1. Introduction
Influenza virus is a major respiratory pathogen which remained the
world’s most deadly communicable disease[1]. Studies have shown that
the prognosis of viral pneumonia caused by influenza virus is related to
the interaction between the virus and the host [2-4]. In mild cases,
the hosts can effectively remove pathogens and result to a good
prognosis [2]. However, in severe cases, the violent inflammatory
response causes extensive lung tissue damage and hypoxemia which may
progress to acute respiratory distress syndrome (ARDS). As a result, the
mortality rate for severe influenza infection ranges from 10% (seasonal
influenza) [3] to 65% (pandemic influenza) [4]. Early antiviral
treatment can improve the prognosis of influenza patients. But Dobso et
al. found that antiviral treatment alone could not effectively reduce
the mortality of severe influenza patients [5]. HeroldS et al.
further confirmed that the high mortality rate of severe influenza is
related to the excessive inflammatory response of the host lung [2].
Thus, excessive host inflammatory response to influenza virus is the
main cause of death in patients with severe influenza.
NOD-like receptor thermal protein domain associated protein 3 (NLRP3)
inflammasome is a high molecular weight polyprotein complex whose
formation is strictly regulated by initiation and activation signals
[6]. The NLRP3 inflammasome plays a key regulatory role in the
innate immune system, recognizing signals from a variety of
microorganisms (such as bacteria and viruses), both endogenous and
exogenous (crystalline particles, etc.) [6]. After the NLRP3
inflammasome is activated, it can activate the downstream effector
Caspase-1 to mediate pyroptosis. Tate et al. found that the delaying
administration of NLPR3 inhibitors in the early stage of influenza virus
infection could significantly improve the survival rate of mice and
reduce lung injury[7]. Ong et al. suggest that controlling the
activation of the NLRP3 inflammasome at a reasonable level is necessary
to maintain homeostasis[8]. Reactive oxygen species (ROS) is a key
factor regulating NLRP3 activation [9]. Heid ME et al. have shown
that increased ROS can activate NLRP3 inflammasome-mediated cell damage
[10]. Further, increased ROS can also promote the spread of viruses
between cells and increase the body’s susceptibility to respiratory
viruses [11-13].
Radix Astragali , the root
of Astragalus membranaceus var. mongholicus (Bunge) P.K.
Hsiao. is one of the most popular herbs with multiple functions such as
anti-inflammatory[14] and antiviral effects [15]. The study of
Liang et al. showed that Radix Astragali injection significantly
inhibited the proliferation of H1N1 and improved the survival rate of
cells infected with the H1N1 virus [16]. Khan et al. demonstrated
that aqueous extract of Radix Astragali has antiviral activity
and can be used to treat avian influenza virus infection [17]. In
addition, Radix Astragali has been shown to possess
anti-hepatitis B virus activities both in vitro and in
viro [18] and exhibits therapeutic effect on myocarditis caused by
Coxsackie virus [19]. Astragaloside IV (AS-IV) is the main active
component of Radix Astragali , which has strong antioxidant,
anti-fibrosis, anti-inflammatory, and
antiviral effects [20]. AS-IV can
reduce lung injury caused by various pathological factors by reducing
ROS [21,22]. AS-IV can improve pulmonary fibrosis induced by
Bleomycin-Induced Pulmonary Fibrosis by inhibiting ROS [22,23].
AS-IV alleviates the progression of
Chronic Obstructive Pulmonary Disease (COPD) by inhibiting the
production of ROS and inflammatory factors [24].
Recently, Zhang et al. reported that in H1N1 infection, AS-IV attenuates
the secretion of the inflammatory factor IL-1β by enhancing autophagy
[25]. However, the specific mechanism of action of AS-IV in
influenza virus infection remains unclear. In many diseases, AS-IV
reduces inflammation by inhibiting the production of ROS. Therefore, in
this study, we combined the antioxidant properties of AS-IV to further
explore the possible mechanism of AS-IV in influenza viral pneumonia and
develop effective anti-influenza viral pneumonia drugs from the
perspective of reducing viral inflammation and body damage.