A Broad Spectrum Chemokine Inhibitor Prevents Preterm Labor but Not Microbial Invasion of the Amniotic Cavity or Neonatal Morbidity in a Non-human Primate Model
A Broad Spectrum Chemokine Inhibitor Prevents Preterm Labor but Not Microbial Invasion of the Amniotic Cavity or Neonatal Morbidity in a Non-human Primate Model
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DOI：
10.3389/fimmu.2020.00770
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发表时间：
2020-04-30
影响因子：
7.3
通讯作者：
Waldorf, Kristina M. Adams
中科院分区：
文献类型：
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作者：
Coleman, Michelle;Orvis, Austyn;Waldorf, Kristina M. Adams
绒毛膜羊膜内的白细胞活化与炎症和早产 (PTL) 密切相关。我们假设使用广谱趋化因子抑制剂 (BSCI) 进行预防会下调 B 族链球菌（GBS、无乳链球菌）诱导的炎症微环境，从而抑制 PTL 和微生物侵入羊膜腔 (MIAC)。为了将 BSCI 给药与 PTL 和 MIAC 相关联，我们使用了 B 族链球菌 (GBS) 诱导的 PTL 的独特的长期插管非人灵长类动物模型。在妊娠晚期（妊娠 128-138 天；类似于人类妊娠 29-32 周），动物接受绒毛膜蜕膜接种：(1) 生理盐水 (N = 6)，(2) GBS，1-5 x 10(8) 菌落形成单位 (CFU)/ml； N = 5)，或 (3) 预处理和每日输注 BSCI（10 mg/kg 静脉内和羊膜内）和 GBS (1-5 x 10(8) CFU/ml；N = 4)。我们测量了羊膜腔压力（子宫收缩强度），并连续采集了羊水（AF）和母血以及分娩时的脐带血。 PTL 接种后 3 天或更早进行剖腹产。数据分析使用 Fisher 精确检验、Wilcoxon 秩和和带 Bonferroni 校正的单向方差分析。盐水接种不会诱发 PTL 或感染性后遗症。相反，GBS 接种通常会诱导 PTL（4/5，80%）、MIAC 和胎儿菌血症（3/5；60%）。值得注意的是，尽管所有病例均出现 MIAC 和胎儿菌血症 (4/4；100%)，但 BSCI+GBS 组并未发生 PTL（0/4，0%；相对于 GBS，p = 0.02）。与 GBS 组相比，BSCI 预防与显着降低的细胞因子水平相关，包括羊水中的 IL-8 (p = 0.03)、胎儿血浆中的 TNF-α (p < 0.05)、胎儿肺中的 IFN-α 和 IL-7 (p = 0.02) 以及胎儿脑中的 IL-18、IL-2 和 IL-7 (p = 0.03)。中性粒细胞性绒毛膜羊膜炎在 BSCI 和 GBS 组中常见，但在 BSCI+GBS 组中更为严重，羊膜和绒毛膜中的髓过氧化物酶染色（粒细胞标记物）更强（与 GBS 相比，p < 0.05）。总的来说，这些观察结果表明，阻断趋化因子对感染的反应可以有效抑制子宫收缩力、PTL 和细胞因子反应，但不能预防 MIAC 和胎儿肺炎。 PTL 免疫疗法的开发应与 AF 微生物的评估和考虑抗生素治疗同时进行。
Leukocyte activation within the chorioamniotic membranes is strongly associated with inflammation and preterm labor (PTL). We hypothesized that prophylaxis with a broad-spectrum chemokine inhibitor (BSCI) would downregulate the inflammatory microenvironment induced by Group B Streptococcus (GBS, Streptococcus agalactiae) to suppress PTL and microbial invasion of the amniotic cavity (MIAC). To correlate BSCI administration with PTL and MIAC, we used a unique chronically catheterized non-human primate model of Group B Streptococcus (GBS)-induced PTL. In the early third trimester (128-138 days gestation; similar to 29-32 weeks human pregnancy), animals received choriodecidual inoculations of either: (1) saline (N = 6), (2) GBS, 1-5 x 10(8) colony forming units (CFU)/ml; N = 5), or (3) pre-treatment and daily infusions of a BSCI (10 mg/kg intravenous and intra-amniotic) with GBS (1-5 x 10(8) CFU/ml; N = 4). We measured amniotic cavity pressure (uterine contraction strength) and sampled amniotic fluid (AF) and maternal blood serially and cord blood at delivery. Cesarean section was performed 3 days post-inoculation or earlier for PTL. Data analysis used Fisher's exact test, Wilcoxon rank sum and one-way ANOVA with Bonferroni correction. Saline inoculation did not induce PTL or infectious sequelae. In contrast, GBS inoculation typically induced PTL (4/5, 80%), MIAC and fetal bacteremia (3/5; 60%). Remarkably, PTL did not occur in the BSCI+GBS group (0/4, 0%; p = 0.02 vs. GBS), despite MIAC and fetal bacteremia in all cases (4/4; 100%). Compared to the GBS group, BSCI prophylaxis was associated with significantly lower cytokine levels including lower IL-8 in amniotic fluid (p = 0.03), TNF-alpha in fetal plasma (p < 0.05), IFN-alpha and IL-7 in the fetal lung (p = 0.02) and IL-18, IL-2, and IL-7 in the fetal brain (p = 0.03). Neutrophilic chorioamnionitis was common in the BSCI and GBS groups, but was more severe in the BSCI+GBS group with greater myeloperoxidase staining (granulocyte marker) in the amnion and chorion (p < 0.05 vs. GBS). Collectively, these observations indicate that blocking the chemokine response to infection powerfully suppressed uterine contractility, PTL and the cytokine response, but did not prevent MIAC and fetal pneumonia. Development of PTL immunotherapies should occur in tandem with evaluation for AF microbes and consideration for antibiotic therapy.