IL-9 blockade attenuates inflammation in a murine model of mechanical ventilation-induced lung injury by inhibiting the NLRP3 inflammasome pathway.

Abstract

Ventilation-induced lung injury (VILI) causes a huge economic and social burden, and its prevention and treatment have gained increasing attention in recent years. IL-9 is an important inflammatory factor, but its potential role in VILI remains unclear. This study intended to explore whether blocking IL-9 could alleviate VILI and explore its underlying mechanism. Lung injury was induced by mechanical ventilation (MV) in C57BL/6 mice. Changes in inflammatory factors and NLRP3-related proteins were assessed using quantitative reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Subsequently, Nlrp3-/- mice were used to further elucidate the underlying mechanism. The percentage of Th9 cells in the peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissues of MV mice was increased compared to those of control mice. Treatment with anti-IL-9 mAb significantly alleviated the changes in lung histopathology, wet/dry lung proportion, total protein content, and neutrophil content in BALF induced by VILI. Additionally, administering anti-IL-9 mAb significantly downregulated the expression levels of inflammatory factors in BALF and lung tissues of mice with VILI. In addition, administering anti-IL-9 mAb inhibited NLRP3 inflammasome activation, as evidenced by the observed downregulation of NLRP3, ASC, cleaved caspase-1, and GSDMD-N. Additionally, NLRP3-deficient mice had lower lung injury induced by VILI than wild-type mice. Furthermore, the anti-IL-9 mAb only partially inhibited VILI in Nlrp3-/- mice. In MV mice, the anti-IL-9 mAb alleviated lung injury and reduced the secretion and expression of inflammatory factors partly by inhibiting the NLRP3 inflammasome pathway.