Particulate matter (PM), the primary constituent of air pollution, poses an escalating threat to human health as it exacerbates air pollution globally. When combined with toxic metals, polycyclic aromatic hydrocarbons, and other detrimental components, PM can accumulate on the surface of pulmonary bronchioles and ultimately reach the alveoli, instigating damage to lung tissue [1,2]. Exposure to PM is linked to numerous respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and pneumonia due to excessive activation of oxidative stress and inflammatory responses [[3], [4], [5]]. Recently, research on PM-induced acute lung injury (ALI) has gained significant attention.

Although underlying mechanisms of PM-induced ALI have yet to be fully elucidated, excessive oxidative stress and NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis have been identified as two crucial factors in the pathogenesis of ALI [6]. Excessive accumulation of oxygen radicals lead to oxidative stress, impairing the function of cellular lipids, proteins, nucleic acids, and other molecules [7]. Therefore, imbalance between antioxidant and oxidative systems contributes to immunomodulatory dysfunction and inflammatory response [8]. Pyroptosis is a programmed cell death form characterized by continuous cell swelling, membrane rupture, release of cellular contents, and activation of a robust inflammatory response [9,10]. The NLRP3 inflammasome is a multiprotein complex composed of NLRP3, pro-caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). Upon receiving appropriate stimulus signals such as Nigericin-induced potassium outflux or monosodium urate (MSU)-induced disruption of calcium homeostasis or mitochondrial dysfunction, activated NLRP3 inflammasome processes pro-caspase-1 into mature caspase-1. Whereafter, caspase-1 cleaves gasdermin D (GSDMD), resulting in the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18) [11]. Pyroptosis is associated with various inflammation-related diseases including asthma, COPD, lung cancer, and ALI [12]. Previous studies have clarified the relationship between pyroptosis and PM-induced ALI [13,14], which suggests that NLRP3 may become a therapeutic target in PM-induced ALI.

Nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant proteins by interacting with the antioxidant response element (ARE) [15]. Under physiological conditions, Nrf2 primarily locates in the cytoplasm and bonds with Kelch-like ECH-associated protein 1 (Keap1). When exposed to oxidative stress, Nrf2 dissociates from Keap1 and translocates into the nucleus to bind with ARE. Subsequently, downstream proteins of Nrf2 such as heme oxygenase-1 (HO-1) and NAD(P)H: Quinone Oxidoreductase 1 (NQO1) are upregulated to initiate antioxidant stress responses and alleviate oxidative stress [16]. Furthermore, several studies have confirmed that PM-induced lung injury can activate the Nrf2 signaling pathway to attenuate oxidative stress and pyroptosis. Thus, the activation of Nrf2 also has the potential to be a therapeutic target for PM-induced ALI [17,18].

Paeoniflorin (PAE), a traditional Chinese medicine extracted from the dried roots of Paeonia lactiflora Pallas, has anti-inflammatory and immunomodulatory properties. Numerous studies have proved that PAE can effectively ameliorate ALI induced by influenza virus, acute pancreatitis, and lipopolysaccharide (LPS) in animal experimental models [19,20]. However, little research has been conducted to explore the effect of PAE on PM-induced ALI. Furthermore, PAE can suppress oxidative stress by activating the Nrf2 signaling pathway and regulate NLRP3 inflammasome-mediated pyroptosis [21,22]. In summary, our study aims to explore the protective effect of PAE against PM-induced ALI and its underlying mechanisms.