Toll-like receptor-9 agonist inhibits airway inflammation, remodeling and hyperreactivity in mice exposed to chronic environmental tobacco smoke and allergen.
BACKGROUND
As passive environmental tobacco smoke (ETS) exposure in nonsmokers can increase both asthma symptoms and the frequency of asthma exacerbations, we utilized a mouse model, in which ovalbumin (OVA) + ETS induce significantly increased levels of eosinophilic airway inflammation and remodeling compared to either stimulus alone, to determine whether a Toll-like receptor-9 (TLR-9) agonist could reduce levels of airway inflammation, airway remodeling and airway hyperreactivity (AHR).


METHODS
Mice treated with or without a TLR-9 agonist were sensitized to OVA and challenged with OVA + ETS for 1 month. AHR to methacholine was assessed in intubated and ventilated mice. Lung Th2 cytokines and TGF-beta(1) were measured by ELISA. Lungs were processed for histology and immunohistology to quantify eosinophils, mucus, peribronchial fibrosis and smooth muscle changes using image analysis.


RESULTS
Administration of a TLR-9 agonist to mice coexposed to chronic ETS and chronic OVA allergen significantly reduced levels of eosinophilic airway inflammation, mucus production, peribronchial fibrosis, the thickness of the peribronchial smooth muscle layer, and AHR. The reduced airway remodeling in mice treated with the TLR-9 agonist was associated with significantly reduced numbers of peribronchial MBP+ and peribronchial TGF-beta(1)+ cells, and with significantly reduced levels of lung Th2 cytokines [interleukin-5 and interleukin-13] and TGF-beta(1).


CONCLUSIONS
These studies demonstrate that TLR-9-based therapies inhibit airway inflammation, remodeling and AHR in mice coexposed to ETS and allergen who exhibit enhanced airway inflammation and remodeling.
Department of Medicine, University of California San Diego, San Diego, CA, USA.
Dae Jin
DJ
Song
Myung Goo
MG
Min
Marina
M
Miller
Jae Youn
JY
Cho
Hye Yung
HY
Yum
David H
DH
Broide
D000393:Air Pollutants / Q000009:adverse effects; D056151:Airway Remodeling / Q000187:drug effects; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D010047:Ovalbumin / Q000276:immunology; D011658:Pulmonary Fibrosis; D012907:Smoking / Q000009:adverse effects; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000393:Air Pollutants; D000485:Allergens; D018793:Interleukin-13; D015848:Interleukin-5; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; C489630:1018 oligonucleotide; D010047:Ovalbumin