Elevated amount of Toll-like receptor 4 mRNA in bronchial epithelial cells is associated with airway inflammation in horses with recurrent airway obstruction

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 292; no. 4; pp. L936 - L943
• Main Authors: Berndt, Annerose, Derksen, Frederik J, Venta, Patrick J, Ewart, Susan, Yuzbasiyan-Gurkan, Vilma, Robinson, N. Edward
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2007
• Subjects: Airway Obstruction - physiopathology; Airway Obstruction - veterinary; Animals; Bronchi - cytology; Bronchi - metabolism; Bronchoalveolar Lavage Fluid - cytology; Cells; Dust; Epithelial Cells - metabolism; Female; Horse Diseases - physiopathology; Horses; Housing, Animal; Immune system; Inflammation - etiology; Inflammation - veterinary; Interleukin-8 - biosynthesis; Lungs; Male; Respiratory diseases; Respiratory Function Tests - veterinary; Ribonucleic acid; RNA; RNA, Messenger - metabolism; Toll-Like Receptor 4 - genetics
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00394.2006

Pulmonary Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan Submitted 5 October 2006 ; accepted in final form 8 December 2006 Recurrent airway obstruction (RAO) is characterized by neutrophilic airway inflammation and obstruction, and stabling of susceptible horses triggers acute disease exacerbations. Stable dust is rich in endotoxin, which is recognized by Toll-like receptor (TLR) 4. In human bronchial epithelium, TLR4 stimulation leads to elevation of interleukin (IL)-8 mRNA expression. The zinc finger protein A20 negatively regulates this pathway. We hypothesized that TLR4 and IL-8 mRNA and neutrophil numbers are elevated and that A20 mRNA is not increased in RAOs during stabling compared with controls and with RAOs on pasture. We measured the maximal change in pleural pressure ( Ppl max ), determined inflammatory cell counts in bronchoalveolar lavage fluid (BAL), and quantified TLR4, IL-8, and A20 mRNA in bronchial epithelium by quantitative RT-PCR. We studied six horse pairs, each pair consisting of one RAO and one control horse. Each pair was studied when the RAO-affected horse had airway obstruction induced by stabling and after 7, 14, and 28 days on pasture. Stabling increased BAL neutrophils, Ppl max , and TLR4 (4.14-fold change) significantly in RAOs compared with controls and with RAOs on pasture. TLR4 correlated with IL-8 ( R 2 = 0.75). Whereas stabling increased IL-8 in all horses, A20 was unaffected. IL-8 was positively correlated with BAL neutrophils ( R 2 = 0.43) and negatively with A20 ( R 2 = 0.44) only in RAO-affected horses. Elevated TLR4 expression and lack of A20 upregulation in bronchial epithelial cells from RAO-affected horses may contribute to elevated IL-8 production, leading to exaggerated neutrophilic airway inflammation in response to inhalation of stable dust. heaves; bronchial epithelium; innate immunity Address for reprint requests and other correspondence: A. Berndt, G320 Veterinary Medical Center, Michigan State Univ., East Lansing, MI 48824 (e-mail: berndtan{at}cvm.msu.edu )