Possible Role of Matrix Metalloproteinases and TGF-β in COVID-19 Severity and Sequelae

Ramírez-Martínez, Gustavo; Jiménez-Álvarez, Luis Armando; Cruz‐Lagunas, Alfredo; Ignacio-Cortés, Sergio; Gómez-García, Itzel Alejandra; Rodríguez‐Reyna, Tatiana Sofía; Lugo-Goytia, Gustavo; Zúñiga, Joaquı́n

doi:10.1089/jir.2021.0222

Cited by 19 publications

(22 citation statements)

References 153 publications

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“…Under steady-state conditions, MMPs are poorly expressed in tissues. However, upon injury, inflammation, extracellular matrix turnover, and repair, their expression is enhanced ( 33 ). It has been also reported that overactivation of MMPs may contribute to the dengue pathogenesis and disease severity.…”

Section: Discussionmentioning

confidence: 99%

“…It has been also reported that overactivation of MMPs may contribute to the dengue pathogenesis and disease severity. In addition, few other studies reported that MMPs might significantly impact the pathogenesis of respiratory viral infections including MIS-C and COVID-19 ( 33 ). In addition, studies in adult COVID-19 have reported that circulating levels of MMP-7 are potential biomarkers of disease severity in patients requiring invasive mechanical ventilation ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

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Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

et al. 2022

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IntroductionMultisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases.MethodsTo elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations).ResultsChildren with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84–100% and specificity 80–100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels.DiscussionOur findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

et al. 2022

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“…Tissue damage during SARS-CoV-2 lung infection is associated with activation of members of the MMPs family ( 28 , 29 ). Targeting MMPs pathway has been proposed as therapeutic strategy to counterbalance the host marked pro-inflammatory response to the SARS-CoV-2 infection ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Circulating tissue inhibitor of metalloproteinases 1 (TIMP-1) at COVID-19 onset predicts severity status

et al. 2022

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BackgroundSystemic biomarkers for severity of SARS-CoV-2 infection are of great interest. In this study, we evaluated a set of collagen metabolites and extracellular matrix remodeling biomarkers including procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1) and hyaluronic acid (HA) as prognostic indicators in COVID-19 patients.MethodsNinety COVID-19 patients with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, and HA were measured and correlated with inflammatory indices and clinical variables. Patients were stratified for disease severity according to WHO criteria in two groups, based on the requirement of oxygen support.ResultsSerum TIMP-1, but not PIIINP and HA was significantly higher in patients with WHO score ≥5 compared to patients with WHO score <5 [PIIINP: 7.2 (5.4–9.5) vs. 7.1 (4.5–9.9), p = 0.782; TIMP-1: 298.1 (20.5–460) vs. 222.2 (28.5–452.8), p = 0.01; HA: 117.1 (55.4–193.7) vs. 75.1 (36.9–141.8), p = 0.258]. TIMP-1 showed moderate correlation with CRP (r = 0.312, p = 0.003) and with LDH (r = 0.263, p = 0.009). CRP and serum LDH levels were significantly higher in COVID-19 patients with WHO score ≥5 compared to the group of patients with WHO score < 5 [15.8 (9–44.5) vs. 9.3 (3.4–33.8), p = 0.039 and 373 (282–465) vs. 289 (218–383), p = 0.013, respectively].ConclusionIn patients with COVID-19, circulating TIMP-1 was associated with disease severity and with systemic inflammatory index, suggesting that TIMP-1 could represent a promising non-invasive prognostic biomarker in COVID-19 patients. Interestingly, our results prompted that serum TIMP-1 level may potentially be used to select the patients for therapeutic approaches targeting matrix metalloproteases pathway.

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“…Notably, we found that matrix metalloproteinase family members (MMPs), MMP8 and MMP27, were highly correlated. It has been reported that MMPs contribute to the COVID-19 severity (51–53). Taken together, our findings indicate the critical roles of S100 family members and other genes (e.g., MMPs) in the progression of COVID- 19.…”

Section: Resultsmentioning

confidence: 99%

Integrated analyses of single-cell RNA-seq public data reveal the gene regulatory network landscape of respiratory epithelial and peripheral immune cells in COVID-19 patients

Zhang

Nishi

Kinoshita

2023

Preprint

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Introduction: Infection with SARS-CoV-2 leads to coronavirus disease 2019 (COVID-19), which can result in acute respiratory distress syndrome and multiple organ failure. However, its comprehensive influence on pathological immune responses in the respiratory epithelium and peripheral immune cells is not yet fully understood. Methods: In this study, we integrated multiple public scRNA-seq datasets of nasopharyngeal swab and peripheral blood results to investigate the gene regulatory networks (GRNs) of healthy individuals and COVID-19 patients with mild/moderate and severe disease, respectively. Similar and dissimilar regulons were identified within or between epithelial and immune cells during COVID-19 severity progression. The relative transcription factors (TFs) and their targets were used to construct GRNs among different infection sites and conditions. Results: Between respiratory epithelial and peripheral immune cells, different TFs tended to be used to regulate the activity of a cell between healthy individuals and COVID-19 patients, although they had some TFs in common. For example, XBP1, FOS, STAT1, and STAT2 were activated in both the epithelial and immune cells of virus-infected individuals. In contrast, severe COVID-19 cases exhibited activation of CEBPD in peripheral immune cells, while CEBPB was exclusively activated in respiratory epithelial cells. Moreover, in patients with severe COVID-19, CEBPD upregulated S100A8 and S100A9 in CD14 and CD16 monocytes, while S100A9 genes were co-upregulated by different regulators (SPEDEF and ELF3) in goblet and squamous cells. The cell-cell communication analysis suggested that epidermal growth factor receptor signaling among epithelial cells contributes to mild/moderate disease, and chemokine signaling among immune cells contributes to severe disease. Conclusions: This study identified cell type- and condition-specific regulons in a wide range of cell types from the initial infection site to the peripheral blood, and clarified the diverse mechanisms of maladaptive responses to SARS-CoV-2 infection.

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Possible Role of Matrix Metalloproteinases and TGF-β in COVID-19 Severity and Sequelae

Cited by 19 publications

References 153 publications

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

Circulating tissue inhibitor of metalloproteinases 1 (TIMP-1) at COVID-19 onset predicts severity status

Integrated analyses of single-cell RNA-seq public data reveal the gene regulatory network landscape of respiratory epithelial and peripheral immune cells in COVID-19 patients

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