LPS exacerbates functional and inflammatory responses to ovalbumin and decreases sensitivity to inhaled fluticasone propionate in a guinea pig model of asthma

Abstract

Background and PurposeAsthma exacerbations contribute to corticosteroid insensitivity. LPS is ubiquitous in the environment. It causes bronchoconstriction and airway inflammation and may therefore exacerbate allergen responses. This study examined whether LPS and ovalbumin co-administration could exacerbate the airway inflammatory and functional responses to ovalbumin in conscious guinea pigs and whether these exacerbated responses were insensitive to inhaled corticosteroid treatment with fluticasone propionate (FP).Experimental ApproachGuinea pigs were sensitized and challenged with ovalbumin and airway function recorded as specific airway conductance by whole body plethysmography. Airway inflammation was measured from lung histology and bronchoalveolar lavage. Airway hyper-reactivity (AHR) to inhaled histamine was examined 24 h after ovalbumin. LPS was inhaled alone or 24 or 48 h before ovalbumin and combined with ovalbumin. FP (0.05–1 mg·mL−1) or vehicle was nebulized for 15 min twice daily for 6 days before ovalbumin or LPS exposure.Key ResultsOvalbumin inhalation caused early (EAR) and late asthmatic response (LAR), airway hyper-reactivity to histamine and influx of inflammatory cells into the lungs. LPS 48 h before and co-administered with ovalbumin exacerbated the response with increased length of the EAR, prolonged response to histamine and elevated inflammatory cells. FP 0.5 and 1 mg·mL−1 reduced the LAR, AHR and cell influx with ovalbumin alone, but was ineffective when guinea pigs were exposed to LPS before and with ovalbumin.Conclusions and ImplicationsLPS exposure exacerbates airway inflammatory and functional responses to allergen inhalation and decreases corticosteroid sensitivity. Its widespread presence in the environment could contribute to asthma exacerbations and corticosteroid insensitivity in humans.

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

“…More specifically, combined LPS/IFN-g-induced IL-27 production has been linked to steroidresistant AHR (7)(8)(9)(10). A recent report has characterized and differentiated severe asthma from mild-moderate asthma by high level of IFN-g in lung tissues and BAL fluid, where IFN-g was found to promote steroid-refractory AHR (7).…”

“…High levels of LPS and Th1 cytokine IFN-g have been detected in the airways of asthmatics, which are often correlated with asthma severity (3)(4)(5)(6)(7). LPS and IFN-g are two key mediators for exacerbative inflammatory responses and the decrease in sensitivity to steroid in experimental models of asthma (7)(8)(9). Macrophage-derived IL-27 has been shown to be upregulated by LPS/IFN-g and mediate LPS/IFN-g-induced steroid-resistant AHR, as neutralizing IL-27 Ab significantly attenuated this response (10).…”

Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats

“…Histamine H 1 -receptors play a major role in the pathogenesis of extrinsic asthma, and blockade of this receptor is well-known to protect against asthmatic attacks [58,59,60]. Moreover, calcium channel blockade in bronchial tree was reported to decrease airway remodeling [16], while inhibition of calcium influx into mast cells decreases their ability for degranulation and histamine release [49].…”

Bufalin Inhibits the Inflammatory Effects in Asthmatic Mice through the Suppression of Nuclear Factor-Kappa B Activity

“…Although the advances in understanding its pathogenesis have been made, there is still no cure for this disease [7]. Inhaled corticosteroids (ICS) are widely used to be a frontline therapy for treating allergic asthma, but subsets of asthmatic patients exhibited a decreased sensitivity to these drugs, and long-term treatment has resulted in numerous side effects [8]. Therefore, the development of novel anti-inflammatory agents is needed for the treatment of asthma.…”