Livraghi Alessandra, Grubb Barbara R, Hudson Elizabeth J, Wilkinson Kristen J, Sheehan John K, Mall Marcus A, O'Neal Wanda K, Boucher Richard C, Randell Scott H
Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, 27599, USA.
J Immunol. 2009 Apr 1;182(7):4357-67. doi: 10.4049/jimmunol.0802557.
Overexpression of the epithelial Na(+) channel beta subunit (Scnn1b gene, betaENaC protein) in transgenic (Tg) mouse airways dehydrates mucosal surfaces, producing mucus obstruction, inflammation, and neonatal mortality. Airway inflammation includes macrophage activation, neutrophil and eosinophil recruitment, and elevated KC, TNF-alpha, and chitinase levels. These changes recapitulate aspects of complex human obstructive airway diseases, but their molecular mechanisms are poorly understood. We used genetic and pharmacologic approaches to identify pathways relevant to the development of Scnn1b-Tg mouse lung pathology. Genetic deletion of TNF-alpha or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4Ralpha abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4Ralpha deficiency decreased MuSC and eosinophils in neonatal Scnn1b-Tg mice, which correlated with improved neonatal survival. However, chronic lung pathology in adult Scnn1b-Tg mice was not affected by IL-4Ralpha status. Prednisolone treatment ablated eosinophilia and MuSC in adult Scnn1b-Tg mice, but did not decrease mucus plugging or neutrophilia. These studies demonstrate that: 1) normal neonatal mouse airway development entails an IL-4Ralpha-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4Ralpha improved neonatal survival of Scnn1b-Tg mice, likely reflecting decreased formation of asphyxiating mucus plugs; and 3) in Scnn1b-Tg mice, neutrophilia, mucus obstruction, and airspace enlargement are IL-4Ralpha- and TNF-alpha-independent, and only MuSC and eosinophilia are sensitive to glucocorticoids. Thus, manipulation of multiple pathways will likely be required to treat the complex pathogenesis caused by airway surface dehydration.
上皮钠通道β亚基（Scnn1b基因，βENaC蛋白）在转基因（Tg）小鼠气道中的过表达会使黏膜表面脱水，导致黏液阻塞、炎症和新生儿死亡。气道炎症包括巨噬细胞活化、中性粒细胞和嗜酸性粒细胞募集以及KC、TNF-α和几丁质酶水平升高。这些变化概括了复杂的人类阻塞性气道疾病的某些方面，但其分子机制尚不清楚。我们使用遗传学和药理学方法来确定与Scnn1b-Tg小鼠肺部病理发展相关的途径。TNF-α或其受体TNFR1的基因缺失对该表型没有可测量的影响。IL-4Rα的缺失消除了新生野生型小鼠中通常观察到的短暂黏液分泌细胞（MuSC）丰度和嗜酸性粒细胞增多现象。同样，IL-4Rα缺乏降低了新生Scnn1b-Tg小鼠中的MuSC和嗜酸性粒细胞，这与新生儿存活率提高相关。然而，成年Scnn1b-Tg小鼠的慢性肺部病理不受IL-4Rα状态的影响。泼尼松龙治疗消除了成年Scnn1b-Tg小鼠中的嗜酸性粒细胞增多和MuSC，但并未减少黏液阻塞或中性粒细胞增多。这些研究表明：1）正常新生小鼠气道发育需要IL-4Rα依赖性的短暂MuSC和嗜酸性粒细胞丰度；2）IL-4Rα的缺失提高了Scnn1b-Tg小鼠的新生儿存活率，可能反映了窒息性黏液栓形成减少；3）在Scnn1b-Tg小鼠中，中性粒细胞增多、黏液阻塞和气腔扩大与IL-4Rα和TNF-α无关，只有MuSC和嗜酸性粒细胞增多对糖皮质激素敏感。因此，可能需要操纵多种途径来治疗由气道表面脱水引起的复杂发病机制。
