Recilisib Sodium

Sepsis-induced lung injury is an acute hypoxic respiratory insufficiency caused by systemic infectious factors that results in alveolar epithelial cell and capillary endothelial cell injury, diffuse pulmonary interstitial edema, and alveolar edema. Heme oxygenase (HO)-1 is usually associated with inflammation and has anti-inflammatory effects. Autophagy is a degradation pathway that eliminates cellular metabolic waste and plays an important protective role during stress. The phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) signaling pathway plays a key role in mediating cellular responses to inflammatory reactions. Therefore, we hypothesized that HO-1 is associated with autophagy and regulated by the PI3K/Akt signaling pathway in mice with sepsis-induced lung injury. Sepsis-induced lung injury was induced in mice using cecal ligation and puncture (CLP). Hemin or Sn-protoporphyrin IX (SnPP) was administered via intraperitoneal injection before surgery. Survival rates were observed during days 1-7 after the surgery; lung histology was discerned 24 h after the surgery; pro-inflammatory and anti-inflammatory factors in plasma and lung tissue were measured using enzyme-linked immunosorbent assay (ELISA); HO-1, Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, p62 and lysosome associated membrane protein (LAMP)2 protein expression levels were measured 24 h after the surgery; HO-1 and LC3B-II protein expression levels were observed using immunofluorescence 24 h after the surgery; and autophagosomes were detected using electron microscopy 24 h after the surgery. Furthermore, when PI3K inhibitors LY294002, PI3K activators Recilisib and hemin were administered before the surgery, Akt, p-Akt, HO-1, and LC3-II levels were measured 24 h post-surgery. We found that HO-1 overexpression increased the survival rate and inhibited sepsis-induced lung injury. HO-1 overexpression attenuated the levels of proinflammatory cytokines (TNF-α, IL-1β) and increased the anti-inflammatory cytokine (IL-10, HO-1) overexpression. Moreover, HO-1 overexpression was also associated with increased expression of Beclin-1, LC3B-II and LAMP2 protein expression; decreased p62 protein expression; and significantly increased autophagosome formation. The results for HO-1-downregulated mice contrasted with those mentioned above. LY294002 inhibited p-Akt/Akt, HO-1, and LC3B-II protein expression; and hemin reversed the inhibitory effect of LY294002. The protective effect of HO-1 was involved in the mediation of autophagy, which may be regulated by the PI3K/Akt signaling pathway during sepsis-induced lung injury in mice.

The disruption of the blood-brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior.