Current molecular pharmacology · 2023
Oral Hydroxychloroquine Mitigates Lipopolysaccharide-induced Lung Injury by Inhibiting Pyroptosis in Mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Xiong Rui, Li Ning, Xiong Juan, Liu Bohao, He Ruyuan, Wang Bo, Geng Qing
Аннотация
BACKGROUND AND OBJECTIVE: Hydroxychloroquine (HCQ) is a molecule derived from quinacrine; it displays a wide range of pharmacological properties, including anti-inflammatory, immunomodulatory, and antineoplastic. However, little is known about this molecule's role in lung injury. This study aimed to identify HCQ's regulatory role of HCQ in sepsis-induced lung injury and its molecular mechanism.
METHODS: To test the protective properties of HCQ, we established an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice. The extent of the injury was determined by evaluating histopathology, inflammatory response, oxidative stress, and apoptosis. Mechanistically, conventional nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) knockout mice were employed to investigate whether HCQ exerted pulmonary protection by inhibiting NLRP3-mediated pyroptosis.
RESULTS: Our findings revealed that HCQ pretreatment significantly mitigated LPS-induced lung injury in mice in terms of histopathology, inflammatory response, oxidative stress, and apoptosis, while inhibiting LPS-induced NLRP3 inflammasome activation and pyroptosis. Additionally, the indicators of lung injury, including histopathology, inflammatory response, oxidative stress, and apoptosis, were still reduced drastically in LPS-treated NLRP3 (-/-) mice after HCQ pretreatment. Notably, HCQ pretreatment further decreased the levels of pyroptosis indicators, including IL-1β, IL-18 and Cle-GSDMD, in LPS-treated NLRP3 (-/-) mice.
CONCLUSION: Taken together, HCQ protects against lung injury by inhibiting pyroptosis, maybe not only through the NLRP3 pathway but also through non-NLRP3 pathway; therefore, it may be a new therapeutic strategy in the treatment of lung injury.
METHODS: To test the protective properties of HCQ, we established an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice. The extent of the injury was determined by evaluating histopathology, inflammatory response, oxidative stress, and apoptosis. Mechanistically, conventional nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) knockout mice were employed to investigate whether HCQ exerted pulmonary protection by inhibiting NLRP3-mediated pyroptosis.
RESULTS: Our findings revealed that HCQ pretreatment significantly mitigated LPS-induced lung injury in mice in terms of histopathology, inflammatory response, oxidative stress, and apoptosis, while inhibiting LPS-induced NLRP3 inflammasome activation and pyroptosis. Additionally, the indicators of lung injury, including histopathology, inflammatory response, oxidative stress, and apoptosis, were still reduced drastically in LPS-treated NLRP3 (-/-) mice after HCQ pretreatment. Notably, HCQ pretreatment further decreased the levels of pyroptosis indicators, including IL-1β, IL-18 and Cle-GSDMD, in LPS-treated NLRP3 (-/-) mice.
CONCLUSION: Taken together, HCQ protects against lung injury by inhibiting pyroptosis, maybe not only through the NLRP3 pathway but also through non-NLRP3 pathway; therefore, it may be a new therapeutic strategy in the treatment of lung injury.