Abstract
Some asthmatic individuals undergoing allergen inhalation challenge develop an isolated early response whereas others develop a dual response (early plus late response). In the present study we have used transcriptomics (microarrays) and metabolomics (mass spectrometry) of peripheral blood to identify molecular patterns that can discriminate allergen-induced isolated early from dual asthmatic responses. Peripheral blood was obtained prior to (pre-) and 2 hours post allergen inhalation challenge from 33 study participants. In an initial cohort of 14 participants, complete blood counts indicated significant differences in neutrophil and lymphocyte counts at pre-challenge between early and dual responders. At post-challenge, significant genes (ALOX15, FADS2 and LPCAT2) and metabolites (lysolipids) were enriched in lipid metabolism pathways. Enzymes encoding for these genes are involved in membrane biogenesis and metabolism of fatty acids into pro-inflammatory and anti-inflammatory mediators. Correlation analysis indicated a strong negative correlation between ALOX15, FADS2, and IL5RA expression with 2-arachidonoylglycerophosphocholine levels in dual responders. However, measuring arachidonic acid and docosahexaenoic acid levels in a validation cohort of 19 participants indicated that the free form of DHA (nmoles/µg of protein) was significantly (p = 0.03) different between early and dual responders after allergen challenge. Collectively these results may suggest an imbalance in lipid metabolism which dictates pro- (anti-) inflammatory and pro-resolving mechanisms. Future studies with larger sample sizes may reveal novel mechanisms and therapeutic targets of the late phase asthmatic response.
Highlights
Asthma is the most common chronic lung disease, but remains poorly understood due to its complexity and heterogeneity [1]
We demonstrate the utility of applying omics-based approaches to peripheral blood in order to identify molecular patterns that can discriminate allergen-induced isolated early from dual asthmatic responses
Asthma is a complex disease consisting of multiple subphenotypes such that current therapies perform well in some phenotypes compared to others [45]
Summary
Asthma is the most common chronic lung disease, but remains poorly understood due to its complexity and heterogeneity [1]. The early asthmatic response (EAR) is initiated upon allergen inhalation and results in the activation of IgE-bearing cells such as mast cells and basophils [8,9,10]. Upon degranulation, these cells release proinflammatory mediators such as histamine and eicosanoids triggering bronchoconstriction and increased vascular permeability [11,12]. The late asthmatic response (LAR) occurs 4 to 6 hours [13] after allergen exposure and is characterized by cellular infiltration of the airway, increased bronchovascular permeability, and mucus secretion [14]. The molecular mechanisms leading to the early and late asthmatic responses are not fully understood
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