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Kininogen deficiency or depletion reduces enhanced pause independent of pulmonary inflammation in a house dust mite induced murine asthma model.

Yang, Jack; van 't Veer, Cornelis; Roelofs, Joris J T H; van Heijst, Jeroen W; de Vos, Alex F; McCrae, Keith R; Revenko, Alexey; Crosby, Jeff R; van der Poll, Tom.
Artigo em Inglês | MEDLINE | ID: mdl-30358441


High molecular weight kininogen is an important substrate of the kallikrein-kinin system. Activation of this system has been associated with aggravation of hallmark features in asthma.


We aimed to determine the role of kininogen in enhanced pause (Penh) measurements and lung inflammation in a house dust mite (HDM) induced murine asthma model.


Normal wild-type mice and mice with a genetic deficiency of kininogen were subjected to repeated HDM exposure (sensitization on days 0,1 and 2; challenge on days 14, 15, 18 and 19) via the airways to induce allergic lung inflammation. Alternatively, kininogen was depleted after HDM sensitization by twice weekly injections of a specific anti-sense oligonucleotide (KNG ASO) starting at day 3.


In kininogen deficient mice HDM induced in Penh was completely prevented. Remarkably, kininogen deficiency did not modify HDM induced eosinophil/neutrophil influx, Th2 responses, mucus production or lung pathology. KNG ASO treatment started after HDM sensitization reduced plasma kininogen levels by 75% and reproduced the phenotype of kininogen deficiency: KNG ASO administration prevented the HDM induced increase in Penh without influencing leukocyte influx, Th2 responses, mucus production or lung pathology. CONCLUSIONS AND CLINICAL RELEVANCE: This study suggests that kininogen could contribute to HDM induced rise in Penh independently of allergic lung inflammation. Further research is warranted to confirm these data using invasive measurements of airway responsiveness.
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