Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs
Abstract 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 a...
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2024-11-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-024-03050-3 |
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| author | Yujiao Xiang Jielu Liu Mu Nie Gunnar Nilsson Jesper Säfholm Mikael Adner |
| author_facet | Yujiao Xiang Jielu Liu Mu Nie Gunnar Nilsson Jesper Säfholm Mikael Adner |
| author_sort | Yujiao Xiang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-d7ad19844760458bafd02e2ff5ac7bc2 |
| institution | DOAJ |
| issn | 1465-993X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-d7ad19844760458bafd02e2ff5ac7bc22025-08-20T02:49:18ZengBMCRespiratory Research1465-993X2024-11-0125111110.1186/s12931-024-03050-3Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigsYujiao Xiang0Jielu Liu1Mu Nie2Gunnar Nilsson3Jesper Säfholm4Mikael Adner5Experimental Asthma and Allergy Research Unit, Institute of Environmental Medicine, Karolinska InstitutetExperimental Asthma and Allergy Research Unit, Institute of Environmental Medicine, Karolinska InstitutetExperimental Asthma and Allergy Research Unit, Institute of Environmental Medicine, Karolinska InstitutetDivision of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine, Karolinska University HospitalUnit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska InstitutetExperimental Asthma and Allergy Research Unit, Institute of Environmental Medicine, Karolinska InstitutetAbstract 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.https://doi.org/10.1186/s12931-024-03050-3Respiratory infectionsPoly (I:C)Lipopolysaccharide (LPS)ImiquimodInflammationMast cell |
| spellingShingle | Yujiao Xiang Jielu Liu Mu Nie Gunnar Nilsson Jesper Säfholm Mikael Adner Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs Respiratory Research Respiratory infections Poly (I:C) Lipopolysaccharide (LPS) Imiquimod Inflammation Mast cell |
| title | Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs |
| title_full | Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs |
| title_fullStr | Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs |
| title_full_unstemmed | Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs |
| title_short | Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs |
| title_sort | toll like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs |
| topic | Respiratory infections Poly (I:C) Lipopolysaccharide (LPS) Imiquimod Inflammation Mast cell |
| url | https://doi.org/10.1186/s12931-024-03050-3 |
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