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Matrix Metalloproteinases on Severe COVID-19 Lung Disease Pathogenesis: Cooperative Actions of MMP-8/MMP-2 Axis on Immune Response through HLA-G Shedding and Oxidative Stress.

ABSTRACT: Patients with COVID-19 predominantly have a respiratory tract infection and acute lung failure is the most severe complication. While the molecular basis of SARS-CoV-2 immunopathology is still unknown, it is well established that lung infection is associated with hyper-inflammation and tissue damage. Matrix metalloproteinases (MMPs) contribute to tissue destruction in many pathological situations, and the activity of MMPs in the lung leads to the release of bioactive mediators with inflammatory properties. We sought to characterize a scenario in which MMPs could influence the lung pathogenesis of COVID-19. Although we observed high diversity of MMPs in lung tissue from COVID-19 patients by proteomics, we specified the expression and enzyme activity of MMP-2 in tracheal-aspirate fluid (TAF) samples from intubated COVID-19 and non-COVID-19 patients. Moreover, the expression of MMP-8 was positively correlated with MMP-2 levels and possible shedding of the immunosuppression mediator sHLA-G and sTREM-1. Together, overexpression of the MMP-2/MMP-8 axis, in addition to neutrophil infiltration and products, such as reactive oxygen species (ROS), increased lipid peroxidation that could promote intensive destruction of lung tissue in severe COVID-19. Thus, the inhibition of MMPs can be a novel target and promising treatment strategy in severe COVID-19.

SUBMITTER: da Silva-Neto PV

PROVIDER: S-EPMC9138255 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Matrix Metalloproteinases on Severe COVID-19 Lung Disease Pathogenesis: Cooperative Actions of MMP-8/MMP-2 Axis on Immune Response through HLA-G Shedding and Oxidative Stress.

da Silva-Neto Pedro V PV do Valle Valéria B VB Fuzo Carlos A CA Fernandes Talita M TM Toro Diana M DM Fraga-Silva Thais F C TFC Basile Patrícia A PA de Carvalho Jonatan C S JCS Pimentel Vinícius E VE Pérez Malena M MM Oliveira Camilla N S CNS Rodrigues Lilian C LC Bastos Victor A F VAF Tella Sandra O C SOC Martins Ronaldo B RB Degiovani Augusto M AM Ostini Fátima M FM Feitosa Marley R MR Parra Rogerio S RS Vilar Fernando C FC Gaspar Gilberto G GG Rocha José J R da JJRD Feres Omar O Arruda Eurico E Maruyama Sandra R SR Russo Elisa M S EMS Viana Angelina L AL Santos Isabel K F M IKFM Bonato Vânia L D VLD Cardoso Cristina R B CRB Tanus-Santos Jose E JE Donadi Eduardo A EA Faccioli Lucia H LH Dias-Baruffi Marcelo M Fernandes Ana P M APM Gerlach Raquel F RF Sorgi Carlos A CA On Behalf Of The Immunocovid Study Group

Biomolecules 20220419 5

Patients with COVID-19 predominantly have a respiratory tract infection and acute lung failure is the most severe complication. While the molecular basis of SARS-CoV-2 immunopathology is still unknown, it is well established that lung infection is associated with hyper-inflammation and tissue damage. Matrix metalloproteinases (MMPs) contribute to tissue destruction in many pathological situations, and the activity of MMPs in the lung leads to the release of bioactive mediators with inflammatory ...[more]

