Saquinavir plus methylprednisolone ameliorates experimental acute lung injury

Abstract

Glucocorticoid insensitivity is an important barrier to the treatment of several inflammatory diseases, including acute lung injury (ALI). Saquinavir (SQV) is an inhibitor of the human immunodeficiency virus protease, and the therapeutic effects of SQV in ALI accompanied with glucocorticoid insensitivity have not been previously investigated. In this study, the effects of SQV on lipopolysaccharide (LPS)-mediated injury in human pulmonary microvascular endothelial cells (HPMECs), human type I alveolar epithelial cells (AT I), and alveolar macrophages were determined. In addition, the effects of SQV on an LPS-induced ALI model with or without methylprednisolone (MPS) were studied. In LPS-stimulated HPMECs, SQV treatment resulted in a decrease of high mobility group box 1 (HMGB1), phospho-NF-κB (p-NF-κB), and toll-like receptor 4 (TLR4), and an increase of VE-cadherin. Compared to MPS alone, MPS plus SQV attenuated the decrease of glucocorticoid receptor alpha (GRα) and IκBα in LPS-stimulated HPMECs. HMGB1, TLR4, and p-NF-κB expression were also lessened in LPS-stimulated alveolar macrophages with SQV treatment. In addition, SQV reduced the injury in human AT I with a decrease of HMGB1 and p-NF-κB, and with an increase of aquaporin 5 (AQP 5). SQV ameliorated the lung injury caused by LPS in rats with reductions in vascular permeability, myeloperoxidase activity (MPO) and histopathological scores, and with lowered HMGB1, TLR4, and p-NF-κB expression, but with enhanced VE-cadherin expression. By comparison, SQV plus MPS increased GRα and IκBα in lung tissues of rats with ALI. This study demonstrated that SQV prevented experimental ALI and improved glucocorticoid insensitivity by modulating the HMGB1/TLR4 pathway.

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

“…They bind to nuclear receptors to reduce the release of proinflammatory cytokines. Steroids induce a reduction of NET formation in in vitro and vivo models [ 211 ]. Steroids also reduce the release of HMGB1 and its interaction with TLR4 [ 212 ] and modulate autophagy, inhibiting apoptosis and enhancing regulatory autophagosomes [ 212 , 213 ].…”

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…It is worthy of note that HIV protease inhibitors such as ritonavir, saquinavir, indinavir and lopinavir strongly reduce MMP-9 expression and/or activity in normal or cancer cells and in treated patients [ 20 , 169 , 170 , 171 , 172 , 173 , 174 ]. This is because HIV protease inhibitors repress the MAPK/ERK and/or PI3K/AKT signaling pathways, thereby functionally impairing transcription factors targeting the mmp-9 gene, including NF-kB, Specificity protein-1 or the Fra-1 element of the Activator Protein-1 transcriptional complex [ 164 , 169 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 ]. It should be noted that the AKT activation process starts when PI3K promotes the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3); this is followed by AKT recruitment to the cell membrane and AKT phosphorylation on Thr308 and Ser473 by the phosphoinosotide-dependent kinase-1 and the mammalian target of rapamycin, respectively [ 191 ].…”

[Retracted] Study on the Efficacy and Safety of Ambroxol Combined with Methylprednisolone in Patients with Acute Lung Injury

“…Methylprednisolone has strong anti-inflammatory and anti-immune effects. Early application of methylprednisolone can improve the body's tolerance to harmful factors, reduce severe inflammatory reaction caused by paraquat poisoning, reduce inflammatory exudation, and has an antifibrosis effect [ 8 , 9 ]. Previous studies have found that [ 10 ] high-dose ambroxol has an objective effect in the treatment of ALI caused by paraquat poisoning.…”