Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Abstract

Background: Acute lung injury (ALI) is characterized by dysfunction of the alveolar epithelial membrane caused by acute inflammation and tissue injury. Qingwenzhike (QWZK) prescription has been demonstrated to be effective against respiratory viral infections in clinical practices, including coronavirus disease 2019 (COVID-19) infection. So far, the chemical compositions, protective effects on ALI, and possible anti-inflammatory mechanisms remain unknown.Methods: In this study, the compositions of QWZK were determined via the linear ion trap/electrostatic field orbital trap tandem high-resolution mass spectrometry (UHPLC-LTQ-Orbitrap MS). To test the protective effects of QWZK on ALI, an ALI model induced by lipopolysaccharide (LPS) in rats was used. The effects of QWZK on the LPS-induced ALI were evaluated by pathological changes and the number and classification of white blood cell (WBC) in bronchoalveolar lavage fluid (BALF). To investigate the possible underlying mechanisms, the contents of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP-1), interleukin-1β (IL-1β), interleukin-18 (IL-18), and immunoregulatory-related factors interferon-γ (IFN-γ) were detected by ELISA. Furthermore, the expression of Toll-like receptor 4 (TLR4), p-IKKα/β, IKKα, IKKβ, p-IκBα, IκBα, p-NF-κB, nuclear factor-κB (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, pro-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), and β-actin were tested by Western blot.Results: A total of 99 compounds were identified in QWZK, including 33 flavonoids, 23 phenolic acids, 3 alkaloids, 3 coumarins, 20 triterpenoids, 5 anthraquinones, and 12 others. ALI rats induced by LPS exhibited significant increase in neutrophile, significant decrease in lymphocyte, and evidently thicker alveolar wall than control animals. QWZK reversed the changes in WBC count and alveolar wall to normal level on the model of ALI induced by LPS. ELISA results revealed that QWZK significantly reduced the overexpression of proinflammatory factors IL-6, TNF-α, MCP-1, IL-1β, IL-18, and IFN-γ induced by LPS. Western blot results demonstrated that QWZK significantly downregulated the overexpression of TLR4, p-IKKα/β, p-IκBα, p-NF-κB, NLRP3, cleaved caspase-1, and ASC induced by LPS, which suggested that QWZK inhibited TLR4/NF-κB signaling pathway and NLRP3 inflammasomes.Conclusions: The chemical compositions of QWZK were first identified. It was demonstrated that QWZK showed protective effects on ALI induced by LPS. The possible underlying mechanisms of QWZK on ALI induced by LPS was via inhibiting TLR4/NF-kB signaling pathway and NLRP3 inflammasome activation. This work suggested that QWZK is a potential therapeutic candidate for the treatments of ALI and pulmonary inflammation.

Xiongshao Zhitong Recipe Attenuates Nitroglycerin-Induced Migraine-Like Behaviors via the Inhibition of Inflammation Mediated by Nitric Oxide Synthase

“…Therefore, the dosage of XZR-middle is almost equivalent to the human clinical dose, and the low dose is half of the equivalent clinical dose, while the high dose is double the equivalent clinical dose. The doses of XZR extract used in rats in this study were also consistent with that in most previous studies, that is, the dosage of decoction in rodents reached crude drug g/kg/day ( Jiang et al, 2020 ; Zhang et al, 2021 ). It is worth emphasizing that the quantitative analysis of bioactive compounds in XZR and studies on the low dose levels assessing the therapeutic effect of XZR decoction warrant further exploration in the future.…”

“…The rat dose in our study was calculated based on the body surface area and the corresponding clinically prescribed dose for a 70 kg human body [70.01 g (raw herbs)/70 kg/day] ( Zhang et al, 2021 ). Therefore, the dosage of XZR-middle is almost equivalent to the human clinical dose, and the low dose is half of the equivalent clinical dose, while the high dose is double the equivalent clinical dose.…”

Efficacy of terpenoids in attenuating pulmonary edema in acute lung injury: A meta-analysis of animal studies

“…The investigators extracted the abstracts and titles and identified 38 studies that met the inclusion criteria. After reviewing all of the publications, 10 studies were excluded because of missing outcome data ( Ehrhart et al, 2000 ; Tawadros et al, 2007 ; Nader and Baraka, 2012 ; An et al, 2014 ; Wang et al, 2015 ; Liu and Chen, 2016 ; Shen et al, 2017 ; Ni et al, 2019 ; Wang et al, 2019 ; Yang et al, 2019 ), and another 12 studies were excluded because multiple interventions were investigated ( Murakami et al, 2000 ; Lin et al, 2011 ; Li et al, 2014b ; Li et al, 2016a ; Li et al, 2016b ; Baradaran Rahimi et al, 2019 ; Ye et al, 2019 ; Duan et al, 2020 ; Yue et al, 2020 ; Choi et al, 2021 ; Zhang et al, 2021 ; Liu et al, 2022 ). In conclusion, 16 studies were included in this meta-analysis, as described below ( Shi et al, 2007 ; Yang et al, 2011 ; Chen et al, 2014 ; Yang et al, 2014 ; Yuan et al, 2014 ; Wei and Wang, 2017 ; Li et al, 2018a ; Li et al, 2018b ; Luo et al, 2019 ; Ren et al, 2019 ; Zhang et al, 2020 ; Ali et al, 2021 ; Dikmen et al, 2021 ; Li et al, 2021 ; Wang et al, 2021 ; Wu et al, 2021 ) ( Figure 1 ).…”

Study of the anti-inflammatory and anti-apoptosis effect of the traditional Mongolian Hohgardi-9 in acute lung injury

“…TP53, CASP3, and BCL2 play an important role in the regulation of apoptosis signal transduction, and the ALI mechanism has been proved to be closely related to apoptosis[28]. Inhibiting the activation of TLR-4/NF-κB signal pathways can reduce the secretion and expression of inflammatory cytokines, such as TNF-α and IL-1β and reduce the inflammatory cascade reaction and thus reduce inflammation’s damage to the lung[29, 30]. The GO and KEGG pathways analysis shows that the NF-kappa B signalling pathway, TNF signalling pathway, MAPK signalling pathway, apoptosis, p53 signalling pathway, HIF-1 signalling pathway and Coronavirus disease - COVID-19 were the key targets signal pathways.…”

“…TP53, CASP3, and BCL2 play an important role in the regulation of apoptosis signal transduction, and the ALI mechanism has been proved to be closely related to apoptosis [28]. Inhibiting the activation of TLR-4/NF-κB signal pathways can reduce the secretion and expression of inflammatory cytokines, such as TNF-α and IL-1β and reduce the inflammatory cascade reaction and thus reduce inflammation's damage to the lung [29,30]…”