NLRX1 knockdown attenuates pro-apoptotic signaling and cell death in pulmonary hyperoxic acute injury

Abstract

Abstract Hyperoxia is frequently used for treating acute respiratory failure, but it can cause acute lung injury. Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) is localized in mitochondria and related to reactive oxygen species production, inflammation, and apoptosis, which are the features of hyperoxic acute lung injury (HALI). However, the contribution of NLRX1 in HALI has not been addressed, so we designed to demonstrate the role of NLRX1 in hyperoxia. A murine model of HALI was generated in wild-type mice (WT) and NLRX1−/− mice by exposing them to over 95% oxygen for 72 h. As a result, NLRX1 expression was elevated in mice exposed to hyperoxia. In acute lung injury, levels of inflammatory cells, protein leakage, cell cytotoxicity, and pro-inflammatory cytokines were diminished in NLRX1−/− mice compared to WT mice. In survival test, NLRX1−/− mice showed alleviated mortality under hyperoxic conditions, and apoptotic cell death and caspase expression and activity were reduced in NLRX1−/− mice. Furthermore, levels of MAPK signaling proteins ERK 1/2, JNK, and p38 were decreased in NLRX1-deficient mice than in WT mice exposed to hyperoxia. This study reveals that the genetic deficiency of NLRX1 dampens hyperoxia-induced apoptosis, suggesting NLRX1 acts as a pivotal regulator of HALI.