Experimental Asthma and Allergy Research Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Respir Res. 2024 Nov 29;25(1):421. doi: 10.1186/s12931-024-03050-3.
Microbial infections, particularly those caused by rhinovirus (RV) and respiratory syncytial virus (RSV), are major triggers for asthma exacerbations. These viruses activate toll-like receptors (TLRs), initiating an innate immune response. To better understand microbial-induced asthma exacerbations, animal models that closely mimic human lung characteristics are essential. This study aimed to assess airway responses in guinea pigs exposed to TLR agonists, simulating microbial infections.
The agonists poly(I: C) (TLR3), lipopolysaccharide (LPS; TLR4) and imiquimod (TLR7), or the combination of poly(I: C) and imiquimod (P/I) were administered intranasally once a day over four consecutive days. The latter group received daily intraperitoneal injections of dexamethasone starting one day before the TLR agonists challenge. Respiratory functions were measured by whole-body plethysmography and forced oscillatory technique. Bronchoalveolar lavage fluid (BALF) cells and lungs were collected for analysis.
The intranasal exposure of LPS and P/I caused an increase in enhanced pause (Penh) after challenge, whereas neither poly(I: C) nor imiquimod alone showed any effect. After the challenges of LPS, poly(I: C) or P/I, but not imiquimod alone, induced an increase of both Rrs (resistance of the respiratory system) and Ers (elastance of the respiratory system). LPS exposure caused an increase of neutrophils in BALF, whereas none of the other exposures affected the composition of cells in BALF. Exposure to LPS, poly (I: C), imiquimod, and P/I all caused a marked infiltration of inflammatory cells and an increase of mast cells around the small airways. For the expression of inflammatory mediators, LPS increased CXCL8, poly(I: C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ. Imiquimod increased CXCL8 and IL-6, whereas P/I decreased IL-5, and increased IL-6 and IFNγ. The increases in Rrs, Ers, and airway inflammation, but not the altered expression of inflammatory cytokines, were attenuated by dexamethasone.
TLR agonists promote acute airway inflammation and induce airway obstruction and hyperresponsiveness in guinea pigs. The severity of these effects varies depending on the specific agonists used. Notably, dexamethasone reversed pulmonary functional changes and mitigated bronchial inflammation caused by the combined treatment of P/I. However, it had no impact on the expression of inflammatory mediators.
微生物感染，尤其是鼻病毒（RV）和呼吸道合胞病毒（RSV）引起的感染，是哮喘加重的主要诱因。这些病毒激活 Toll 样受体（TLR），引发先天免疫反应。为了更好地了解微生物引起的哮喘加重，需要使用模拟人类肺部特征的动物模型。本研究旨在评估 TLR 激动剂诱导的豚鼠气道反应，模拟微生物感染。
将 TLR3 的聚肌苷酸：聚胞苷酸（poly(I:C)）、TLR4 的脂多糖（LPS）和 TLR7 的咪喹莫特（imiquimod），或 poly(I:C)和 imiquimod 的组合（P/I）一次性鼻内给药，连续 4 天，每天 1 次。后者组在 TLR 激动剂挑战前一天开始每天腹腔注射地塞米松。通过全身 plethysmography 和强迫振荡技术测量呼吸功能。收集支气管肺泡灌洗液（BALF）细胞和肺组织进行分析。
LPS 和 P/I 的鼻内暴露在挑战后引起增强呼气暂停（Penh）增加，而 poly(I:C)或 imiquimod 单独使用均无影响。在 LPS、poly(I:C)或 P/I 挑战后，不仅 Rrs（呼吸系统阻力）和 Ers（呼吸系统弹性）均增加，而且只有 LPS 暴露增加。LPS 暴露导致 BALF 中性粒细胞增加，而其他暴露均不影响 BALF 细胞组成。LPS、poly（I:C）、imiquimod 和 P/I 暴露均导致小气道周围炎症细胞和肥大细胞明显浸润。对于炎症介质的表达，LPS 增加 CXCL8，poly(I:C)和 imiquimod 降低 IL-4 和 IL-5，增加 IFNγ。Imiquimod 增加 CXCL8 和 IL-6，而 P/I 降低 IL-5，增加 IL-6 和 IFNγ。地塞米松减轻了 Rrs、Ers、气道炎症的增加，但对炎症细胞因子表达的改变没有影响。
TLR 激动剂可促进豚鼠急性气道炎症，并诱导气道阻塞和高反应性。这些效应的严重程度取决于使用的特定激动剂。值得注意的是，地塞米松逆转了 P/I 联合治疗引起的肺功能变化和支气管炎症，但对炎症介质的表达没有影响。
