Upregulation of Matrix Metalloproteinase‐9 Protects against Sepsis‐Induced Acute Lung Injury via Promoting the Release of Soluble Receptor for Advanced Glycation End Products
Abstract:Dysregulation of matrix metalloproteinase- (MMP-) 9 is implicated in the pathogenesis of acute lung injury (ALI). However, it remains controversial whether MMP-9 improves or deteriorates acute lung injury of different etiologies. The receptor for advanced glycation end products (RAGE) plays a critical role in the pathogenesis of acute lung injury. MMPs are known to mediate RAGE shedding and release of soluble RAGE (sRAGE), which can act as a decoy receptor by competitively inhibiting the binding of RAGE ligand… Show more
“…Etiologies such as sepsis were implicated in the activation of the RAGE-dependent NF-kB signaling cascade associated with inflammatory processes and oxidative stress [ 75 ]. Zhang H et al reported that MMP9 mediated the shedding of RAGE , and might exacerbate sepsis-associated pulmonary inflammation by controlling RAGE/NF-κB signaling [ 76 ]. MMP9 is also considered to be a macrophage gene [ 77 ], where its overexpression in the lung tissue of septic mice model correlates with our study.…”
Sepsis is a clinical syndrome with high mortality and morbidity rates. In sepsis, the abrupt release of cytokines by the innate immune system may cause multiorgan failure, leading to septic shock and associated complications. In the presence of a number of systemic disorders, such as sepsis, infections, diabetes, and systemic lupus erythematosus (SLE), cardiorenal syndrome (CRS) type 5 is defined by concomitant cardiac and renal dysfunctions Thus, our study suggests that certain mRNAs and unexplored pathways may pave a way to unravel critical therapeutic targets in three debilitating and interrelated illnesses, namely, sepsis, SLE, and CRS. Sepsis, SLE, and CRS are closely interrelated complex diseases likely sharing an overlapping pathogenesis caused by erroneous gene network activities. We sought to identify the shared gene networks and the key genes for sepsis, SLE, and CRS by completing an integrative analysis. Initially, 868 DEGs were identified in 16 GSE datasets. Based on degree centrality, 27 hub genes were revealed. The gProfiler webtool was used to perform functional annotations and enriched molecular pathway analyses. Finally, core hub genes (EGR1, MMP9, and CD44) were validated using RT-PCR analysis. Our comprehensive multiplex network approach to hub gene discovery is effective, as evidenced by the findings. This work provides a novel research path for a new research direction in multi-omics biological data analysis.
“…Etiologies such as sepsis were implicated in the activation of the RAGE-dependent NF-kB signaling cascade associated with inflammatory processes and oxidative stress [ 75 ]. Zhang H et al reported that MMP9 mediated the shedding of RAGE , and might exacerbate sepsis-associated pulmonary inflammation by controlling RAGE/NF-κB signaling [ 76 ]. MMP9 is also considered to be a macrophage gene [ 77 ], where its overexpression in the lung tissue of septic mice model correlates with our study.…”
Sepsis is a clinical syndrome with high mortality and morbidity rates. In sepsis, the abrupt release of cytokines by the innate immune system may cause multiorgan failure, leading to septic shock and associated complications. In the presence of a number of systemic disorders, such as sepsis, infections, diabetes, and systemic lupus erythematosus (SLE), cardiorenal syndrome (CRS) type 5 is defined by concomitant cardiac and renal dysfunctions Thus, our study suggests that certain mRNAs and unexplored pathways may pave a way to unravel critical therapeutic targets in three debilitating and interrelated illnesses, namely, sepsis, SLE, and CRS. Sepsis, SLE, and CRS are closely interrelated complex diseases likely sharing an overlapping pathogenesis caused by erroneous gene network activities. We sought to identify the shared gene networks and the key genes for sepsis, SLE, and CRS by completing an integrative analysis. Initially, 868 DEGs were identified in 16 GSE datasets. Based on degree centrality, 27 hub genes were revealed. The gProfiler webtool was used to perform functional annotations and enriched molecular pathway analyses. Finally, core hub genes (EGR1, MMP9, and CD44) were validated using RT-PCR analysis. Our comprehensive multiplex network approach to hub gene discovery is effective, as evidenced by the findings. This work provides a novel research path for a new research direction in multi-omics biological data analysis.
“…MMP9 is one of the key enzymes involved in the production of sRAGE. MMP9-mediated sRAGE production inhibited the RAGE/NF-κB activation and consequently reduced the severity of pulmonary edema, inflammation, and oxidative stress ( Zhang et al, 2021 ). During SARS-CoV-2 infection, patients showed increased expression of MMP9 compared to controls ( Gelzo et al, 2022 ).…”
Section: Discussionmentioning
confidence: 99%
“…Moreover, the extracellular domain of RAGE is cleaved by the metalloproteinases ADAM10 and metalloprotease 9 (MMP9), and the extracellular segment of RAGE is released, forming soluble RAGE (sRAGE) ( Metz et al, 2012 ). sRAGE acts as a decoy and binds to RAGE ligands, reducing RAGE activation ( Zhang et al, 2021 ). These processes form an elegant negative-feedback loop to contain RAGE concentrations and activation, and control the extent of inflammatory responses.…”
Human adenovirus (HAdV) infection causes excessive inflammation associated with severe tissue injury, such as pneumonia. The molecules involved in the underlying inflammatory mechanisms remain to be elucidated. Receptor for advanced glycation end product (RAGE) is mainly expressed on immune cells and lung tissues, and it is a key factor in the initiation and development of inflammation. RAGE can be cleaved by metalloprotease 9 (MMP9) to release the extracellular segment, which is named soluble RAGE (sRAGE), into the intercellular space, where it can bind to RAGE ligands and block RAGE activation and subsequent inflammation. In our study, we enrolled HAdV-infected patients and their contacts to examine the relationship between sRAGE and inflammation induced by HAdV infection. The results showed that HAdV infection stimulated inflammatory cytokine secretion, increased such as high mobility group box 1 (HMGB1) levels, and suppressed sRAGE expression. sRAGE levels were significantly different between patients with or without pneumonia. We also found that MMP9 was significantly lower in patients with pneumonia, and it was positively correlated with sRAGE levels over 7 days after disease onset. The mitogen-activated protein kinase (MAPK) pathway is an important immune activation signaling pathway that is regulated by RAGE. We observed the activation of the MAPK pathway in the peripheral blood mononuclear cells (PBMCs) of patients. Negative correlations between sRAGE and phosphorylated JNK and p38 were observed. These results suggest that sRAGE is involved in HAdV-induced inflammatory responses, and might be a potential therapeutic target to alleviate the HAdV-induced excessive inflammation.
“…Mechanistically, ROS contribute to the damage of the epithelial barrier. ROS-dependent induction of the matrix metalloproteinase (MMP)-9 causes damage, internalization, and downregulation of proteins of intercellular connections, so-called tight junctions [ 150 ], such as claudins, occludins, and E-cadherins, linking the extracellular glycocalyx with the intracellular cytoskeleton ( Figure 4 a) [ 151 , 152 ]. The loss of cell–cell interactions consequently is associated with an increase in permeability and gap formation [ 117 ], leading to edema formation [ 153 ].…”
Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.
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