Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation.
Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation.
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DOI：
10.3109/01902140903131200
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发表时间：
2010-03
影响因子：
1.7
通讯作者：
Panettieri RA Jr
中科院分区：
文献类型：
--
作者：
Damera G;Jester WF;Jiang M;Zhao H;Fogle HW;Mittelman M;Haczku A;Murphy E;Parikh I;Panettieri RA Jr
有证据表明，抑制白细胞运输可以部分减轻臭氧引起的炎症。在本研究中，作者假设抑制肉豆蔻酰化富含丙氨酸的 C 激酶底物 (MARCKS)（一种具有多种生物学作用的 82 kDa 蛋白质）可以抑制臭氧诱导的白细胞运输和细胞因子分泌。 BALB/c 小鼠（n = 5/队列）暴露于臭氧 (100 ppb) 或强制空气 (FA) 中 4 小时。在臭氧暴露之前，气管内施用 MARCKS 抑制肽、MANS、BIO-11000、BIO-11006 或乱序对照肽 RNS。与接触 FA 的组相比，臭氧选择性增强支气管肺泡灌洗 (BAL) 杀伤细胞（KC；6 ± 0.9 倍）、白细胞介素 6（IL-6；12.7 ± 1.9 倍）和肿瘤坏死因子（TNF；2.1 ± 0.5 倍）的水平。此外，臭氧使 BAL 中性粒细胞增加了 21% ± 2%，而其他细胞类型没有显着 (P > .05) 变化。 MANS、BIO-11000 和 BIO-11006 分别显着减少臭氧诱导的 KC 分泌 66% ± 14%、47% ± 15% 和 71.1% ± 14%，以及 IL-6 分泌 69% ± 12%、40% ± 7% 和 86.1% ± 11%。 MANS (86% ± 7%) 和 BIO-11006 (84% ± 2.5%) 可减少臭氧介导的 BAL 中性粒细胞增加，但 BIO-11000 则不会。这些研究首次发现了 MARCKS 蛋白抑制剂在消除臭氧引起的 BAL 液中中性粒细胞、细胞因子和趋化因子增加方面的新潜力。 BIO-11006 正在开发用于治疗慢性阻塞性肺病 (COPD)，目前正在 2 期临床研究中进行评估。
Evidence suggests inhibition of leukocyte trafficking mitigates, in part, ozone-induced inflammation. In the present study, the authors postulated that inhibition of myristoylated alanine-rich C kinase substrate (MARCKS), an 82-kDa protein with multiple biological roles, could inhibit ozone-induced leukocyte trafficking and cytokine secretions. BALB/c mice (n = 5/cohort) were exposed to ozone (100 ppb) or forced air (FA) for 4 hours. MARCKS-inhibiting peptides, MANS, BIO-11000, BIO-11006, or scrambled control peptide RNS, were intratracheally administered prior to ozone exposure. Ozone selectively enhanced bronchoalveolar lavage (BAL) levels of killer cells (KCs; 6 ± 0.9-fold), interleukin-6 (IL-6; 12.7 ± 1.9-fold), and tumor necrosis factor (TNF; 2.1 ± 0.5-fold) as compared to cohorts exposed to FA. Additionally, ozone increased BAL neutrophils by 21% ± 2% with no significant (P > .05) changes in other cell types. MANS, BIO-11000, and BIO-11006 significantly reduced ozone-induced KC secretion by 66% ± 14%, 47% ± 15%, and 71.1% ± 14%, and IL-6 secretion by 69% ± 12%, 40% ± 7%, and 86.1% ± 11%, respectively. Ozone-mediated increases in BAL neutrophils were reduced by MANS (86% ± 7%) and BIO-11006 (84% ± 2.5%), but not BIO-11000. These studies identify for the first time the novel potential of MARCKS protein inhibitors in abrogating ozone-induced increases in neutrophils, cytokines, and chemokines in BAL fluid. BIO-11006 is being developed as a treatment for chronic obstructive pulmonary disorder (COPD) and is currently being evaluated in a phase 2 clinical study.