Antibiotic modulation of mucins in otitis media; should this change our approach to watchful waiting?
Antibiotic modulation of mucins in otitis media; should this change our approach to watchful waiting?
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DOI：
10.1016/j.ijporl.2019.07.002
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发表时间：
2019-10-01
影响因子：
1.5
通讯作者：
Kerschner, Joseph E.
中科院分区：
文献类型：
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作者：
Hong, Wenzhou;Khampang, Pawjai;Kerschner, Joseph E.
背景：凝胶形成粘蛋白（GFM）在中耳炎（OM）发病机制中发挥重要作用。粘蛋白表达增加由病原体和促炎细胞因子激活。细菌生物膜影响炎症和 OM 的消退，并可能有助于延长粘蛋白的产生。特定病原体对粘蛋白表达和慢性渗出性 OM (OME) 发展的影响仍然是一个严重的知识缺陷领域。目的：评估 GFM 表达、特定病原体、中耳粘膜 (MEM) 变化、生物膜形成和抗生素利用之间的关系。方法：给混合性别龙猫接种不可分型流感嗜血杆菌 (NTHi) 菌株 86028NP 或肺炎链球菌 (SP) 菌株TIGR4 通过经大泡注射。接种后第3-5天施用抗生素。通过定量PCR测量GFM表达。鉴定生物膜形成并测量中耳组织学变化。结果：与NTHi感染相比，SP感染导致生物膜和ME积液的发生率更高。然而，NTHi 在 ME 中的持续时间比 SP 长，并且在第 10 天没有检测到实质性的细菌清除，而在第 10 天，50-60% 的 SP 感染的龙猫细菌被完全清除。两种感染均增加了 MEM 炎症细胞浸润和增厚。 NTHi 在第 10 天上调了 Muc5AC、Muc5B 和 Mucl9 的表达（分别为 p = 0.0004、0.003 和 0.002）。 SP 诱导的 GFM 上调呈显着趋势。在 NTHi 和 SP 感染中，GFM 上调程度与 MEM 肥大、炎症细胞浸润和生物膜形成增加有直接关系。抗生素治疗降低了 ME 积液和生物膜的发生率，限制了 MEM 的变化并逆转了 GFM 的上调。在NTHi感染中，经过治疗的龙猫GFM恢复到基线水平的速度比未经治疗的龙猫更快。结论：在OM动物模型中，GFM基因上调并伴随着MEM肥大和生物膜形成。在 NTHi 感染中，通过适当的抗生素治疗，这种上调不太强烈，并且可以更快地得到显着程度的改善。这些发现有助于了解 OM 发病机制中病原体对粘蛋白表达的特异性影响，并提供可能对 OM 治疗临床方法产生影响的新数据。
Background: Gel-forming mucins (GFMs) play important roles in otitis media (OM) pathogenesis. Increased mucin expression is activated by pathogens and proinflammatory cytokines. Bacterial biofilms influence inflammation and resolution of OM and may contribute to prolonged mucin production. The influence of specific pathogens on mucin expression and development of chronic OM with effusion (OME) remains an area of significant knowledge deficit.Objectives: To assess the relationship between GFM expression, specific pathogens, middle ear mucosal (MEM) changes, biofilm formation, and antibiotic utilization.Methods: Mixed gender chinchillas were inoculated with nontypeable Haemophilus influenzae (NTHi) strain 86028NP or Streptococcus pneumoniae (SP) strain TIGR4 via transbulla injection. Antibiotic was administered on day 3-5 post inoculation. GFM expression was measured by quantitative PCR. Biofilm formation was identified and middle ear histologic changes were measured.Results: SP infection resulted in higher incidence of biofllm and ME effusion compared with NTHi infection. However, NTHi persisted in the ME longer than SP with no substantive bacterial clearance detected on day 10 compared with complete bacterial clearance on day 10 for 50-60% of the SP-infected chinchillas. Both infections increased MEM inflammatory cell infiltration and thickening. NTHi upregulated the Muc5AC, Muc5B and Mucl9 expression on day 10 (p = 0.0004, 0.003, and 0.002 respectively). SP-induced GFM upregulations were trended toward significant. In both NTHi and SP infections, the degree of GFM upregulation had a direct relationship to increased MEM hypertrophy, inflammatory cell infiltration and biofilm formation. Antibiotic treatment reduced the incidence of ME effusion and biofilm, limited the MEM changes and reversed the GFM upregulation. In NTHi infection, the rate of returning to baseline level of GFMs in treated chinchillas was quicker than those without treatment.Conclusions: In an animal model of OM, GFM genes are upregulated in conjunction with MEM hypertrophy and biofllm formation. This upregulation is less robust and more quickly ameliorated to a significant degree in the NTHi infection with appropriate antibiotic therapy. These findings contribute to the understanding of pathogen specific influences on mucin expression during OM pathogenesis and provide new data which may have implications in clinical approach for OM treatment.