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

Jack Yang, Cornelis van ’t Veer, Joris J. T. H. Roelofs, Jeroen W. J. van Heijst, Alex F. de Vos, Keith R. McCrae, Alexey S. Revenko, Jeff Crosby, Tom van der Poll, Cornelis van 't Veer

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


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 antisense oligonucleotide (kininogen 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, T helper 2 responses, mucus production, or lung pathology. kininogen ASO treatment started after HDM sensitization reduced plasma kininogen levels by 75% and reproduced the phenotype of kininogen deficiency: kininogen ASO administration prevented the HDM-induced increase in Penh without influencing leukocyte influx, Th2 responses, mucus production, or lung pathology. 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.
Original languageEnglish
Pages (from-to)L187-L196
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number1
Publication statusPublished - 1 Jan 2019

Cite this