Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction

Rationale Oxidised phosphatidylcholines (OxPC) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored.

Objectives Characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild-asthma. Determine the capacity of OxPC to contribute to pathobiology associated with asthma.

Methods Using bronchoalveolar lavage (BAL) from two human cohorts, OxPC species were quantified using ultra high performance liquid chromatography tandem mass spectrometry. Murine thin cut lung slices (TCLS) were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.

Measurements and Main Results OxPC profiles were different in the airways of people with or without AHR and correlated with methacholine responsiveness. Exposure of mild-asthmatics to allergens produced unique OxPC signatures that were associated with the late asthma response severity. OxPCs dose-dependently induced 15% airway narrowing in murine TCLS. In HASM, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, IL-6, IL-8, GM-CSF, and the production of oxylipins via protein kinase C-dependent pathways.

Conclusions Data from human cohorts and primary HASM culture we show that OxPCs are present in the airways, increase after allergen challenge, and correlate with metrics of a dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.