration, accumulation, and degranulation of eosinophils in the lung are hallmarks of active allergic asthma. The pulmonary response to inhaled allergen triggers the secretion of eosinophil chemoattractants and antiapoptotic cytokines, including GM-CSF, IL-3, IL-4, IL-5, and eotaxin, among others. We recently showed that in vitro pint regulated eosinophil production of and response to GM-CSF.Objective: We sought to determine the effect of Pint inhibition on pulmonary eosinophilia after allergen challenge.Methods: The Pint inhibitorjuglone (5-bydroxy-1,4-naphthoquinone) was administered to allergen-sensitized and allergen-challenged Brown Norway rats. Bronchoalveolar lavage fluid and lungs were assessed for inflammation, cytokine expression, and Pin1 activity.Results: Juglone-treated rats showed a dramatic reduction (approximately 75%) in bronchoalveolar lavage fluid and pulmonary eosinophilia but no change in lymphocyte, monocyte/macrophage, or neutrophil numbers. GM-CSF and IL-5 expression were also significantly reduced, whereas Pin1-independent cytokines, such as eotaxin or IL-4, as well as housekeeping mRNAs and proteins, including actin, were unaffected by juglone. The eosinophils present in the lung in juglone-treated rats showed significantly greater apoptosis.Conclusion: These data suggest that in vivo Pint blockade attenuates GM-CSF and IL-5 production and can selectively reduce eosinophilic allergic inflammation.Clinical implications: Eosinophils can be selectively reduced by Pint blockade, despite allergen challenge.