CCSP regulates cross talk between secretory cells and both ciliated cells and macrophages of the conducting airway
CCSP regulates cross talk between secretory cells and both ciliated cells and macrophages of the conducting airway
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DOI：
10.1152/ajplung.00014.2007
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发表时间：
2007-07-01
影响因子：
4.9
通讯作者：
Stripp, Barry R.
中科院分区：
文献类型：
--
作者：
Reynolds, Susan D.;Reynolds, Paul R.;Stripp, Barry R.
肺宿主防御采用生物化学和生物物理活动的组合来识别、抑制和介导环境因子的清除，以及调节对这种挑战的总体反应。这种反应的炎性臂的失调与慢性肺疾病（CLD）相关，包括囊性纤维化和慢性阻塞性肺疾病。虽然介导免疫调节的机制是不完全的特点，递减的水平无纤毛分泌细胞的产品克拉拉细胞分泌蛋白（CCSP）在许多CLD和识别促炎状态的小鼠纯合子的无效等位基因的CCSP基因（CCSP-/-）的无纤毛分泌细胞在这一过程中的核心作用。为了确定与CCSP缺陷相关的免疫调节缺陷的分子基础，我们利用差异凝胶电泳结合基质辅助激光解吸电离飞行时间来比较野生型和CCSP-/-小鼠的蛋白质组。我们证明了CCSP-/-小鼠中免疫调节蛋白膜联蛋白A1（ANXA 1）的等电点向更酸性的亚型的转变。野生型和CCSP-/-组织中ANXA 1 mRNA和蛋白丰度相似，ANXA 1蛋白在肺泡巨噬细胞和纤毛细胞睫状床中的定位相同，这表明CCSP缺乏只与ANXA 1的翻译后修饰改变相关.这些结果表明，无纤毛分泌细胞和免疫系统细胞和上皮细胞之间的长距离和短距离旁分泌信号传导影响细胞类型特异性蛋白的修饰，并将无纤毛分泌细胞牵连到可能整合宿主防御关键方面的调节轴中。
Pulmonary host defense employs a combination of biochemical and biophysical activities to recognize, inactivate, and mediate clearance of environmental agents as well as modulate the overall response to such challenge. Dysregulation of the inflammatory arm of this response is associated with chronic lung diseases ( CLD) including cystic fibrosis and chronic obstructive lung disease. Although mechanisms mediating immunoregulation are incompletely characterized, decrements in levels of the nonciliated secretory cell product Clara cell secretory protein ( CCSP) in numerous CLD and identification of proinflammatory state in mice homozygous for a null allele of the CCSP gene ( CCSP-/-) suggest a central role for the nonciliated secretory cell in this process. In an effort to determine the molecular basis for immunoregulatory defects associated with CCSP deficiency, we utilized difference gel electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight to compare the proteomes of wild- type and CCSP-/- mice. We demonstrate a shift in the isoelectric point of the immunomodulatory protein annexin A1 ( ANXA1) to more acidic isoforms in CCSP-/- mice. Similar ANXA1 mRNA and protein abundance in wild- type and CCSP-/- tissue and identical localization of ANXA1 protein to alveolar macrophages and the ciliary bed of ciliated cells demonstrated that CCSP deficiency was associated exclusively with altered posttranslational modification of ANXA1. These results suggest that both long- and short- range paracrine signaling between nonciliated secretory cells and cells of the immune system and epithelium impact modification of cell typespecific proteins and implicate nonciliated secretory cells in a regulatory axis that might integrate critical aspects of host defense.