Introduction
Acute lung injury (ALI) and its more severe form, acute respiratory
distress syndrome (ARDS), are common and devastating clinical disorders
with high morbidity and mortality rates (Rubenfeld et al., 2005; Ware &
Matthay, 2000). ALI is characterized by intense inflammation of lung
tissue with neutrophil accumulation, interstitial edema, disruption of
endothelial and epithelial integrity, and leakage of protein into the
alveolar space. These symptoms can lead to pulmonary edema,
intrapulmonary hemorrhage, and severely impaired pulmonary gas exchange
(Mohan et al., 2008; Schell-Chaple et al., 2015). Many conditions can
lead to ALI, including sepsis, pancreatitis, multiple trauma, pneumonia,
aspiration of gastric contents, pulmonary contusion, and inhalation of
injurious gases (Standiford & Ward, 2016). Despite the great progress
that has been made in understanding the pathophysiology of ALI/ARDS,
limited therapeutic strategies have been effective for treating ARDS
patients. Moreover, no Food and Drug Administration-approved ALI/ARDS
treatment exists (Johnson & Matthay, 2010). Therefore, to research and
develop effective drugs to treat ALI/ARDS is imperative.
Previous studies indicated that NLRP3 inflammasome is always involved in
ALI (Dolinay et al., 2012). NLRP3 inflammasome is a multi-protein
complex which comprises the innate immune sensor NLRP3, ASC, and
caspase-1, which serves as a platform for caspase-1 activation (Jo et
al., 2015). The inflammasome promotes the pro-IL-1β and pro-IL-18
cleavage to produce mature and functional IL-1β and IL-18, respectively.
Activation of the NLRP3 inflammasome in macrophages requires two steps:
priming and activation (Sutterwala et al., 2014; Yang et al., 2019). The
priming step (signal 1) is provided by inflammatory stimuli such as TLR4
agonists, which induce NF-κB-mediated NLRP3 and pro-IL-1β expression.
The activation step (signal 2) is triggered by PAMPs and DAMPs, which
promotes NLRP3 inflammasome assembly and caspase-1-mediated IL-1β and
IL-18 secretion (Tschopp & Schroder, 2010). The level of NLRP3
expression is considered as a limiting step in inflammasome activation
(Song et al., 2016). In resting macrophages, the concentration of NLRP3
protein is relatively low, therefore NLRP3 inflammasome assembly is
rarely induced. When the NF-κB pathway is activated, NF-κB/p65 is
released and translocated from the cytoplasm to the nucleus (Gao et al.,
2017), leading to NLRP3 protein expression (He et al., 2016) and
initiating the transcription of pro-inflammatory mediators such as
TNF-α, iNOS, COX-2, IL-1β, and IL-6. To suppress the NF-κB pathway
causes inhibition of NLRP3 inflammasome activation, eventually blocking
the secretion of these cytokines. In addition, TRIM31 is a member of the
TRIM protein family (Liu et al., 2017), which directly binds to NLRP3
and promotes K48-linked ubiquitination, leading to NLRP3 proteasomal
degradation and inhibition (Song et al., 2016). This feature makes
TRIM31 a good potential target for the inhibition of NLRP3 inflammasome
activation (Song et al., 2016). Therefore, to enhance TRIM31 expression
leads to inhibition of NLRP3 inflammasome is an important strategy for
anti-inflammatory drug discovery.
Yadanzigan (YDZG) (Figure 1A) is a compound isolated from seeds ofBrucea javanica (Linn.) Merr (Simaroubaceae) (Yadanzi) that has
been widely used in traditional Chinese medicine. Yadanzi oil emulsion
has demonstrated anti-inflammatory activity via the suppression of NF-κB
activation (Huang et al., 2017). However, evidence for the
anti-inflammatory activity of YDZG has not been shown. In this study, we
aimed to illustrated anti-inflammatory activities and mechanism of YDZG
in vitro and in vivo.