A study of worsening COVID-19 in the lungs paves the way for treatment

Brazilian researchers have discovered a mechanism associated with worsening COVID-19 in the lungs, opening up a new possibility for treatment. Study published in the scientific journal biomolecules showed for the first time that the enzyme activity and expression of two types of metalloproteinases, MMP-2 and MMP-8, were significantly increased in the lungs of critically ill patients infected with SARS-CoV-2.

Such a “storm” of enzymes helps with worsening inflammation of the lungs, leading to changes in the body’s functions. Normally, metalloproteinases (a group of enzymes involved in the process of breaking down proteins) are important in healing and tissue regeneration, but with overproduction they appear to damage the lungs.

Other studies have already shown that the hyperinflammatory response to COVID-19 is characterized by a cytokine “storm” leading to acute respiratory distress syndrome (ARDS). Now, a team of scientists has uncovered a mechanism for deregulating metalloproteinases that may be involved in the formation of fibrosis in the organ, leaving traces on patients.

Tracheal aspirated fluid samples from 39 people hospitalized for serious COVID-19 cases and intubated in the intensive care units of Santa Casa and São Paulo, both in Ribeirão Preto between June 2020 and January 2021, were analyzed. We also included 13 people. critically ill volunteers in hospital, but due to different clinical conditions, in the control group, in addition to proteomic data from lung biopsies from individuals who died as a result of the disease.

“We found that metalloproteinases act in the lung by two mechanisms: tissue damage and modulating immunosuppression by releasing inflammatory mediators in the cell membrane, such as sHLA-G, an important mediator of the immune response,” he explains. FAPESP agency Carlos Arterio SorgiProfessor at the Department of Chemistry (FFCLRP-USP) of the Faculty of Philosophy, Science and Literature of the University of São Paulo, Ribeirão Preto, and one of the corresponding authors of the study.

Damage occurs when the tissue detects a harmful external stimulus or foreign body. Under these conditions, inflammation occurs, and during this process, the scenario changes as defense cells emerge that produce neurotransmitters that lead to uncontrolled oxidative stress.

At the USP campus in Ribeirão Preto, Sorgi is one of the coordinators of the ImunoCovid research consortium, a multidisciplinary coalition of 11 researchers from the USP and the Federal University of São Carlos (UFSCar) working together to share data and samples.

The consortium, supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), is led by Lucia Helena Faccioli, A professor at the FCLRP-USP who also signs the article. The work received funding through six projects (20 / 05207-6, 14 / 07125-6, 20 / 08534-8, 20 / 05270-0, 14 / 23946-0, 21 / 04590-3).

In addition, a teacher was present in the group Raquel Fernanda Gerlach, Ribeirão Preton Faculty of Dentistry, metalloproteinase expert who shares article correspondence. “The consortium is looking for this partnership to be able to answer the most complex questions that have arisen in this case,” Sorgi says.

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Analyzing the samples, the researchers found that the levels of MMP-2 and MMP-8 were significantly higher in the trachea of ​​COVID-19 patients compared to patients not contaminated with SARS-CoV-2. In addition, the dead had higher levels of these active enzymes than the survivors.

During the action of metalloproteinases in the lungs, molecules of the immune system, including sHLA-G and STREM-1, which are responsible for causing immunosuppression in the organ, are released from the cell membranes. In other words, instead of stimulating anti-viral immunity, the virus does not confront the body’s resistance.

Data from the study indicated that sHLA-G and STREM-1 levels were elevated in COVID-19 patients, and after several tests, MMP-2 was shown to be involved in sHLA-G release.

Another study by the ImunoCovid consortium in 2020 found that monitoring STREM-1 plasma levels from the onset of symptoms would be an important tool in health team decision-making and a predictor of the development and consequences of COVID-19 (Read more at: agentia.fapesp.br/34265/).

According to the results published in biomoleculespatients with the disease also had an increased number of neutrophils (a type of leukocyte responsible for the body’s defenses that can produce some metalloproteinases and reactive oxygen species) in the lungs.

Although the molecular basis of SARS-CoV-2 immunopathology is not yet known, lung infection has been shown to be associated with hyperinflammation and tissue damage. MMPs are key components in the processes leading to pneumonia and exacerbation of COVID-19 cases.

Until then, metalloproteinases had been studied as biomarkers of disease, as was done published article last year, another group of USP researchers from Ribeirão Pretosta in the journal Biomedicine and pharmacotherapy.

In the present work, these molecules are present in the pathogenesis of the lungs as a potential therapeutic target. According to Sorg, the idea is to continue working by testing an anti-inflammatory metalloproteinase inhibitor in animal models to reverse the severe state of COVID-19. One of these drugs is doxycycline, an antibiotic available on the Brazilian market that is currently used to treat diseases such as typhoid and pneumonia.

“We have to start from scratch. The idea is to set up a new project that involves partnerships with international teams, to work on an animal model and then a clinical application,” the professor says.

Article Matrix metalloproteinases in the severe pathogenesis of COVID-19 lung disease: MMP-8 / MMP-2 axis cooperative response to the immune response through HLA-G release and oxidative stress can be read at: www.mdpi.com/2218-273X/12/5/604/htm#.

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