Epigenetic modifications, especially N6-methyladenosine (m6A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m6A modification in the TME of lung adenocarcinoma (LUAD) remains unclear. A total of 2506 patients with LUAD were included in the analysis and divided into different groups according to distinct m6A modification-related patterns based on 23 m6A regulators. A comprehensive analysis was performed to explore TME infiltration in different m6A modification-related patterns. Principal component analysis was performed to obtain the m6Ascore and to quantify m6A modification-related patterns in different individuals. Three distinct m6A modification-related patterns were identified by 23 m6A regulators. The pathway enrichment analysis showed that m6Acluster-A was associated with immune activation; m6Acluster-B was associated with carcinogenic activation; m6Acluster-C was prominently related to substance metabolism. M6Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m6Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m6Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m6Ascore exhibited significantly improved clinical response to anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) immunotherapy. This study explored the regulatory mechanisms of TME infiltration in LUAD. The comprehensive analysis of m6A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.

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Objective: To investigate the effects of cigarette smoke extract (CSE) and lipopolysaccharide (LPS) on the activity and pyroptosis of pulmonary microvascular endothelial cells (PMVECs). Methods: PMVECs were cultured without treatment or with CSE (1%-25%), LPS, or CSE+LPS. Cell viability was detected using the CCK8 method. Apoptosis was evaluated by flow cytometry. Cell morphology was evaluated using optical microscopy. The content of IL-1β and IL-18 was measured by ELISA. Results: CSE decreased cell viability in a dose-dependent manner. The cells in the CSE+LPS group showed the most obvious cytomorphological changes and the highest pyroptosis rate under the microscope. Flow cytometry showed that the CSE and LPS groups showed higher apoptosis rates than the blank group; the apoptotic rate in the CSE+LPS group was even higher (P<0.01). Compared with the bkank group, the levels of IL-18 and IL-1β in the cell supernatant of the CSE, LPS, and CSE+LPS groups increased significantly, with significant differences (P<0.01). There were no differences between the CSE and LPS groups (P>0.05). Compared with the CSE and LPS groups, the CSE+LPS group had higher IL-18 and IL-1β (P<0.01). Conclusion: The effect of CSE on cell viability is dose-dependent. CSE+LPS can induce cell pyroptosis and increase the levels of inflammatory cytokines in PMVECs. These observations demonstrated that pyroptosis caused by CSE and LPS might play an important role in pulmonary vascular remodeling.

Objective To observe the effect of compound Tinglizi Decoction on non-classical pathway of cell death in rats with pulmonary hypertension, and to explore its mechanism of action in the treatment of COPD-related pulmonary hypertension. Methods 60 male SD rats were randomly divided into Western group, normal group, model group, high-dose group, medium dose group and low-dose group, with 10 rats per group. We detected the protein expression levels of caspase-11, GSDMD and IL-6 by Western blot, detected serum TNF-α by ELISA, and observed the morphology of lung tissue by hematoxylin and eosin (HE) staining. Results In the expression of caspase11, GSDMD, IL-6 mRNA and protein in lung tissue, the model group was significantly higher than the normal group (P < 0.01), and the high-dose group, middle-dose group, low-dose group and western medicine group were significantly lower than the model group (P < 0.01). The levels of serum TNF-α and serum creatinine in the model group were significantly higher than those in the normal group (P < 0.01); and those in the high-dose group, middle-dose group, low-dose group and western medicine group were significantly lower than those in the model group (P < 0.05). Conclusion The mechanism of compound Tinglizi Decoction in the intervention of COPD-related pulmonary hypertension rats is related to the inhibition of non-classical pathway of cell death.