Sepsis is a life-threatening syndrome caused by an abnormal host response to infection, often leading to multiple organ dysfunction syndrome (MODS)(Singer et al., 2016). Acute lung injury (ALI) is one of the most common complications of sepsis, and its pathological characteristic is excessive inflammatory response, which is manifested as diffuse inflammatory infiltration, refractory hypoxemia and respiratory failure(Shi et al., 2022). At present, ALI is still one of the leading causes of death in patients with sepsis(Fowler et al., 2019). There are no specific and effective treatments for ALI/ARDS, although many ventilation strategies and medicines have been tried(Matthay et al., 2019).

Excessive apoptosis or programmed cell death is an important mechanism in sepsis and MODS. Pyroptosis, another important form of programmed cell death, is characterized by production of inflammatory factors, and closely related to the uncontrolled inflammatory response in sepsis(Shi et al., 2017, Wang et al., 2020, Wang et al., 2018). Recent evidences suggest that pyroptosis of cells, including pulmonary vascular endothelial cells and alveolar macrophages, plays a key role in the development of ALI(Shi et al., 2022, Li et al., 2022). Studies have shown that the damage of capillary endothelial cells caused by pyroptosis leads to increased vascular permeability, the accumulation of a large amount of protein-rich exudate in alveoli, resulting in reduced effective ventilation and refractory hypoxemia(Matthay et al., 2019, Fan et al., 2018). In addition, numerous studies have shown that inhibition of the pyroptosis exerts protective effects in sepsis‐induced lung injury(Shi et al., 2022, Li et al., 2022, He et al., 2022, Liu et al., 2021, Wang et al., 2019). Therefore, pyroptosis is considered as an important target for the treatment acute lung injury.

Bruton's Tyrosine kinase (BTK) belongs to a family of non-receptor tyrosine kinases(Brown, 2013, Qiu and Kung, 2000). Previous studies that using BTK deficient mice and BTK inhibitors have reported that blocking the BTK signaling pathway can improve inflammatory responses in animal models of autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus(Neys et al., 2021, Arneson et al., 2021). Therefore, BTK is considered as a promising drug target for the treatment of inflammatory diseases. Ibrutinib, a Bruton's Tyrosine kinase inhibitor, has been shown to play an anti-inflammatory role in inflammation-related diseases(Li et al., 2021, Ito et al., 2015). Studies have shown that Ibrutinib can clear pneumonia cytokines and relieve lung injury in fatal influenza models(Florence et al., 2018). In addition, Ibrutinib may help protect lung damage and improve lung function in COVID-19 patients(Roschewski et al., 2020). Recent studies have found that Ibrutinib can regulate the activation of NLRP3 in macrophages and play an anti-inflammatory role in treating of metabolic inflammation in T2 diabetes and microvascular disease(Coll et al., 2022, Roskoski, 2020). Therefore, this study aimed to investigate the effect of Ibrutinib on ALI induced by cecal ligation puncture (CLP) in mice.