Sipeimine attenuates PM2.5-induced lung toxicity via suppression of NLRP3 inflammasome-mediated pyroptosis through activation of the PI3K/AKT pathway

Air pollution is the leading environment-related risk factor for human health and fourth in terms of global mortality [1,2], accounting for nearly 7 million people deaths annually worldwide [3]. Particularly, particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5) results in more than 1 million premature deaths per year in China [4]. PM2.5 could penetrate the bronchioles and reach blood circulation, which causes various diseases involving multiple organs, such as the lung, brain, kidney as well as cardiovascular system [[5], [6], [7]]. Therefore, the attention must be paid to PM2.5 exposure and inhalation. Inflammatory response and oxidative stress were found to be involved in PM2.5-induced acute and chronic respiratory system disorders [8,9]. However, no effective approaches are available for the prevention and treatment of PM2.5-induced lung injury.

Cell damage and inflammatory response induced by PM2.5 were reported to be associated with complex types of cell death, including apoptosis [10], ferroptosis [11], and pyroptosis [12]. Pyroptosis, a new pro-inflammatory type of programmed cell death, is mediated by the nod-like receptor protein-3 (NLRP3) inflammasome and caspase-1 signaling. The NLRP3 inflammasome is a key mediator of inflammatory responses and a cytoplasmic multi-protein complex comprising NLRP3, ASC, and caspase-1 [13]; it is involved in both pathogen and endogenous activators mediated inflammatory reactions and diverse inflammatory diseases. The components of the NLRP3 inflammasome are recruited and assembled, following stimulation by a variety of microbial pathogen-associated molecular patterns and endogenous markers of cell damage. This process could prompt cleavage of pro-caspase-1 into its active form, which, in turn, promotes cleavage and activation of IL-1β and IL-18, triggering local and systemic inflammatory responses [14]. Activation of the NLRP3 inflammasome may contribute to cell pyroptosis and cause various disorders, such as murine dry eye [15], ocular hypertension and glaucoma [16], pulmonary fibrosis [17,18], lung inflammation [19], as well as lung injury [20,21]. Moreover, PM2.5 could activate the NLRP3 inflammasome and the nuclear factor-κB pathway, upregulate the transcription and secretion of pro-inflammatory cytokines, and cause pulmonary inflammation [22,23]. Activation of the NLRP3 inflammasome maybe play a key role in the PM2.5-induced progression and development of lung injury. Moreover, suppression of the NLRP3 inflammasome alleviated pulmonary injury in vivo [24,25]. Accordingly, inhibiting and controlling inflammatory key mediators including the NLRP3 inflammasome might be a promising therapeutic approach for PM2.5 exposure-induced lung toxicity.

Natural herbs, along with their bioactive compounds have proven effective against some respiratory complaints owing to their therapeutic properties and have become the focus of extensive investigations. Bulbus Fritillariae Cirrhosae, also known as “Chuan-Bei-Mu”, belongs to the Liliaceae family and is found primarily in Southwestern China [26]. It has been commonly used as a Chinese medicine for a long time to treat cough, asthma, and cancer [27,28]. Sipeimine (Sip) is a steroidal alkaloid from Fritillariae Cirrhosae Bulbus [29]. It has a wide range of pharmacological properties, including anti-asthmatic activity [26], hypotensive effect [30], antitumor properties [31], as well as antibacterial and anti-inflammatory [27]. Alkaloids of Fritillariae are reported to be effective against the symptoms caused by exposure to PM2.5 [11]. However, the possible mechanisms and potential targets of Sip in protecting against PM2.5-induced lung toxicity have not been fully elucidated. Thus, the aim of the present study was to explore the underlying pharmacological mechanisms of Sip in inhibiting PM2.5-caused lung toxicity.

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