Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia

Aguirre, Alina; Blázquez-Prieto, Jorge; Amado-Rodríguez, Laura; López-Alonso, Inés; Batalla-Solís, Estefanía; González-López, Adrián; Sánchez-Pérez, Moisés; Mayoral-Garcia, Carlos; Gutiérrez‐Fernández, Ana; Albaiceta, Guillermo M.

doi:10.1007/s00109-017-1510-z

Cited by 26 publications

(26 citation statements)

References 37 publications

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“…Apln + ECs may play an anti-inflammatory role required to maintain a balanced BM microenvironment. Apln + ECs show enriched expression of anti-inflammatory factors such as Mmp, Tgfb2, Nos3, and Ptgis (Aguirre et al, 2017;Bougaki et al, 2010;Jin et al, 2014;Manicone and McGuire, 2008;Dorris and Peebles, 2012;Knudsen et al, 1986). Accordingly, ablation of Apln + ECs leads to an increase of PB myeloid cells, which is a hallmark of numerous conditions with compromised BM function including aging, inflammation, or compromised stromal support (Kusumbe et al, 2016;Mann et al, 2018;Pietras, 2017;Tikhonova et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury

et al. 2019

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“…Blocking CALR activity attenuated murine acute lung injury by inducing polarization of M2 subtype macrophages, which are anti-inflammatory 57 . MMP14 was shown to trigger the anti-inflammatory proteolytic cascade to prevent lung injury in mice 58 . Interestingly, so far only a few studies have reported some biological functions of CGP-60474 59 – 61 .…”

Section: Discussionmentioning

confidence: 99%

Prediction of repurposed drugs for treating lung injury in COVID-19

Garmire

2020

F1000Res

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Background: Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Methods: Inhibition of angiotensin-converting enzyme 2 (ACE2) caused by the spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We performed drug repositioning analysis to identify drug candidates that reverse gene expression pattern in L1000 lung cell line HCC515 treated with ACE2 inhibitor. We confirmed these drug candidates by similar bioinformatics analysis using lung tissues from patients deceased from COVID-19. We further investigated deregulated genes and pathways related to lung injury, as well as the gene-pathway-drug candidate relationships. Results: We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19. Further bioinformatics analysis shows that 12 significantly enriched pathways (P-value <0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues. These include signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and chemokine signaling pathways. All 12 pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares 11 of 12 pathways with COL-3 and common target genes such as RHOA. It also uniquely targets other genes related to lung injury, such as CALR and MMP14. Conclusions: This study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have potential as repurposed drugs for its treatment.

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“…Recently, we have demonstrated that the matrix metalloproteinase MMP14 expression levels are strongly increased in the AT of obese mice ( Li and Zhao, 2020 ). Application of LPS substantially reduced the expression level of MMP14 in lungs; moreover, MMP14 -/- mice receiving LPS demonstrated 100% mortality connected with severe lung injury ( Aguirre et al, 2017 ). At the same time, MMP14 is strongly involved in amelioration of inflammation induced by endotoxins ( Aguirre et al, 2017 ).…”

Section: The Role Of the Angiotensin System For The Integral Viral Lomentioning

confidence: 99%

“…Application of LPS substantially reduced the expression level of MMP14 in lungs; moreover, MMP14 -/- mice receiving LPS demonstrated 100% mortality connected with severe lung injury ( Aguirre et al, 2017 ). At the same time, MMP14 is strongly involved in amelioration of inflammation induced by endotoxins ( Aguirre et al, 2017 ). Remarkably, ACE2 KO mice exacerbate Ang II-mediated inflammation and myocardial injury via substantial overexpression of MMP2, −9 and −14 ( Song et al, 2013 ), which can strongly degrade the extracellular and perivascular matrix.…”

Section: The Role Of the Angiotensin System For The Integral Viral Lomentioning

confidence: 99%

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral–bacterial interactions

Kruglikov¹,

Shah

Scherer

2020

eLife

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Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.

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Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia

Cited by 26 publications

References 37 publications

Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury

Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury

Prediction of repurposed drugs for treating lung injury in COVID-19

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral–bacterial interactions

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