Role of cysteinyl leukotrienes in airway inflammation and responsiveness following RSV infection in BALB/c mice.
Cysteinyl leukotrienes (CysLTs) contribute to the development of airway obstruction and inflammation in asthma; however little information is available on the role of these molecules in the pathophysiology of respiratory syncytial virus (RSV) bronchiolitis. This study was designed to evaluate the effects of RSV infection on CysLTs production in a well-established mouse infection model. Furthermore, we assessed the effect of anti-inflammatory agents (a leukotriene receptor antagonist, MK-571, and dexamethasone) on the functional and immune changes induced by RSV infection. Six to 8-wk-old BALB/c mice were infected with human RSV (strain A2). Measurements of airway function were performed using whole body plethysmography. Lung inflammation was assessed by cell counts, measurement of cytokines and CysLTs in bronchoalveolar lavage fluid (BALF) in the absence and presence of treatment with MK-571 or dexamethasone. RSV infection produced a marked increase in CysLTs in the BALF and lung tissue, recruitment of neutrophils and lymphocytes into the airways, increased IFN-gamma levels and airway hyperresponsiveness (AHR). Treatment with MK-571 decreased RSV-induced AHR without affecting the cellular and inflammatory responses to RSV. Dexamethasone decreased AHR and markedly reduced the recruitment of inflammatory cells and production of IFN-gamma. Our findings suggest CysLTs play an important role in the pathogenesis of RSV-induced airway dysfunction. Treatment with MK-571 decreases RSV-induced AHR but does not appear to alter the lung inflammatory responses to RSV. In contrast, dexamethasone decreases RSV-induced AHR but interferes with recruitment of inflammatory cells, resulting in decreased Th1 cytokines (a potentially Th2-prone environment) in this model. These studies support recent reports on the beneficial effects of CysLT receptor antagonist in human trials and provide a model for investigating the role of CysLTs in RSV bronchiolitis.
Fullmer
Jason J
JJ
Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
Khan
Amir M
AM
Elidemir
Okan
O
Chiappetta
Connie
C
Stark
James M
JM
Colasurdo
Giuseppe N
GN
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001249:Asthma / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000821:virology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects; D003545:Cysteine / Q000032:analysis / Q000096:biosynthesis*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000821:virology; D007371:Interferon-gamma / Q000032:analysis; D015289:Leukotrienes / Q000032:analysis / Q000096:biosynthesis*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D018077:Receptors, Leukotriene; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D018113:Respiratory Syncytial Virus, Human
D000893:Anti-Inflammatory Agents; D015289:Leukotrienes; D008565:Membrane Proteins; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; C059141:verlukast; D003907:Dexamethasone; D007371:Interferon-gamma; D003545:Cysteine; C083169:leukotriene D4 receptor