The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9

  • Cell Death Dis. 2021 Jan 11;12(1):67. doi: 10.1038/s41419-020-03320-0.
Yao Tong  1  2  3 ,  Zhuang Yu  3 ,  Zhixia Chen  1 ,  Renlingzi Zhang  3 ,  Xibing Ding  3 ,  Xiaohu Yang  3 ,  Xiaoyin Niu  4 ,  Mengzhu Li  4 ,  Lingling Zhang  4 ,  Timothy R Billiar  5 ,  Bruce R Pitt  6 ,  Quan Li  7
Affiliations
  • 1. Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China.
  • 2. Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200000, Shanghai, China.
  • 3. Department of Anesthesiology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China.
  • 4. Department of Anesthesiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China.
  • 5. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
  • 6. Department of Environmental and Occupational Health, University of Pittsburgh Graduate School Public Health, Pittsburgh, PA, 15219, USA.
  • 7. Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China. [email protected].
PMID: 33431821 DOI: 10.1038/s41419-020-03320-0
Abstract

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.

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