Fig. 6.

Pyroptosis in ALI and silicosis. Exposure to LPS, which is an important component of bacteria, is a common cause of ALI. LPS binds to TLR4 and activates the NLRP3 inflammasome. Meanwhile, LPS activates the p38 MAPK pathway via the TLR2/NF-κB signaling pathway, which results in the activation of the NLRP3 inflammasome. The activated NLRP3 inflammasome excites caspase-1, and active caspase-1 sequentially cleaves GSDMD. Finally, GSDMD-dependent pyroptosis of AMs occurs, which leads to consistent excessive alveolar inflammation and diffuse alveolar edema. Additionally, the lethal toxin-activated NLRP1 inflammasome induces pyroptosis of AMs, contributing to the development of ALI. Furthermore, pyroptosis of AMs aggravates ALI by releasing caspase-1-dependent PyrBDs, which trigger the vascular interstitial edema and neutrophil recruitment. In addition, LPS circulating in the blood triggers pyroptosis of pulmonary endothelial cells via activating the caspase-4/11/GSDMD pathway. Inhaled silica activates the NLRP3 inflammasome, which is dependent or independent of ROS. Activated NLRP3 inflammasome processes caspase-1 which cleaves GSDMD. Additionally, silica activates caspase-4/11, which leads to the release of GSDMD-NTD. Consequently, GSDMD-mediated pyroptosis occurs in AMs and results in chronic inflammation and pulmonary fibrosis. Note: ALI, acute lung injury; LPS, lipopolysaccharide; GSDMD, gasdermin D; AMs, alveolar macrophages; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa-B; PyrBDs, pyroptotic bodies