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Published on: April 13, 2010
Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs
Yujiao Xiang1, Jielu Liu1, Mu Nie1
1Experimental Asthma and Allergy Research Unit, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Toll-like receptor (TLR) agonists like LPS and poly(I:C)/imiquimod induced airway inflammation and obstruction in guinea pigs. Dexamethasone partially reversed these effects, highlighting TLRs' role in asthma exacerbations.
Area of Science:
- Immunology
- Respiratory Medicine
- Pharmacology
Background:
- Microbial infections, particularly viral, trigger asthma exacerbations by activating toll-like receptors (TLRs).
- Animal models are crucial for studying microbial-induced asthma exacerbations and human lung responses.
- This study investigated airway responses in guinea pigs exposed to TLR agonists.
Purpose of the Study:
- To assess guinea pig airway responses to various toll-like receptor (TLR) agonists.
- To simulate microbial infections and understand their role in asthma exacerbations.
- To evaluate the therapeutic effect of dexamethasone on TLR agonist-induced airway responses.
Main Methods:
- Guinea pigs were intranasally administered poly(I:C), LPS, imiquimod, or a combination (P/I) over four days.
- Dexamethasone was administered to a P/I-treated group to assess its effects.
- Respiratory function was measured using whole-body plethysmography and forced oscillatory technique; BALF and lung tissues were analyzed.
Main Results:
- LPS and P/I increased Penh, while poly(I:C) and imiquimod alone did not.
- LPS, poly(I:C), and P/I increased respiratory system resistance (Rrs) and elastance (Ers).
- All TLR agonists induced airway inflammation and mast cell infiltration; LPS increased neutrophils. Dexamethasone attenuated functional changes and inflammation but not mediator expression.
Conclusions:
- TLR agonists induce acute airway inflammation, obstruction, and hyperresponsiveness in guinea pigs.
- The effects varied depending on the specific TLR agonist used.
- Dexamethasone reversed functional and inflammatory changes from combined P/I treatment but not mediator expression.
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