TLR Agonists Induce Airway Functional Changes and Inflammation in Guinea Pigs.

<bold>Background:</bold> Microbial infections is common triggers for asthmatic exacerbations. To investigate the mechanisms, the present study aimed to determine airway responses in guinea pigs exposed to Toll-like receptors (TLR) agonists, mimicking microbial infections. <bold>Method:</bold> Agonists for TLR3(poly(I:C)), TLR4(LPS), and TLR7(imiquimod), or the combination of poly(I:C) and imiquimod (PI) were given intranasally once, day 1-4. The latter group received daily ip injections of dexamethasone starting one day before the challenges. After each challenge, the enhanced pause (Penh) was measured. After the last challenge, lung resistance (Rrs) and elastance (Ers) were measured. Bronchial lavage fluid (BALF) and lung tissues were collected for histology and PCR. <bold>Result:</bold> LPS and the combination PI caused an increase in Penh, whereas poly(I:C) or imiquimod alone had no effect. Exposure to LPS, poly(I:C), or the combination PI, but not imiquimod, increased Rrs and Ers. In BALF, only LPS caused an increase in neutrophils. LPS, poly(I:C), imiquimod, and the combination of PI caused infiltration of inflammatory cells and mast cells in the lung. For the expression, LPS increased CXCL8, poly(I:C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ, imiquimod increased CXCL8 and IL-6, whereas the combination PI decreased IL-5, and increased IL-6 and IFNγ (0.6±0.1; 4.2±0.6 and 10.7±2.1 fold change). The treatment with dexamethasone reversed the alterations induced by the combination PI, except for the inflammatory cytokine expression profile. <bold>Conclusion:</bold> Activation of TLR agonists promotes acute airway inflammation, leading to airway hyperresponsiveness in the guinea pigs, which partly can be blocked by dexamethasone.