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Molecular profiling of the peripheral blood response to allergen inhalation challenge in asthmatics

University of British Columbia

Allergen inhalation challenge (AIC) triggers biphasic responses in allergic asthmatic individuals. Airway narrowing represents the early phase response, which typically occurs within 30 minutes of allergen inhalation. In 50-60% of allergic asthmatic adults, the early response is followed by the late phase response, usually starting around 3 hours after AIC, and characterized by cellular inflammation of the airway, increased lung tissue permeability, and mucus secretion. The pathways leading to the late response are not completely understood. The purpose of this thesis is to investigate the mechanisms behind the allergic asthmatic response profiles using peripheral blood samples obtained from asthmatics prior to and 2 hours following AIC. Subjects exhibited either an isolated early response of ≥20% fall in FEV₁ (isolated early responder – ER), or an early response followed by a late phase response of ≥15% fall in FEV₁ (dual responder – DR). Genome-wide transcriptional profiling using microarrays indicated significant perturbations in the Nrf2 (NF-E2-related factor 2)-mediated oxidative stress response pathway following allergen inhalation. Notably, the ABCC1 (ATP-binding cassette, sub-family C (CFTR/MRP), member 1) gene within the pathway showed a decreased expression post-challenge, as validated through RT-qPCR. Furthermore, a significant decrease in the level of plasma chemokine (C-C motif) ligand 2 (CCL2) was evident, which was replicated using immunoassays in additional cohorts of allergic rhinitis and individuals with occupational asthma. However, this may be attributable to inherent fluctuations, based on similar results from control subjects. The comparison of transcriptomic response profiles between ERs and DRs undergoing cat allergen inhalation challenge revealed linoleic acid metabolism as the most significant pathway. Separation of whole-blood gene expression profiles into cell-specific signals using the csSAM algorithm suggested that key transcriptomic differences lie in eosinophils and lymphocytes when comparing between ERs and DRs at the post-challenge time point. These findings are in support of the current model of asthma pathophysiology and provide valuable insights into molecular changes occurring as early as 2 hours after allergen inhalation. Further study into the underlying mechanisms leading to the different response patterns may expose new therapeutic targets effective in minimizing the late response, which is associated with chronic asthma.

Text

2012-04-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42098

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/