Alveolar Barrier Injury Research Articles

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

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.

Oxypaeoniflorin Prevents Acute Lung Injury Induced by Lipopolysaccharide through the PTEN/AKT Pathway in a Sirt1-Dependent Manner.

Acute lung injury (ALI) is featured by pulmonary edema, alveolar barrier injury, inflammatory response, and oxidative stress. The activation of Sirt1 could relieve lipopolysaccharide- (LPS-) induced murine ALI by maintaining pulmonary epithelial barrier function. Oxypaeoniflorin (Oxy) serves as a major component of Paeonia lactiflora Pall., exerting cardioprotection by activating Sirt1. However, the role of Oxy in ALI induced by LPS remains unclear. The aim of the present study is to illustrate the modulatory effects and molecular mechanisms by which Oxy operates in ALI induced by LPS. The intraperitoneal injection of LPS was performed to establish the murine ALI model while LPS-treated alveolar epithelial cells were used to mimic the in vitro ALI model. Levels of lung injury, oxidative stress, and inflammatory response were detected to observe the potential effects of Oxy on ALI. Oxy treatment mitigated lung edema, inflammatory response, and oxidative stress in mouse response to LPS, apart from improving 7-day survival. Meanwhile, Oxy also increased the expression and activity of Sirt1. Intriguingly, Sirt1 deficiency or inhibition counteracted the protective effects of Oxy treatment in LPS-treated mice or LPS-treated alveolar epithelial cells by regulating the PTEN/AKT signaling pathway. These results demonstrated that Oxy could combat ALI in vivo and in vitro through inhibiting inflammatory response and oxidative stress in a Sirt1-dependent manner. Oxy owns the potential to be a promising candidate against ALI.

Biomimetic Human Disease Model of SARS-CoV-2-Induced Lung Injury and Immune Responses on Organ Chip System.

Coronavirus disease 2019 (COVID‐19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The models that can accurately resemble human‐relevant responses to viral infection are lacking. Here, a biomimetic human disease model on chip that allows to recapitulate lung injury and immune responses induced by SARS‐CoV‐2 in vitro at organ level is created. This human alveolar chip reproduce the key features of alveolar‐capillary barrier by coculture of human alveolar epithelium, microvascular endothelium, and circulating immune cells under fluidic flow in normal and disease. Upon SARS‐CoV‐2 infection, the epithelium exhibits higher susceptibility to virus than endothelium. Transcriptional analyses show activated innate immune responses in epithelium and cytokine‐dependent pathways in endothelium at day 3 post‐infection, revealing the distinctive responses in different cell types. Notably, viral infection causes the immune cell recruitment, endothelium detachment, and increased inflammatory cytokines release, suggesting the crucial role of immune cells involved in alveolar barrier injury and exacerbated inflammation. Treatment with remdesivir can inhibit viral replication and alleviate barrier disruption on chip. This organ chip model can closely mirror human‐relevant responses to SARS‐CoV‐2 infection, which is difficult to be achieved by in vitro models, providing a unique platform for COVID‐19 research and drug development.