PI3K and MAPKs regulate neutrophil migration toward the airways in heaves.
Abstract: Neutrophils accumulate in the airways of horses with heaves. They likely play an important role in the disease pathogenesis. Understanding the pathways regulating their migration may help identifying new therapeutic targets. Objective: MAPK and PI3K pathways are involved in neutrophil migration toward the airway lumen in heaves. Methods: Twelve heaves-affected horses and 4 healthy horses. Methods: Migratory activity of bronchoalveolar lavage fluids (BALF) from horses with heaves and healthy horses was compared by means of a Boyden chamber. Involvement of MAPK and PI3K pathways in neutrophil migration was investigated by pretreating neutrophils with inhibitors of p38 MAPK, JNK, MEK1/2, and PI3K. The capacity of a p38 MAPK inhibitor at decreasing neutrophil chemotaxis toward the airways was also evaluated in vivo. Results: BALF from symptomatic heaves-affected horses induced a greater degree of chemokinesis (P = .0004) than BALF from healthy horses. Although all pathways tested were involved in neutrophil migration, inhibition of PI3K was most potent in vitro. An inhibitor of p38 MAPK administered before challenge in horses with heaves did not alter BALF chemokinetic properties. BALF neutrophil percentage and BALF migratory activity were positively correlated after 14 and 35 days of antigen challenge in healthy (P = .05; R(2) = 0.82) and heaves-affected horses (P = .03; R(2) = 0.76), respectively. Conclusions: MAPK and PI3K pathways regulate neutrophil migration induced by BALF of horses with heaves. Inhibition of multiple pathways might be required to completely abolish BALF-induced neutrophil migratory activity and possibly inflammation in heaves.
Copyright © 2012 by the American College of Veterinary Internal Medicine.
Publication Date: 2012-11-29 PubMed ID: 23194017DOI: 10.1111/jvim.12008Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research studies the involvement of certain biological processes (MAPK and PI3K pathways) in the migration of a type of white blood cells (neutrophils) in horses affected with a respiratory disease (heaves). The researchers aimed to determine if inhibiting these pathways could discourage cell migration, potentially reducing inflammation in heaves.
Methodology
- The team of researchers studied 12 horses diagnosed with heaves and also used 4 healthy horses as a control group.
- They analyzed bronchoalveolar lavage fluid (BALF) – a fluid that provides a snapshot of what’s happening in the lungs – from both the affected and healthy horses in a Boyden chamber, an apparatus used to study cell migration.
- They pre-treated neutrophils – the cells they’re studying – with specific inhibitors of p38 MAPK, JNK, MEK1/2, and PI3K to understand the role of these pathways in neutrophil migration.
- The in-vivo effects of a p38 MAPK inhibitor on neutrophil migration towards the airways were also studied.
Results
- The BALF from horses with heaves caused more neutrophil migration than that from healthy horses.
- All the pathways analyzed were found contributing to neutrophil migration, but PI3K blockage proved to be the most successful in controlling this migration in-vitro.
- Administering a p38 MAPK inhibitor prior to antigen challenge in heaves-affected horses, however, did not change the properties of bronchoalveolar lavage fluid.
- The team found a positive correlation between the percentage of neutrophils in BALF and their migratory activity after 14 and 35 days of antigen challenge in healthy and heaves-affected horses, respectively.
Conclusions
- The research results underline the role of MAPK and PI3K pathways in regulating the migration of neutrophils, as stimulated by the bronchoalveolar lavage fluid of heaves-affected horses.
- To fully curb the migration of these cells and potentially the consequent inflammation in horses with heaves, multiple pathways might need to be inhibited.
Cite This Article
APA
Bullone M, Moran K, Lavoie-Lamoureux A, Lavoie JP.
(2012).
PI3K and MAPKs regulate neutrophil migration toward the airways in heaves.
J Vet Intern Med, 27(1), 164-170.
https://doi.org/10.1111/jvim.12008 Publication
Researcher Affiliations
- Faculté de Médicine Vétérinaire, Département de Sciences Cliniques, Université de Montréal, St-Hyacinthe, Québec, Canada.
MeSH Terms
- Animals
- Bronchoalveolar Lavage Fluid / chemistry
- Bronchoalveolar Lavage Fluid / cytology
- Case-Control Studies
- Cell Movement / physiology
- Gene Expression Regulation, Enzymologic / physiology
- Horse Diseases / metabolism
- Horses
- Lung Diseases, Obstructive / metabolism
- Lung Diseases, Obstructive / veterinary
- Mitogen-Activated Protein Kinase Kinases / genetics
- Mitogen-Activated Protein Kinase Kinases / metabolism
- Neutrophils / enzymology
- Phosphatidylinositol 3-Kinases / genetics
- Phosphatidylinositol 3-Kinases / metabolism
Citations
This article has been cited 8 times.- Bayless RL, Sheats MK, Jones SL. Withaferin A Inhibits Neutrophil Adhesion, Migration, and Respiratory Burst and Promotes Timely Neutrophil Apoptosis.. Front Vet Sci 2022;9:900453.
- Bright LA, Dittmar W, Nanduri B, McCarthy FM, Mujahid N, Costa LR, Burgess SC, Swiderski CE. Modeling the pasture-associated severe equine asthma bronchoalveolar lavage fluid proteome identifies molecular events mediating neutrophilic airway inflammation.. Vet Med (Auckl) 2019;10:43-63.
- da Palma RK, Fratini P, Schiavo Matias GS, Cereta AD, Guimarães LL, Anunciação ARA, de Oliveira LVF, Farre R, Miglino MA. Equine lung decellularization: a potential approach for in vitro modeling the role of the extracellular matrix in asthma.. J Tissue Eng 2018 Jan-Dec;9:2041731418810164.
- Wang Y, Kong X, Wang M, Li J, Chen W, Jiang D. Luteolin Partially Inhibits LFA-1 Expression in Neutrophils Through the ERK Pathway.. Inflammation 2019 Feb;42(1):365-374.
- Vargas A, Boivin R, Cano P, Murcia Y, Bazin I, Lavoie JP. Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma.. Respir Res 2017 Dec 12;18(1):207.
- Herteman N, Vargas A, Lavoie JP. Characterization of Circulating Low-Density Neutrophils Intrinsic Properties in Healthy and Asthmatic Horses.. Sci Rep 2017 Aug 10;7(1):7743.
- Xu X, Xie G, Hu Y, Li X, Huang P, Zhang H. Neural differentiation of mesenchymal stem cells influences their chemotactic responses to stromal cell-derived factor-1α.. Cell Mol Neurobiol 2014 Oct;34(7):1047-58.
- Polesskaya O, Wong C, Lebron L, Chamberlain JM, Gelbard HA, Goodfellow V, Kim M, Daiss JL, Dewhurst S. MLK3 regulates fMLP-stimulated neutrophil motility.. Mol Immunol 2014 Apr;58(2):214-22.
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