PMID: 35625532

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Project description:BackgroundThe alveolar epithelium is protected by a heparan sulfate-rich, glycosaminoglycan layer called the epithelial glycocalyx. It is cleaved in patients with acute respiratory distress syndrome (ARDS) and in murine models of influenza A (IAV) infection, shedding fragments into the airspace from the cell surface. Glycocalyx shedding results in increased permeability of the alveolar-capillary barrier, amplifying acute lung injury. The mechanisms underlying alveolar epithelial glycocalyx shedding in IAV infection are unknown. We hypothesized that induction of host sheddases such as matrix metalloproteinases (MMPs) during IAV infection results in glycocalyx shedding and increased lung injury.Materials and methodsWe measured glycocalyx shedding and lung injury during IAV infection with and without treatment with the pan-MMP inhibitor Ilomastat (ILO) and in an MMP-7 knock out (MMP-7KO) mouse. C57BL/6 or MMP-7KO male and female mice were given IAV A/PR/8/34 (H1N1) at 30,000 PFU/mouse or PBS intratracheally. For some experiments, C56BL/6 mice were infected in the presence of ILO (100mg/kg) or vehicle given daily by IP injection. Bronchoalveolar lavage (BAL) and lung tissue were collected on day 1, 3, and 7 for analysis of glycocalyx shedding (BAL Syndecan-1) and lung injury (histology, BAL protein, BAL cytokines, BAL immune cell infiltrates, BAL RAGE). Expression and localization of the sheddase MMP-7 and its inhibitor TIMP-1 was examined by RNAScope. For in vitro experiments, MLE-12 mouse lung epithelial cells were cultured and treated with active or heat-inactivated heparinase (2.5 U/mL) prior to infection with IAV (MOI 1) and viral load and MMP-7 and TIMP-1 expression analyzed.ResultsIAV infection caused shedding of the epithelial glycocalyx into the BAL. Inhibition of MMPs with ILO reduced glycocalyx shedding by 36% (p = 0.0051) and reduced lung epithelial injury by 40% (p = 0.0404). ILO also reduced viral load by 68% (p = 0.027), despite having no significant effect on lung cytokine production. Both MMP-7 and its inhibitor TIMP-1 were upregulated in IAV infected mice: MMP-7 colocalized with IAV, while TIMP-1 was limited to cells adjacent to infection. However, MMP-7KO mice had similar glycocalyx shedding, epithelial injury, and viral load compared to WT littermates, suggesting redundancy in MMP sheddase function in the lung. In vitro, heparinase treatment before infection led to a 52% increase in viral load (p = 0.0038) without altering MMP-7 or TIMP-1 protein levels.ConclusionsGlycocalyx shedding and MMPs play key roles in IAV-induced epithelial injury, with significant impact on IAV viral load. Further studies are needed to understand which specific MMPs regulate lung epithelial glycocalyx shedding.

Project description:Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ?95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than 40 years old, the second group ranging from 40 to 64 years old, the third group ranging from 65 to 89 years old, the fourth group ranging from 90 to 94 years old, and the fifth group with subjects more than 95 years old. A relationship was observed between LLIs and MMP-2, but not between LLIs and MMP-9. However, in the LLI group, MMP-2 and MMP-9 values were significantly correlated. Furthermore, in LLIs, we found a positive correlation of MMP-2 with the antioxidant catabolite uric acid and a negative correlation with the inflammatory marker C-reactive protein. Finally, in LLIs MMP-9 values correlated directly both with cholesterol and with low-density lipoproteins. On the whole, our data suggest that the observed increase of MMP-2 in LLIs might play a positive role in the attainment of longevity. This is the first study that shows that serum activity of MMP-2 is increased in LLIs as compared to younger subjects. As far as we are concerned, it is difficult to make wide-ranging conclusions/assumptions based on these observations in view of the relatively small sample size of LLIs. However, this is an important starting point. Larger-scale future studies will be required to clarify these findings including the link with other systemic inflammatory and antioxidant markers.

Dataset Information

Matrix Metalloproteinases on Severe COVID-19 Lung Disease Pathogenesis: Cooperative Actions of MMP-8/MMP-2 Axis on Immune Response through HLA-G Shedding and Oxidative Stress.

Publications

Matrix Metalloproteinases on Severe COVID-19 Lung Disease Pathogenesis: Cooperative Actions of MMP-8/MMP-2 Axis on Immune Response through HLA-G Shedding and Oxidative Stress.

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