Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

巨噬细胞极化的不平衡在急性肺损伤 (ALI) 中起着不可或缺的作用，被认为是一个有希望的目标。基质金属蛋白酶 9 (MMP-9) 在巨噬细胞中表达，在分泌炎性细胞因子中起关键作用。我们报道了沙奎那韦 (SQV)，一种第一代人类免疫缺陷病毒蛋白酶抑制剂，限制了过度的炎症反应。然而，MMP-9 是否可以调节巨噬细胞极化并被 SQV 抑制仍然未知。我们关注巨噬细胞极化在 CLP（盲肠结扎穿刺）介导的 ALI 中的重要作用，并确定 SQV 部分通过抑制 MMP-9 维持 M2 而非 M1 表型的能力。我们还进行了一项有限的临床研究，以确定 MMP-9 是否是败血症的生物标志物。脂多糖 (LPS) 增加 MMP-9 表达，重组 MMP-9 (rMMP-9) 加剧 LPS 介导的 M1 转换。MMP-9 的小干扰 RNA 抑制了 LPS 介导的 M1 表型，而 SQV 对这种转换的抑制被 rMMP-9 逆转，表明 MMP-9 在介导 LPS 诱导的 M1 表型中起重要作用。这 14 名患者的外周血单核细胞中的 MMP-9 信使 RNA 水平与其临床评估相关。使用 SQV 进行 CLP 后死亡率和 ALI 显着剂量依赖性降低。SQV 显着抑制了 LPS 介导的 M1 表型，并增加了培养的 RAW 264.7 和原代鼠骨髓衍生巨噬细胞以及来自 CLP 处理小鼠的肺巨噬细胞的 M2 表型。