RIP1 kinase inactivation protects against LPS-induced acute respiratory distress syndrome in mice

Emmauel Mago; Xunan Zhao; Weigao Zhang; Qianchao Shao; Peiqi Li; Shuxian Huang; Xinyu Ding; Hu Liu; Tingzhe Sun; Fei He; Dan Weng

doi:10.1016/j.intimp.2024.112060

RIP1 kinase inactivation protects against LPS-induced acute respiratory distress syndrome in mice

Int Immunopharmacol. 2024 Apr 22:133:112060. doi: 10.1016/j.intimp.2024.112060. Online ahead of print.

Authors

Emmauel Mago¹, Xunan Zhao¹, Weigao Zhang¹, Qianchao Shao¹, Peiqi Li¹, Shuxian Huang¹, Xinyu Ding¹, Hu Liu¹, Tingzhe Sun², Fei He³, Dan Weng⁴

Affiliations

¹ School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, China.
² School of Life Sciences, Anqing Normal University, Anqing 246133, Anhui, China.
³ Department of Emergency Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China. Electronic address: hefei1201@njglyy.com.
⁴ School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, China. Electronic address: danweng@njust.edu.cn.

PMID: 38652970
DOI: 10.1016/j.intimp.2024.112060

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by lung tissue oedema and inflammatory cell infiltration, with limited therapeutic interventions available. Receptor-interacting protein kinase 1 (RIPK1), a critical regulator of cell death and inflammation implicated in many diseases, is not fully understood in the context of ARDS. In this study, we employed RIP1 kinase-inactivated (Rip1^K45A/K45A) mice and two distinct RIPK1 inhibitors to investigate the contributions of RIP1 kinase activity in lipopolysaccharide (LPS)-induced ARDS pathology. Our results indicated that RIPK1 kinase inactivation, achieved through both genetic and chemical approaches, significantly attenuated LPS-induced ARDS pathology, as demonstrated by reduced polymorphonuclear neutrophil percentage (PMN%) in alveolar lavage fluid, expression of inflammatory and fibrosis-related factors in lung tissues, as well as histological examination. Results by tunnel staining and qRT-PCR analysis indicated that RIPK1 kinase activity played a role in regulating cell apoptosis and inflammation induced by LPS administration in lung tissue. In summary, employing both pharmacological and genetic approaches, this study demonstrated that targeted RIPK1 kinase inactivation attenuates the pathological phenotype induced by LPS inhalation in an ARDS mouse model. This study enhances our understanding of the therapeutic potential of RIPK1 kinase modulation in ARDS, providing insights for the pathogenesis of ARDS.

Keywords: Acute respiratory distress syndrome; Cell death; Nec-1s; RIPA-56; Receptor-interacting protein kinase 1.