Abstract
Acute lung injury (ALI) induced by paraquat (PQ) progresses rapidly with high mortality; however, there is no effective treatment, and the specific mechanism is not well understood. The antiaging protein klotho (KL) has multiple functions and exerts significant influences on various pathophysiological processes. This work evaluated the impact of KL on PQ-induced ALI and investigated its underlying mechanisms. As for in vivo research, C57BL/6 mice were treated with PQ (30 mg/kg) intraperitoneal (IP) injection to create a toxicity model of ALI (PQ group). The mice were divided into control group, KL group, PQ group, and PQ+KL group. For in vitro experiment, A549 cells were incubated with or without KL and then treated in the presence or absence of PQ for 24 h. In vivo result indicated that KL reduced the mortality, reduced IL-1β and IL-6 in the bronchoalveolar lavage fluid (BALF), attenuated ALI, and decreased apoptosis in situ. In vitro result revealed that KL significantly improved cell viability, reduced the levels of IL-1β and IL-6 in culture supernatants, suppressed cell apoptosis, inhibited caspase-3 activation, and enhanced mitochondrial membrane potential (ΔΨm) after PQ treatment. Besides, KL effectively abated reactive oxygen species (ROS) production, improved GSH content, and lowered lipid peroxidation in PQ-exposed A549 cells. Further experiments indicated that phosphorylated JNK and P38 MAPK was increased after PQ treatment; however, KL pretreatment could significantly lower the phosphorylation of P38 MAPK. Suppression of P38 MAPK improved cell viability, alleviated inflammatory response, and reduced apoptosis-related signals; however, it had no obvious effect on the production of ROS. Treatment with N-acetylcysteine (NAC), a classic ROS scavenger, could suppress ROS production and P38 MAPK activation. These findings suggested that KL could alleviate PQ-caused ALI via inhibiting ROS/P38 MAPK signaling-regulated inflammatory responses and mitochondria-dependent apoptosis.
Highlights
Paraquat (PQ), which is a quaternary nitrogen herbicide, is extensively utilized in agriculture for weed control
The enrichment of PQ in alveolar epithelial cells could lead to alveolar epithelial rupture, impaired surfactant production, hemorrhage, edema, and inflammatory cell infiltration, which leads to Acute lung injury (ALI) and progressive respiratory failure [5]
We proved for the first time that KL could attenuate the pathophysiological process of ALI caused by PQ via inhibiting oxidative stress in lung epithelial cells
Summary
Paraquat (PQ), which is a quaternary nitrogen herbicide, is extensively utilized in agriculture for weed control. An in vitro experiment demonstrated that increasing KL expression in lung epithelial cells reduced cigarette smoke extract-induced cell death by decreasing intracellular ROS production and suppressing cellular senescence [15]. Based on the above findings, we hypothesized that administration of KL protein could attenuate PQ-caused pulmonary injury and dysfunction via reducing intracellular ROS production. To test this hypothesis, we performed both in vitro and in vivo experiments to determine whether KL protein exerts protective effects on oxidative injuries in lung epithelial cells and try to clarify the relevant mechanisms involved in this process
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