GM-1111 reduces radiation-induced oral mucositis in mice by targeting pattern recognition receptor-mediated inflammatory signaling.
GM-1111 reduces radiation-induced oral mucositis in mice by targeting pattern recognition receptor-mediated inflammatory signaling.
复制标题
DOI：
10.1371/journal.pone.0249343
复制
发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Lee WY
中科院分区：
文献类型：
--
作者：
Pulsipher A;Savage JR;Kennedy TP;Gupta K;Cuiffo BG;Sonis ST;Lee WY
口腔粘膜炎（OM）是头颈癌（HNC）放射治疗的常见疼痛副作用。辐射后先天免疫系统的激活已被确定为OM的关键沉淀事件。为了更好地了解OM的发病机制，我们研究了模式识别受体（PRRs）和它们的下游促炎细胞因子在小鼠模型的辐射诱导OM。我们还测试了靶向先天免疫系统以减少辐射诱导的OM的GM-1111的治疗功效。采用X线诱发小鼠OM模型，研究OM的发病机制。通过目视和显微镜检查测量OM的严重程度。测定辐射诱导的PRR及其下游效应细胞因子基因表达水平的变化。在单次和分次照射小鼠模型中测试GM-1111减少OM的功效。还在人HNC的小鼠模型中测试了药物对肿瘤对放射疗法的反应的影响。辐射诱导的组织溃疡是辐射剂量和时间依赖性的。病变显示PRR和促炎细胞因子基因表达水平的选择性增加。GM-1111每日一次给药（≥30 mg/kg，s.c.）显著降低OM的严重程度和发生率。该药物对PRR几乎没有影响，但显著抑制下游促炎细胞因子基因。GM-1111不干扰放射治疗诱导HNC SCC-25肿瘤消退。相反，我们观察到显著的药物诱导的肿瘤消退。辐射引起组织损伤。PRR及其下游促炎细胞因子基因在受损组织中表达水平的增加表明它们在OM的发病机制中起重要作用。针对这些先天免疫分子的药物GM-1111可能是干预OM的潜在候选药物。
Oral mucositis (OM) is a common, painful side effect of radiation therapy used for the treatment of head and neck cancer (HNC). Activation of the innate immune system upon irradiation has been identified as a key precipitating event of OM. To better understand OM’s pathogenesis, we studied pattern recognition receptors (PRRs) and their downstream pro-inflammatory cytokines in a mouse model of radiation-induced OM. We also tested therapeutic efficacy of GM-1111 that targets innate immune system to reduce radiation-induced OM. The pathogenesis of OM was studied in a single X-ray induced mouse model. The severity of OM was measured by visual and microscopical examinations. The irradiation-induced changes of PRRs and their downstream effector cytokine gene expression levels were determined. The efficacy of GM-1111 to reduce OM was tested in single and fractionated irradiation mouse models. The impact of the drug on tumor response to radiation therapy was also tested in a mouse model of human HNC. Radiation-induced tissue ulcerations were radiation-dosage and -time dependent. The lesions showed selective increases in PRR and pro-inflammatory cytokine gene expression levels. Once daily administration of GM-1111 (≥30 mg/kg, s.c.) significantly reduced the severity and the incidence of OM. The drug had little effect on PRRs but significantly inhibited downstream pro-inflammatory cytokine genes. GM-1111 did not interfere radiation therapy to induce HNC SCC-25 tumor regression. Instead, we observed significant drug-induced tumor regression. Radiation induces tissue damages. The increased expression levels of PRRs and their downstream pro-inflammatory cytokine genes in the damaged tissues suggest their important contribution to the pathogenesis of OM. Drug GM-1111 that targets these innate immune molecules may be a potential drug candidate as an intervention for OM.
登录
查看更多内容
影响因子：
8.7
作者：
Man SM;Karki R;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
2.3
作者：
Matsumura, T;Ito, A;Onozaki, K
通讯作者：
Onozaki, K
影响因子：
4.9
作者：
Kondo, Makoto;Yamato, Masayuki;Okano, Teruo
通讯作者：
Okano, Teruo
影响因子：
9.7
作者：
Dicker, Kevin T.;Gurski, Lisa A.;Pradhan-Bhatt, Swati;Witt, Robert L.;Farach-Carson, Mary C.;Jia, Xinqiao
通讯作者：
Jia, Xinqiao
影响因子：
6.2
作者：
Nonzee, Narissa J.;Dandade, Neal A.;Bennett, Charles L.
通讯作者：
Bennett, Charles L.