Isopropyl 3-(3, 4-Dihydroxyphenyl)-2-Hydroxypropanoate, A Novel Metabolite From Salvia Miltiorrhiza, Protects Against LPS-Induced Acute Lung Injury in Mice by Attenuating the Canonical and Non-Canonical Inflammatory Pathway of Pyroptosis
Meiling ZhangMeng WangJian ChenYanjie LiuXiaohui ZhengYing-Chou XiaoXueyi ZhaoYe ZhaoWen NiuZhichao Li
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Abstract Background: The pathological characteristics of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are pulmonary edema resulting from pulmonary permeability increasing. The main cause is uncontrolled inflammatory response leading to the damage of pulmonary vascular endothelial and alveolar epithelial barriers. However, there has not been effective drugs against ALI. In this study, we investigated the function of Isopropyl 3-(3, 4-dihydroxypheny l)-2-hydroxypropanoate (IDHP), a novel metabolite of Danshen dripping pill having anti-inflammatory effect, in lipopolysaccharide (LPS) induced ALI in mice, and its underlying mechanisms. Methods: Pretreatment of IDHP in LPS-induced acute lung injury in mice were observed on survival rate, pulmonary morphologic changes, total protein content in bronchoalveolar lavage fluid (BALF), and inflammatory cytokines in lung tissue and BALF. To further explore its mechanism on ALI, THP-1 macrophages was studied to analyse propotosis related proteins and co-culture with epithelial or endothelial cells to assess protection function of IDHP in vitro. Results: As revealed by survival study, pretreatment with high dose of IDHP reduced the mortality of mice from ALI. IDHP pretreatment significantly improved LPS-induced lung pathological changes, reduced protein leakage and lung myeloperoxidase activity. IDHP also inhibited the release of inflammatory mediators TNFα, IL-1β, IL-6 and IL-18 in BALF and lung tissue. Meanwhile, IDHP decreased the expression of active-caspase1 (in canonical pyroptosis pathway), caspase4/5 (non-canonical pyroptosis pathway), Nrlp3, mature IL-1β, mature IL-18, Asc speck formation, and cleaved Gsdmd, all these are required for pyroptosis, in LPS stimulated THP-1 macrophages. Moreover, IDHP also decreased ROS production in LPS-stimulated THP-1 macrophages, inhibited the expression of tight junction proteins (Occludin, Zo-1) in endothelial cells, and decreased lactate dehydrogenase activity in supernatants of epithelial or endothelial cells, co-cultured with LPS-stimulated THP-1 macrophages. Conclusions: Pretreatment of IDHP improves survival rate and ameliorates LPS-induced ALI in mice possibly via inhibiting canonical and non-canonical pyroptosis pathways.Keywords:
Proinflammatory cytokine
Pyroptosis
Objective Platelet-activating factor (PAF) is a proinflammatory phospholipid that may contribute to inflammation in the acute respiratory distress syndrome (ARDS). PAF acetylhydrolase (PAF-AH) degrades PAF and regulates its biological activity. We characterized PAF-AH in bronchoalveolar lavage fluid from ARDS patients (n = 33, 22 survivors), patients at risk for ARDS (n = 6), and healthy controls (n = 6). Design Bronchoalveolar lavage was performed during acute (<96 hrs from onset), plateau (6 to 12 days), and late (≥14 days) phases of ARDS. Patients Intubated patients with ARDS or a risk factor for ARDS. Measurements and Main Results In ARDS, total bronchoalveolar lavage PAF-AH activity was markedly increased in the acute phase (87 ± 89 mU/mL, n = 33) and then decreased in the plateau (23 ± 14 mU/mL, n = 10) and late phases (19 ± 14 mU/mL, n = 7) (p = .003). Total bronchoalveolar lavage PAF-AH activity during the acute phase of ARDS was also increased as compared with patients at risk for ARDS (16 ± 13 mU/mL, n = 6) and healthy controls (3 ± 3 mU/mL, n = 6) (p < .001). In contrast, plasma PAF-AH activities were the same in controls (3215 ± 858 mU/mL, n = 6), in patients at risk for ARDS (3606 ± 1607 mU/mL, n = 6), and during the acute phase of ARDS (3098 ± 2395 mU/mL, n = 33) (p = .18). PAF-AH mRNA was present in alveolar macrophages in the acute phase of ARDS (five of six) and in at-risk patients (two of three) but not in healthy controls. Conclusions PAF-AH activity is increased in bronchoalveolar lavage fluid from patients with ARDS. Likely sources include leakage of plasma PAF-AH into alveoli or release of PAF-AH from injured cells; however, the presence of PAF-AH mRNA in alveolar macrophages suggests that PAF-AH may be actively synthesized in the lungs of patients with ARDS. PAF-AH activity in the lungs of ARDS patients may regulate inflammation caused by PAF and related oxidized phospholipids generated in the inflammatory response.
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Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.
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Pyroptosis is a newly discovered proinflammatory form of programmed cell death. Pyroptosis, which depends on cysteinyl aspartate specific proteinase-1(caspase-1), is inherently the proinflammatory response of the cell.Triggered by various pathological stimuli, pyroptosis is crucial for controlling virus infections.Despite that there are similarities between pyroptosis and necrosis(or apoptosis), there are apparent differences.This review discusses the feature of pyroptosis and the viruses which induce or inhibit pyroptosis.
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Pyroptosis; Inflammasome; Caspase-1; IL-1β; IL-18
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The gasdermins (GSDM), a family of pore-forming proteins, consist of gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), gasdermin E (GSDME) and DFNB59 (Pejvakin (PJVK)) in humans. These proteins play an important role in pyroptosis. Among them, GSDMD is the most extensively studied protein and is identified as the executioner of pyroptosis. Other family members have also been implicated in certain cancers. As a unique form of programmed cell death, pyroptosis is closely related to tumor progression, and the inflammasome, an innate immune mechanism that induces inflammation and pyroptosis. In this review, we explore the current developments of pyroptosis, the inflammasome, and especially we review the gasdermin family members and their role in inducing pyroptosis and the possible therapeutic values in antitumor effects.
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The sulfidopeptide leukotrienes (LT) C4 and D4 have been reported to promote the formation of pulmonary edema when administered into the pulmonary circulation of laboratory animals. As a first step in the evaluation of the hypothesis that these leukotrienes participate in the edema formation of the adult respiratory distress syndrome (ARDS), we investigated whether LTC4 and LTD4 were present in the bronchoalveolar lavage (BAL) fluid of patients with ARDS compared to nonsmoker control subjects and to patients with acute respiratory failure exhibiting no radiographic evidence of widespread pulmonary infiltrates but having a clinical predisposition for developing ARDS, i.e., the "at risk" group. Bronchoscopic lavage was performed with sterile 0.9% NaCl on 32 control subjects, nine patients with ARDS, and nine patients "at risk" for ARDS. Leukotrienes were measured in BAL fluid by radioimmunoassay after methanol extraction and HPLC purification of a 20-ml aliquot of the BAL sample. LTC4 and LTD4 (mean ± SE) increased from 1.1 ± 0.2 and 1.2 ± 0.5 ng/lavage in the BAL fluid of control subjects to 6.3 ± 2.3 and 20.1 ± 5.9 ng/lavage in patients "at risk" for ARDS and to 12.5 ± 3.0 and 30.5 ± 7.8 ng/lavage in patients with ARDS, respectively. The sulfidopeptide LTs correlated with BAL fluid protein content. These results suggest that increased amounts of LTs in BAL fluid are a general finding in patients with ARDS and those "at risk" for ARDS.
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Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1β release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1β forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.
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