Inhibitor of nuclear factor-κB, SN50, attenuates lipopolysaccharide-induced lung injury in an isolated and perfused rat lung model

NF-kappa B cell permeable inhibitory peptide (SN50) inhibits translocation of nuclear factor-kappa B (NF-kappa B) and production of inflammatory cytokines that are implicated in lipopolysaccharide (LPS)-induced lung injury (LPSLI). However, the protective effect of SN50 in LPSLI is unclear. We explored the cellular and molecular mechanisms of SN50 treatment in LPSLI. LPSLI was induced by intratracheal instillation of 10 mg/kg LPS using an isolated and perfused rat lung model. SN50 was administered in the perfusate 15 minutes before LPS was administered. Hemodynamics, lung histologic change, inflammatory responses, and activation of apoptotic pathways were evaluated. After LPSLI, increased pulmonary vascular permeability and lung weight gain was observed. The levels of interleukin (11)-1/beta, tumor necrosis factor (TNF)-alpha, myeloperoxidase, and macrophage inflammatory protein-2 increased in bronchoalveolar lavage fluids. Lung-tissue expression of TNF-alpha, IL-1 beta, mitogen-activated protein kinases (MAPKs), caspase-3, p-AKT (serine-threonine kinase, also known as protein kinase B), and plasminogen activator inhibitor-1 (PAI-1) was greater in the LPS group compared with controls. Upregulation and activation of NF-kappa B was associated with increased lung injury in LPSLI. SN50 attenuated the inflammatory responses, including expression of IL-1 beta, TNF-alpha, myeloperoxidase, MAPKs, PAI-1, and NF-kappa B; downregulation of apoptosis indicated by caspase-3 and p-AKT expression was also observed. In addition, SN50 mitigated the increase in the lung weight, pulmonary vascular permeability, and lung injury. In conclusion, LPSLI is associated with inflammatory responses, apoptosis, and coagulation. NF-kappa B is an important therapeutic target in the treatment of LPSLI. SN50 inhibits translocation of NF-kappa B and attenuates LPSLI.