Damera Gautam, Jester William F, Jiang Meiqi, Zhao Hengjiang, Fogle Homer W, Mittelman Michael, Haczku Angela, Murphy Edwin, Parikh Indu, Panettieri Reynold A
Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104-3403, USA.
Exp Lung Res. 2010 Mar;36(2):75-84. doi: 10.3109/01902140903131200.
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.
有证据表明，抑制白细胞迁移可部分减轻臭氧诱导的炎症。在本研究中，作者推测，抑制富含肉豆蔻酰化丙氨酸的蛋白激酶C底物（MARCKS）（一种具有多种生物学作用的82 kDa蛋白）可抑制臭氧诱导的白细胞迁移和细胞因子分泌。将BALB/c小鼠（每组n = 5只）暴露于臭氧（100 ppb）或强迫空气（FA）中4小时。在臭氧暴露前经气管内给予MARCKS抑制肽MANS、BIO-11000、BIO-11006或 scrambled对照肽RNS。与暴露于FA的组相比，臭氧选择性地提高了支气管肺泡灌洗（BAL）液中杀伤细胞（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21%±2%，其他细胞类型无显著（P>.05）变化。MANS、BIO-11000和BIO-11006分别使臭氧诱导的KC分泌显著减少了66%±14%、47%±15%和71.1%±14%，使IL-6分泌分别减少了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无此作用。这些研究首次确定了MARCKS蛋白抑制剂在消除臭氧诱导的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疾病（COPD），目前正在进行2期临床研究评估。
