Lithium chloride attenuates sepsis-induced acute respiratory distress syndrome via decreasing the expressions of TNF-α, IL-6, CXCL1, and pulmonary edema

Abstract

Abstract Sepsis is a life-threatening illness caused by an excessive host response to infection. Acute respiratory distress syndrome (ARDS), a serious complication of sepsis, is characterized by pulmonary edema and alveolar barrier injury. However, there is no effective drug proven to reduce the mortality of ARDS yet. Lithium chloride (LiCl) is an inhibitor of glycogen synthase kinase-3β (GSK-3β). Recent studies reveal that GSK-3β inhibition exhibits anti-inflammatory effects in sepsis thereby ameliorating lipopolysaccharide (LPS)-induced acute lung injury. Given that GSK-3β inhibition has been investigated for various diseases, whether LiCl exerting a novel therapeutic effect for treating endotoxemia-induced ARDS remains unclear. Here, we investigated the effects of LiCl on endotoxemia-induced lung inflammation, respiratory failure, and the pulmonary barrier integrity of respiratory membrane. Mice intraperitoneally injected with LPS could induce a significant lymphopenia, lung inflammation with amount immune cells infiltration, and high mobility group box 1 (HMGB1) expression in lung supernatants. LiCl treatment ameliorated lung inflammation and lung function decline in LPS mice. In addition, LPS-induced TNF-α, IL-6, as well as CXCL1 were significantly lessened after LiCl treatment. The measurements of E-cadherin/VE-cadherin expression in lung tissues and IgM in bronchoalveolar lavage fluids indicated that LiCl could partly ameliorate LPS-mediated loss of pulmonary barrier integrity. Accordingly, LiCl effectively attenuated sepsis-caused lung inflammation, lung function decline, and alveolar barrier injury, which suggested that LiCl might act as a potential repurposing drug for treating ARDS in future.