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.
Respiratory syncytial virus (RSV) (family Paramyxoviridae)is an enveloped virus with a single-stranded negative-sense RNA genome of 15.2 kb (8). Human RSV is the leading worldwide viral agent of serious pediatric respiratory tract disease (11). In the United States, ϳ100,000 children under 1 year of age are hospitalized with severe RSV infection, and approximately 90% of all children have been infected one or more times by 2 years of age (11). There is no effective treatment for severe RSV infections, but with high-risk children the RSVneutralizing antibody palivizumab (Synagis) can be used to prevent the development of the disease (6). RSV bronchiolitis is associated with the development of wheezing symptoms and asthma in childhood, and RSV is also a significant cause of morbidity and mortality in the elderly and severely immunocompromised patients (11,12).Inoculation of RSV to the human nose or eyes results in viral replication, with an incubation period of 4 to 5 days, and the virus can then spread to the lower respiratory tract (8). This reflects the anatomical connection between the optic and nasal/upper respiratory tissues, and it is known that the use of eye goggles and nose masks significantly reduces RSV infection from patients to hospital workers (16). With BALB/c mice, instillation of RSV in the eye leads to eye infection, inflammation, and eye-to-lung viral transmission, resulting in respiratory pathology (3). In addition, many chemokines and receptors and interleukin 1␣ (IL-1␣) and tumor necrosis factor (TNF) were induced in the RSV-infected mouse eyes (3). In this study, application of anti-RSV small interfering RNA to the eyes 30 min prior to RSV inoculation prevented both viral growth and virus-induced pathology in the eye and lun...