title: Intranasal administration of poly(I:C) and LPS in BALB/c mice induces airway hyperresponsiveness and inflammation via different pathways.
abstract: BACKGROUND
  Bacterial and viral infections are known to promote airway hyperresponsiveness (AHR) in asthmatic patients. The mechanism behind this reaction is poorly understood, but pattern recognizing Toll-like receptors (TLRs) have recently been suggested to play a role.
  
  
  METHODS
  To explore the relation between infection-induced airway inflammation and the development of AHR, poly(I:C) activating TLR3 and LPS triggering TLR4, were chosen to represent viral and bacterial induced interactions, respectively. Female BALB/c or MyD88-deficient C57BL/6 mice were treated intranasally with either poly(I:C), LPS or PBS (vehicle for the control group), once a day, during 4 consecutive days.
  
  
  RESULTS
  When methacholine challenge was performed on day 5, BALB/c mice responded with an increase in airway resistance. The maximal resistance was higher in the poly(I:C) and LPS treated groups than among the controls, indicating development of AHR in response to repeated TLR activation. The proportion of lymphocytes in broncheoalveolar lavage fluid (BALF) increased after poly(I:C) treatment whereas LPS enhanced the amount of neutrophils. A similar cellular pattern was seen in lung tissue. Analysis of 21 inflammatory mediators in BALF revealed that the TLR response was receptor-specific. MyD88-deficient C57BL/6 mice responded to poly (I:C) with an influx of lymphocytes, whereas LPS caused no inflammation.
  
  
  CONCLUSIONS
  In vivo activation of TLR3 and TLR4 in BALB/c mice both caused AHR in conjunction with a local inflammatory reaction. The AHR appeared to be identical regardless of which TLR that was activated, whereas the inflammation exhibited a receptor specific profile in terms of both recruited cells and inflammatory mediators. The inflammatory response caused by LPS appeared to be dependent on MyD88 pathway. Altogether the presented data indicate that the development of AHR and the induction of local inflammation might be the result of two parallel events, rather than one leading to another.
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Starkhammar
authors.forename: Susanna
authors.initials: S
authors.lastname: Kumlien Georén
authors.forename: Linda
authors.initials: L
authors.lastname: Swedin
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
authors.forename: Lars Olaf
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D000281:Administration, Intranasal; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D016085:Bronchoconstrictor Agents / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D007369:Interferon Inducers / Q000008:administration & dosage / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D016210:Methacholine Chloride / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011070:Poly I-C / Q000008:administration & dosage / Q000633:toxicity*; D015656:Respiratory Mechanics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016085:Bronchoconstrictor Agents; D016207:Cytokines; D007369:Interferon Inducers; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016210:Methacholine Chloride; D011070:Poly I-C