Taiwan. The authors wish to thank Miss Ingrid Kuo and the Center for Big Data Analytics and Statistics (Grant CLRPG3D0046) of Chang Gung Memorial Hospital for creating the graphical abstract used herein. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
BackgroundBu-zhong-yi-qi-tang (BZYQT), an herbal formula of traditional Chinese medicine, has been an effective regimen of allergic diseases for nearly 800 years. Our previous report has demonstrated its anti-inflammatory effects in patients with perennial allergic rhinitis, and the aim of this study is to investigate the anti-asthmatic effect of BZYQT.MethodsFemale BALB/cByJNarl mice were sensitized with normal saline (control group) or OVA. Mice sensitized by OVA were fed with distilled water (OVA group), oral 0.5 g/Kg (low-dose group) or 1 g/Kg (high-dose group) of BZYQT solution once daily on days 36-40 besides their routine diet. Airway hyper-responsiveness (AHR), eosinophil infiltration, levels of cytokines and total immunoglobulin E (IgE) in broncho-alveolar lavage fluid (BALF) were determined. The lungs and tracheas were removed, and histopathologic examination was subsequently performed.ResultsAHR was significantly reduced in both low- and high-dose BZYQT groups compared with the OVA group after inhalation of the highest dose of methacholine (50 mg/ml). The levels of eotaxin, Th2-related cytokines (IL-4, IL-5, IL-13), IgE, and eosinophil infiltration in BALF were significantly decreased in both BZYQT groups compared with the OVA group. Histopathologic examination revealed that eosinophil infiltration of the lung and trachea tissues was remarkably attenuated in both BZYQT groups.ConclusionsOral administration of BZYQT solution may exert anti-asthmatic effect by relieving AHR in OVA-sensitized mice, which is compatible with our clinical experience. Although detailed mechanism is to be determined, we surmise that it may be correlated with the immune-modulatory effects of inhibiting Th2 responses on the basis of our limited results.
The pathogenesis of acute respiratory distress syndrome (ARDS) is very complex. Patients with ARDS still suffer high mortality rates. Infiltration and activation of neutrophils in lungs are critical pathogenic factors in ARDS. In this study, we demonstrate that meso-dihydroguaiaretic acid (MDGA), a natural lignan, inhibits inflammatory responses in human neutrophils and ameliorates ARDS in mice. MDGA inhibited superoxide anion generation and elastase release in various G-protein coupled receptor agonists-induced human neutrophils. However, MDGA did not alter superoxide anion generation and elastase activity in cell-free systems. These results suggest that the anti-inflammatory effects of MDGA are mediated by regulating cellular signals in human neutrophils. In consistent with this, MDGA suppressed phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in activated human neutrophils. Moreover, MDGA inhibited CD11b expression and adhesion in activated human neutrophils. Interestingly, MDGA reduced reactive oxygen species (ROS) generation but not superoxide anion generation in protein kinase C (PKC) activator-induced human neutrophils, suggesting that MDGA may also have ROS scavenging ability. Indeed, MDGA showed strong free radical scavenging activity in cell-free assays. Significantly, MDGA suppressed PKC-induced neutrophil extracellular trap formation. Additionally, treatment of MDGA attenuated neutrophil infiltration and lung damage on lipopolysaccharide-induced ARDS in mice. In conclusion, our results demonstrate that MDGA has anti-neutrophilic inflammatory effects and free-radical scavenging activity. We also suggest that MDGA has potential to serve as a lead for developing new therapeutics to treat ARDS.
BACKGROUND AND PURPOSE Neutrophil overactivation is crucial in the pathogenesis of acute lung injury (ALI). Bletinib (3,3'-dihydroxy-2',6'-bis(p-hydroxybenzyl)-5-methoxybibenzyl), a natural bibenzyl first extracted from Bletilla striata in 1983, has anti-inflammatory, antibacterial, and antimitotic potential. In this study, we evaluated the therapeutic effects of Bletinib in human neutrophilic inflammation and lipopolysaccharide (LPS)-mediated ALI. EXPERIMENTAL APPROACH We assessed integrin expression, superoxide anion production, degranulation, neutrophil extracellular trap (NET) formation, and adhesion in activated human neutrophils through flow cytometry, spectrophotometry, and immunofluorescence microscopy. Moreover, phosphorylation of Src family kinases (SFKs) and downstream proteins was evaluated through immunoblotting. Finally, a murine LPS-induced ALI model was used to investigate the potential therapeutic effects of Bletinib treatment. KEY RESULTS In activated human neutrophils, Bletinib reduced degranulation, respiratory burst, NET formation, adhesion, migration, and integrin expression; suppressed the enzymatic activity of SFKs, including Src, Lyn, Fgr, and Hck; and inhibited the phosphorylation of SFKs as well as Vav and Bruton's tyrosine kinase (Btk). In our mice with ALI, the pulmonary sections demonstrated considerable amelioration of prominent inflammatory changes, such as haemorrhage, pulmonary oedema, and neutrophil infiltration, after Bletinib treatment. CONCLUSION AND IMPLICATIONS This is the first study to provide evidence that Bletinib regulates neutrophilic inflammation by inhibiting the SFKs-Btk-Vav pathway and that Bletinib ameliorates LPS-induced ALI in mice. Further biochemical optimisation of Bletinib may be a promising strategy for the development of novel therapeutics for inflammatory diseases. Bletinib ameliorates neutrophilic inflammation and lung injury by inhibiting Src family kinase phosphorylation and activity Short running title Bletinib mitigates neutrophilic inflammation by inhibiting SFKs
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