Effect of Beclomethasone Dipropionate and Dexamethasone Isonicotinate on Lung Function, Bronchoalveolar Lavage Fluid Cytology, and Transcription Factor Expression in Airways of Horses with Recurrent Airway Obstruction

in Journal of Veterinary Internal Medicine (2006), 20

Glucocorticoid (GC) therapy is recognized to be effective for the treatment of recurrent airway obstruction (RAO) in horses. Anti-inflammatory properties of GC are thought to be mediated by suppression of ... [more ▼]

Glucocorticoid (GC) therapy is recognized to be effective for the treatment of recurrent airway obstruction (RAO) in horses. Anti-inflammatory properties of GC are thought to be mediated by suppression of inflammatory gene expression via inhibition of transcription factors such as nuclear factor-kB (NF-kB) and activator protein-1 (AP-1). The purpose of this study was to evaluate the effect of low-dose inhaled beclomethasone dipropionate and injectable dexamethasone 21- isonicotinate on clinical signs, pulmonary function, airway cytology, and activity of NF-kB and AP-1 in bronchial cells of RAO-affected horses. Seven horses with RAO were exposed to moldy hay until they developed airway obstruction on 3 separate occasions. In a crossover design, they were then treated with a placebo (injection on day 1), inhaled beclomethasone (500 mg q12h for 10 days), or dexamethasone (0.06 mg/kg, IM on day 1) and monitored for 10 days. Pulmonary function, bronchoalveolar lavage fluid cytology, and NF-kB and AP-1 activity in bronchial brushing cells were measured before (day 1) and after treatment (day 10). Treatment with beclomethasone resulted in significantly improved pulmonary function of RAOaffected horses compared with placebo and dexamethasone treatments. However, none of the treatments had an effect on bronchoalveolar lavage fluid cytology or NF-kB and AP-1 activity. These findings reveal that, in a model of severe RAO, the benefits of low-dose inhaled beclomethasone on pulmonary function are not accompanied by a decrease in airway inflammatory cells or a suppression of transcription factors NF-kB and AP-1 DNA-binding activity. [less ▲]

Evidence for a role of heat shock factor 1 in inhibition of NF-kB pathway during heat shock response-mediated lung protection

in American Journal of Physiology - Lung Cellular and Molecular Physiology (2004), 287

Heat shock transcription factor (HSF)-1 is recognized as a central component of the heat shock response, which protects against various harmful conditions. However, the mechanisms underlying the ... [more ▼]

Heat shock transcription factor (HSF)-1 is recognized as a central component of the heat shock response, which protects against various harmful conditions. However, the mechanisms underlying the protection and the role of HSF-1 in these mechanisms have not yet been clearly elucidated. Using HSF-1 knockout mice (Hsf1_/_), we examined whether heat shock responsemediated lung protection involved an inhibition of the proinflammatory pathway via an interaction between HSF-1 and NF-_B, in response to cadmium insult. The HSF-1-dependent protective effect against intranasal instillation of cadmium (10 and 100 _g/mouse) was demonstrated by the higher protein content (1.2- and 1.4-fold), macrophage (1.6- and 1.9-fold), and neutrophil (2.6- and 1.8-fold) number in bronchoalveolar fluids, higher lung wet-to-dry weight ratio, and more severe lung damage evaluated by histopathology in Hsf1_/_compared with wild-type animals. These responses were associated with higher granulocyte/macrophage colony-stimulating factor (GMCSF; 1.7-fold) but not TNF-_ concentrations in bronchoalveolar fluids of Hsf1_/_ mice compared with those of wild-type animals, indicating that HSF-1 behaved as a repressor of specific cytokine production in our model. To further investigate the mechanism of GM-CSF repression, we analyzed the NF-_B activity and I_B stability. The DNA binding NF-_B activity, in particular p50 homodimer activity, was higher in Hsf1_/_ mice than in wild-type mice after cadmium exposure. These results provide a first line of evidence that mechanisms of lung protection depending on HSF-1 involve specific cytokine repression via inhibition of NF-_B activation in vivo. [less ▲]

Effects of thiazolidinediones on tumor necrosis factor-α-induced inflammatory cytokine expression

Poster (2003)