Abstract
BackgroundRecurrent airway obstruction (RAO) is a severe chronic respiratory disease affecting horses worldwide, though mostly in the Northern hemisphere. Environmental as well as genetic factors strongly influence the course and prognosis of the disease. Research has been focused on characterization of immunologic factors contributing to inflammatory responses, on genetic linkage analysis, and, more recently, on proteomic analysis of airway secretions from affected horses. The goal of this study was to investigate the interactions between eight candidate genes previously identified in a genetic linkage study and proteins expressed in bronchoalveolar lavage fluid (BALF) collected from healthy and RAO-affected horses. The analysis was carried out with Ingenuity Pathway Analysis® bioinformatics software.ResultsThe gene with the greatest number of indirect interactions with the set of proteins identified is Interleukin 4 Receptor (IL-4R), whose protein has also been detected in BALF. Interleukin 21 receptor and chemokine (C-C motif) ligand 24 also showed a large number of interactions with the group of detected proteins. Protein products of other genes like that of SOCS5, revealed direct interactions with the IL-4R protein. The interacting proteins NOD2, RPS6KA5 and FOXP3 found in several pathways are reported regulators of the NFκB pathway.ConclusionsThe pathways generated with IL-4R highlight possible important intracellular signaling cascades implicating, for instance, NFκB. Furthermore, the proposed interaction between SOCS5 and IL-4R could explain how different genes can lead to identical clinical RAO phenotypes, as observed in two Swiss Warmblood half sibling families because these proteins interact upstream of an important cascade where they may act as a functional unit.
Highlights
Recurrent airway obstruction (RAO) is a severe chronic respiratory disease affecting horses worldwide, though mostly in the Northern hemisphere
The following candidate genes [20] were investigated for interactions with the set of proteins detected in bronchoalveolar lavage fluid (BALF): Interleukin 4 receptor (IL-4R), interleukin 21 receptor (IL-21R), chemokine (C-C motif) ligand 24 (CCL24), interleukin 27 (IL-27), prostaglandin E receptor 4 (PTGER4), phosphodiesterase 4D (PDE4D), suppressor of cytokine signaling 5 (SOCS5) and IL-7R
Products of the following four gene candidates, SOCS5, IL-7R, PTGER4, and PDE4D, were predicted to directly interact with proteins identified in BALF
Summary
Recurrent airway obstruction (RAO) is a severe chronic respiratory disease affecting horses worldwide, though mostly in the Northern hemisphere. Research has been focused on characterization of immunologic factors contributing to inflammatory responses, on genetic linkage analysis, and, more recently, on proteomic analysis of airway secretions from affected horses. Affected horses exhibit a chronic, spontaneous cough, nasal discharge, and increased respiratory efforts associated with an elevation in maximal transpulmonary pressure change compared to healthy horses or horses with inflammatory airway disease (IAD) [3]. A study performed with horses affected by summer pasture-associated obstructive pulmonary disease (SPAOPD) revealed that the expression of TH1 and TH2 cytokines varies throughout the year [17]. Characterization of key interactions and pathways would be helpful in understanding the inflammatory response in RAO horses and whether it fits the rodent derived TH1/TH2 paradigm
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