ORMDL3-mediated bronchial epithelial pyroptosis leads to lung inflammation in obese mice with asthma

Asthma associated with obesity is a chronic disease that poses a threat to health in children and results in severe wheezing, earlier airway remodeling and increased insensitivity to hormone therapy compared with those who only have asthma. Despite its clinical importance, knowledge on the underlying mechanisms of this disease is limited. The present study aimed to elucidate the pathogenesis of asthma associated with obesity using a murine model. A total of 30 female BALB/c mice were divided into three groups: Normal, mice with asthma and obese mice with asthma. Obese mice with asthma were fed a high-fat diet to induce obesity. Mice with asthma were sensitized and challenged with ovalbumin (OVA). Obese mice were subjected to OVA sensitization and challenge to develop asthma associated with obesity. Airway remodeling was observed in obese mice with asthma through HE and Masson staining. Proteomic and bioinformatics analyses were conducted on lung tissue from obese mice with asthma and normal mice. A total of 200 proteins were differentially expressed in obese mice with asthma compared with normal mice; of these, 53 and 47% were up- and downregulated, respectively. Pathway analysis revealed that asthma associated with obesity primarily affected the 'lysosome', 'phagosome', and 'sphingolipid metabolism' pathways. Gene Set Enrichment Analysis demonstrated the presence of pyroptosis in obese asthmatic mice, along with significant increases in pyroptosis-associated factors such as GSDMD and Caspase. High protein expression of orosomucoid-like 3 (ORMDL3), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin-D (GSDMD) was observed in obese mice with asthma. In vitro experiments using HBE cells infected with ORMDL3-overexpressing lentivirus demonstrated that the overexpression of ORMDL3 led to increased expression of NLRP3, GSDMD and cathepsin D (CTSD). These findings suggested that ORMDL3 may regulate pyroptosis and subsequent airway remodeling in asthma associated with obesity via the CTSD/NLRP3/GSDMD pathway.