Dexmedetomidine alleviates airway hyperresponsiveness and allergic airway inflammation through the TLR4/NF‑κB signaling pathway in mice

Abstract

Dexmedetomidine (DEX) suppresses inflammatory responses and protects against organ injury. The aim of the present study was to investigate the effect of DEX on airway hyperresponsiveness (AHR) and allergic airway inflammation, as well as its underlying mechanism of action in a murine model of ovalbumin (OVA)-induced asthma. A total of 30 female BALB/c mice were divided into 6 groups (n=5 mice/group): Control, OVA, OVA + DEX (20, 30 or 50 µg/kg) and OVA + TAK-242 [a toll-like receptor 4 (TLR4) inhibitor]. The mice were intraperitoneally injected with 20, 30 or 50 µg/kg DEX 1 h before OVA challenge. AHR to inhaled methacholine (Mch) was measured, and the mice were sacrificed 24 h after the last challenge. AHR following Mch inhalation was measured using the FlexiVent apparatus. Hematoxylin and eosin, periodic acid-Schiff and Wright-Giemsa staining was performed to evaluate inflammatory cell infiltration in the lung tissue. The levels of IL-4, IL-5 and IL-13 in the bronchoalveolar lavage fluid were analyzed using ELISA, and their mRNA expression levels in the lung tissue were examined using reverse transcription-quantitative PCR. The protein expression of TLR4, NF-κB and phosphorylated (p) NF-κB in the lung tissue was also detected using immunohistochemistry. In the murine OVA-induced asthma model, DEX decreased AHR following Mch inhalation and reduced the infiltration of inflammatory cells. IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluid were significantly lower following DEX treatment. Furthermore, DEX treatment inhibited the expression of TLR4, NF-κB and p-NF-κB in the lung tissue and exhibited a similar effect to TAK-242 treatment. In conclusion, DEX may attenuate AHR and allergic airway inflammation by inhibiting the TLR4/NF-κB pathway. These results suggested that DEX may represent a potential anti-inflammatory agent for the treatment and management of patients with asthma.

Dexmedetomidine attenuates airway inflammation and oxidative stress in asthma via the Nrf2 signaling pathway

“…In our previous study, it was demonstrated that 30 µg/kg DEX exerted the optimal therapeutic effect on a murine model of asthma induced by OVA ( 25 ). DEX has been reported to have exerted anti-inflammatory and antioxidative effects on brain injury ( 22 ), neuroinflammation ( 24 ) and hepatic ischemia/reperfusion injury ( 35 ) via activation of the Nrf2 signaling pathway.…”

“…The mice were divided into five groups (n=5) as follows: i) Control group; ii) OVA group; iii) DEX group; iv) OVA + DEX group; and v) OVA + DEX + ML385 group. The protocol used for the OVA-induced murine asthma model was described in our previous work ( 25 ). In brief, the mice in the control group received an intraperitoneal (i.p.)…”

“…The scoring systems for H&E and PAS staining were described in our previous work ( 25 ). In brief, the score for H&E staining represented the infiltration of inflammatory cells around the airways and was presented as follows: 0, normal; 1, a low number of cells present around the airways; 2, one cell layer was present around the airways; 3, 2–4 cell layers were present around the airways; 4, 5–7 cell layers were present around the airways; 5, 8–10 cell layers were present around the airways; and 6, >10 cell layers were present around the airways.…”

“…Oxidative stress serves a major role in inducing organ injury and inflammation, and the antioxidative effects of DEX have also been reported by a number of studies ( 22 – 24 ). Our previous study demonstrated that administration of DEX could reduce airway eosinophilic inflammation, AHR and mucus production in an ovalbumin (OVA)-induced murine asthma model ( 25 ). In light of the potential role of oxidative stress in the pathogenesis of asthma, it was hypothesized that DEX could reduce the symptoms of allergic asthma by decreasing oxidative stress.…”

Ketamine Attenuates Airway Inflammation via Inducing Inflammatory Cells Apoptosis and Activating Nrf2 Pathway in a Mixed-Granulocytic Murine Asthma Model

“…Different scoring systems for the evaluation of histological changes in H&E- and PAS-stained sections have been described in our previous work. 34 The scoring system for assessment of peribronchial inflammation in H&E-stained sections: 0, normal; 1, a few cells; 2, one cell layer around airways; 3, two-four cell layers around airways; 4, five-seven cell layers around airways; 5, eight-ten cell layers around airways; 6, more than ten cell layers around airways. The percent of PAS-positive cells in the airway epithelium was measured via Image J software (version 1.8.0), and results were graded to assess mucus secretion using a scoring system as follows: 0, less than 2%; 1, less than 20% and more than 2% (including 2%); 2, less than 40% and more than 20% (including 20%); 3, less than 60% and more than 40% (including 40%); 4, less than 80% and more than 60% (including 60%); and 5, more than 80% (including 80%).…”