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.
Highlights
The coronavirus disease 2019 (COVID-19) pandemic causes tremendous catastrophe worldwide
A variety of components in QWZK could play a protective effect against Acute lung injury (ALI), and all these evidences supported the hypothesis that QWZK could play protective effects on ALI induced by LPS
To investigate the underlying mechanisms of protective effects of QWZK on ALI induced by LPS, Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway was studied
Summary
The coronavirus disease 2019 (COVID-19) pandemic causes tremendous catastrophe worldwide. Acute lung injury (ALI) is a critical step and causes high mortality (Leist et al, 2020; Lin et al, 2021). In ALI, the lungs show widespread destruction of the capillary endothelium, damages in alveolar capillary barrier, lung inflammatory cell infiltration, diffuse alveolar, and pulmonary interstitial edema, which lead to respiratory distress, progressive hypoxemia, and acute respiratory distress syndrome (ARDS) (Gupta et al, 2020; England et al, 2021). ALI/ARDS induced by COVID-19 overproduces early response proinflammatory cytokines TNF-α, interleukin (IL)-6, and IL-1β, which results in cytokine storm, and leads to vascular hyperpermeability, multiorgan failure, high cytokine concentrations unabated over time, and eventually death (England et al, 2021). It is critical to develop protective treatments against ALI. The chemical compositions, protective effects on ALI, and possible antiinflammatory mechanisms remain unknown
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