A novel 5-lipoxygenase-activating protein inhibitor, AM679, reduces inflammation in the respiratory syncytial virus-infected mouse eye.
Respiratory syncytial virus (RSV) is an important cause of viral respiratory disease in children, and RSV bronchiolitis has been associated with the development of asthma in childhood. RSV spreads from the eye and nose to the human respiratory tract. Correlative studies of humans and direct infection studies of BALB/c mice have established the eye as a significant pathway of entry of RSV to the lung. At the same time, RSV infection of the eye produces symptoms resembling allergic conjunctivitis. Cysteinyl leukotrienes (CysLTs) are known promoters of allergy and inflammation, and the first step in their biogenesis from arachidonic acid is catalyzed by 5-lipoxygenase (5-LO) in concert with the 5-LO-activating protein (FLAP). We have recently developed a novel compound, AM679, which is a topically applied and potent inhibitor of FLAP. Here we show with the BALB/c mouse eye RSV infection model that AM679 markedly reduced the RSV-driven ocular pathology as well as the synthesis of CysLTs in the eye. In addition, AM679 decreased the production of the Th2 cell cytokine interleukin-4 but did not increase the viral load in the eye or the lung. These results suggest that FLAP inhibitors may be therapeutic for RSV-driven eye disease and possibly other inflammatory eye indications.
Musiyenko
Alla
A
Department of Biochemistry and Molecular Biology (MSB 2370), University of South Alabama, College of Medicine, 307 University Blvd., Mobile, AL 36688-0002, USA.
Correa
Lucia
L
Stock
Nicholas
N
Hutchinson
John H
JH
Lorrain
Daniel S
DS
Bain
Gretchen
G
Evans
Jilly F
JF
Barik
Sailen
S
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005123:Eye / Q000821:virology; D005128:Eye Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D007155:Immunologic Factors / Q000627:therapeutic use*; D007249:Inflammation / Q000473:pathology* / Q000517:prevention & control*; D015847:Interleukin-4 / Q000096:biosynthesis; D008168:Lung / Q000821:virology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D019562:Viral Load
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D008565:Membrane Proteins; D015847:Interleukin-4