Inhaled salmeterol and/or fluticasone alters structure/function in a murine model of allergic airways disease

Abstract

BackgroundThe relationship between airway structural changes (remodeling) and airways hyperresponsiveness (AHR) is unclear. Asthma guidelines suggest treating persistent asthma with inhaled corticosteroids and long acting β-agonists (LABA). We examined the link between physiological function and structural changes following treatment fluticasone and salmeterol separately or in combination in a mouse model of allergic asthma.MethodsBALB/c mice were sensitized to intraperitoneal ovalbumin (OVA) followed by six daily inhalation exposures. Treatments included 9 daily nebulized administrations of fluticasone alone (6 mg/ml), salmeterol (3 mg/ml), or the combination fluticasone and salmeterol. Lung impedance was measured following methacholine inhalation challenge. Airway inflammation, epithelial injury, mucus containing cells, and collagen content were assessed 48 hours after OVA challenge. Lungs were imaged using micro-CT.Results and DiscussionTreatment of allergic airways disease with fluticasone alone or in combination with salmeterol reduced AHR to approximately naüve levels while salmeterol alone increased elastance by 39% compared to control. Fluticasone alone and fluticasone in combination with salmeterol both reduced inflammation to near naive levels. Mucin containing cells were also reduced with fluticasone and fluticasone in combination with salmeterol.ConclusionsFluticasone alone and in combination with salmeterol reduces airway inflammation and remodeling, but salmeterol alone worsens AHR: and these functional changes are consistent with the concomitant changes in mucus metaplasia.

Therapeutic effects of co-inhaled roflumilast or formoterol and fluticasone on asthma-induced ultrastructural changes in murine airways

“…Failure of long acting β2 agonists (formoterol) to improve remodeling in the current study agrees with a previous study which showed that in OVA -sensitized and -challenged BALB/c mice, LABA treatment (salmeterol) exaggerated airway inflammation, remodeling, and hyperresponsiveness due to mucus metaplasia, while fluticasone separately or combined with salmeterol reduced airway inflammation and remodeling [10].Moreover, aerosolized combined salmeterol and fluticasone in rats reversed goblet cell hyperplasia, but increased fibronectin and collagen in the airway wall [23]. In addition, in asthmatic patients adding salmeterol to ICS reduced airway muscular tone and improved expiratory flows, but exerted a little effect on remodeling shown by decreasing number of vessels in the airway lamina propria [24].…”

“…The phosphate-buffered saline (PBS) was used as a vehicle for OVA. On days 27, 28, 47, 61, and 73 -75, mice were subjected to intranasal OVA (500 µg) or PBS in the control group [10,11].…”

“…Drugs were given by inhalation for 15 min once/day for seven doses with the last dose given 5 -6 h before the final OVA challenge. The drugs given included roflumilast (R, 500 µg/kg) [12], formoterol (Fo, 50 µg/kg) [10], fluticasone (F, 1000 µg/kg) [13,14], roflumilast + fluticasone (R + F, 500+1000 µg/kg) and formoterol + fluticasone (Fo + F, 50 + 1000 µg/kg) [13,15]. Dimethyl sulfoxide (DMSO) was used as a vehicle for the drugs.…”

Noninvasive Intratracheal Intubation to Study the Pathology and Physiology of Mouse Lung

“…Various methods have been used by a number of investigators in different settings to deliver materials of interest to mouse lungs, including inhalation, intranasal instillation, intratracheal instillation, and intratracheal intubation [1][2][3][4] . The latter procedure has not been routinely used because it is considered rather difficult to perform.…”

Neutrophils, airway hyperresponsiveness and COPD: true, true and related?

“…This is particularly important since, first, common wisdom holds that neutrophilia in COPD is steroid insensitive, and secondly, there may be something special about combining an ICS with a LABA. The combination of an ICS and a LABA probably activates a synergistic antiinflammatory mechanism [20], but a beneficial effect of ICS on b 2 -adrenoceptor is also possible [21]. What is clear from this current study is the potential important measurement of airway responsiveness in patients with COPD that may prove to be insightful in terms of understanding the pathogenic mechanisms, guiding ongoing treatment schemes or selecting initial treatment schemes to halt the progression and mortality of COPD.…”