TNFα-blockade stabilizes local airway hyperresponsiveness during TLR-induced exacerbations in murine model of asthma.
Viral infections are a common cause of asthma exacerbation. These maladies are sometimes complicated by bacterial infections. Toll-like receptors (TLRs) are in the forefront of our microbial defence, with TLR3 responding to viral and TLR4 to bacterial stimulation. The present study was designed to evaluate the effect of concomitant TLR3 and TLR4 stimulation in a murine model of allergic asthma.BALB/c mice were stimulated intranasally with a combination of poly(I:C) and LPS activating TLR3 and TLR4, respectively. This resulted in the development of airway hyperresponsiveness (AHR) in the proximal part of the lung, along with signs of neutrophilic inflammation. Analysis of the bronchioalveolar lavage fluid (BALF) revealed a marked increase in TNFα. In contrast, the allergic airway inflammation induced by ovalbumin administration to sensitized mice caused AHR in the whole lung along with an increase in eosinophils and lymphocytes in the BALF and lung.When poly(I:C) + LPS were given to mice with an ongoing allergic airway inflammation induced by ovalbumin, the AHR was further increased in the peripheral lung and neutrophils appeared together with eosinophils and lymphocytes in the BALF and lung. Treatment with the TNFα-blocking antibody infliximab blunted the AHR increase, without affecting the cells influx in BALF.To conclude; a combined TLR3- and TLR4-stimulation, representing a concomitant viral and bacterial infection, causes an AHR that is further exaggerated during an ongoing allergic inflammation. The airway stabilizing effect of infliximab indicates the possible future use of TNFα blockade in treatment of microbial induced exacerbations of allergic asthma.
Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.|Division of ENT diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.|Department of ENT Diseases, Karolinska University Hospital, Stockholm, Sweden.
Magnus
M
Starkhammar
Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.|Division of ENT diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
Susanna
S
Kumlien Georén
Division of ENT diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.|Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Sven-Erik
SE
Dahlén
Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.|Division of ENT diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.|Department of ENT Diseases, Karolinska University Hospital, Stockholm, Sweden.
Lars-Olaf
LO
Cardell
Division of ENT diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden. mikael.adner@ki.se.|Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. mikael.adner@ki.se.|Unit of Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Scheeles väg 1, Karolinska Institutet, SE-171 77, Stockholm, Sweden. mikael.adner@ki.se.
Mikael
M
Adner
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D000069285:Infliximab / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D011070:Poly I-C; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
D018927:Anti-Asthmatic Agents; D008070:Lipopolysaccharides; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; D000069285:Infliximab; D011070:Poly I-C