Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma
Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma
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DOI：
10.1152/japplphysiol.00630.2006
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发表时间：
2007-01-01
影响因子：
3.3
通讯作者：
Dickey, B. F.
中科院分区：
文献类型：
--
作者：
Agrawal, A.;Rengarajan, S.;Dickey, B. F.
过敏性哮喘与气道上皮细胞粘膜化生和粘蛋白高分泌有关，但粘蛋白高分泌对气道功能的影响尚不清楚。最近，一种从富含肉豆蔻酰基丙氨酸的C激酶底物蛋白nh2末端序列（MANS）衍生的肽被证明可以抑制甲基胆碱（MCh）诱导的气道粘膜细胞分泌90%的粘蛋白。我们研究了用这种肽鼻内预处理对MCh刺激致变应原诱导的粘膜细胞化生小鼠的特定气道传导（sGaw）的影响。在自主呼吸受限的小鼠中，使用双腔容积描记器无创测量sGaw。用MANS肽预处理，而不是对照肽[随机nh2末端序列（RNS）]，可以部分抑制60 mM MCh诱导的sGaw下降（平均+/- SE；基线1.15 +/- 0.06;MANS/MCh 0.82 +/- 0.05; RNS/MCh 0.55 +/- 0.05 cmH(2)O/s）。在连续3天受到过敏原刺激增加气道高反应性的小鼠中也观察到MANS的保护作用，尽管保护程度较低（基线1.1 +/- 0.08;MANS/MCh, 0.65 +/- 0.06; RNS/MCh 0.47 +/- 0.03 cmH(2)O/s）。由于小鼠的常规sGaw测量包括鼻气道，因此在鼻腔闭塞后通过口腔呼吸的小鼠中也证实了MANS的有效性（基线0.92 +/- 0.05;MANS/MCh 0.83 +/- 0.06; RNS/MCh 0.61 +/- 0.03 cmH(2)O/s）。在所有情况下，mans预处理组的sGaw比rns处理组的对照组高35%左右，粘膜阻塞占mch诱导的sGaw下降的50%左右。综上所述，在变应性哮喘小鼠模型中，粘蛋白分泌在气道阻塞中具有重要作用，抑制粘蛋白分泌的策略值得进一步研究。
Allergic asthma is associated with airway epithelial cell mucous metaplasia and mucin hypersecretion, but the consequences of mucin hypersecretion on airway function are unclear. Recently, a peptide derived from the myristoylated alanine-rich C kinase substrate protein NH2-terminal sequence (MANS) was shown to inhibit methacholine (MCh)-induced mucin secretion from airway mucous cells by > 90%. We studied the effect of intranasal pretreatment with this peptide on specific airway conductance (sGaw) during challenge with MCh in mice with allergen-induced mucous cell metaplasia. sGaw was noninvasively measured in spontaneously breathing restrained mice, using a double-chamber plethysmograph. Pretreatment with MANS peptide, but not a control peptide [random NH2-terminal sequence (RNS)], resulted in partial inhibition of the fall in sGaw induced by 60 mM MCh (mean +/- SE; baseline 1.15 +/- 0.06; MANS/MCh 0.82 +/- 0.05; RNS/MCh 0.55 +/- 0.05 cmH(2)O/s). The protective effect of MANS was also seen in mice challenged with allergen for 3 consecutive days to increase airway hyperresponsiveness, although the degree of protection was less (baseline 1.1 +/- 0.08; MANS/MCh, 0.65 +/- 0.06; RNS/MCh 0.47 +/- 0.03 cmH(2)O/s). Because routine sGaw measurement in mice includes nasal airways, the effectiveness of MANS was also confirmed in mice breathing through their mouths after nasal occlusion (baseline 0.92 +/- 0.05; MANS/MCh 0.83 +/- 0.06; RNS/MCh 0.61 +/- 0.03 cmH(2)O/s). In all instances, sGaw in the MANS-pretreated group was similar to 35% higher than in RNS-treated controls, and mucous obstruction accounted for similar to 50% of the MCh-induced fall in sGaw. In summary, mucin secretion has a significant role in airway obstruction in a mouse model of allergic asthma, and strategies to inhibit mucin secretion merit further investigation.