Effects of Ligustrazine on Airway Inflammation in A Mouse Model of Neutrophilic Asthma

Objective: To investigate the effects of ligustrazine(LTZ) on airway inflammation in a mouse model of neutrophilic asthma(NA). Methods: Forty healthy C57 BL/6 female mice were randomly divided into 4 groups using a random number table, including the normal control, NA, LTZ and dexamethasone(DXM) groups, with 10 rats in each group. The NA mice model was established by the method of ovalbumin combined with lipopolysaccharide sensitization. At 0.5 h before each challenge, LTZ and DXM groups were intraperitoneally injected with LTZ(80 mg/kg) or DXM(0.5 mg/kg) for 14 d, respectively, while the other two groups were given the equal volume of normal saline. After last challenge for 24 h, the aerosol inhalation of methacholine was performed and the airway reactivity was measured. The bronchoalveolar lavage fluid(BALF) was collected. The Wright-Giemsa staining was used for total white blood cells and differential counts. The levels of cytokines interleukin(IL)-17 and IL-10 were detected by enzyme-linked immunosorbent assay. The pathological change of lung tissue was observed by hematoxylin eosin staining. Results: The airway responsiveness of the NA group was significantly higher than the normal control group(P<0.05), while those in the LTZ and DXM groups were significantly lower than the NA group(P<0.05). The neutrophil and eosinophil counts in the LTZ and DXM groups were significantly lower than the NA group(P<0.05), and those in the LTZ group were significantly lower than the DXM group(P<0.05). There were a large number of peribronchiolar and perivascular inflammatory cells in filtration in the NA group. The airway inflammation in the LTZ and DXM groups were significantly alleviated than the NA group. The infiltration in the LTZ group was significantly reduced than the DXM group. Compared with the normal control group, the IL-17 level in BALF was significantly increased and the IL-10 level in BALF was significantly decreased in the NA group(P<0.05). LTZ and DXM treatment significantly decreased IL-17 levels and increased IL-10 levels compared with the NA group(P<0.05), and the changes in the above indices were more significant in the LTZ group(P<0.05). Conclusion: LTZ could alleviate the airway inflammation in the NA mice model through increasing the IL-10 level and decreasing the IL-17 level.

Intrinsically bioactive and biomimetic nanoparticle-derived therapies alleviate asthma by regulating multiple pathological cells

Asthma is a serious global public health concern. Airway neutrophilic inflammation is closely related to severe asthma, for which effective and safe therapies remain to be developed. Here we report nanotherapies capable of simultaneously regulating multiple target cells relevant to the pathogenesis of neutrophilic asthma. A nanotherapy LaCD NP based on a cyclic oligosaccharide-derived bioactive material was engineered. LaCD NP effectively accumulated in the injured lungs of asthmatic mice and mainly distributed in neutrophils, macrophages, and airway epithelial cells after intravenous or inhalation delivery, thereby ameliorating asthmatic symptoms and attenuating pulmonary neutrophilic inflammation as well as reducing airway hyperresponsiveness, remodeling, and mucus production. Surface engineering via neutrophil cell membrane further enhanced targeting and therapeutic effects of LaCD NP. Mechanistically, LaCD NP can inhibit the recruitment and activation of neutrophils, especially reducing the neutrophil extracellular traps formation and NLRP3 inflammasome activation in neutrophils. Also, LaCD NP can suppress macrophage-mediated pro-inflammatory responses and prevent airway epithelial cell death and smooth muscle cell proliferation, by mitigating neutrophilic inflammation and its direct effects on relevant cells. Importantly, LaCD NP showed good safety performance. Consequently, LaCD-derived multi-bioactive nanotherapies are promising for effective treatment of neutrophilic asthma and other neutrophil-associated diseases.