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.