Research reveals mechanism linked to the worsening of Covid in lung and opens up chance of treatment

Brazilian researchers have discovered a mechanism linked to the worsening of Covid-19 in the lungs, opening up a new possibility for treatment. A study published in the scientific journal Biomolecules showed, for the first time, that the enzymatic activity and expression of two types of metalloproteinase, MMP-2 and MMP-8, were significantly increased in the lungs of critically ill patients infected with SARS-CoV-2.

This kind of “storm” of enzymes helps in the process of exacerbated inflammation of the lung, which ends up altering the organ’s functions. Normally, metalloproteinases (a group of enzymes that participate in the process of protein degradation) are important in healing and tissue remodeling, but with excessive production, it is as if they act to injure the lung.

Other studies had already proven that the hyperinflammatory response to Covid-19 is characterized by the cytokine “storm”, leading to acute respiratory distress syndrome (ARDS). Now, the group of scientists has unraveled a mechanism of deregulation of metalloproteinases, which may be associated with the formation of fibrosis in the organ, leaving sequelae in patients.

Tracheal aspirated fluid samples from 39 people hospitalized with severe cases of Covid-19, intubated in Intensive Care Units (ICUs) of Santa Casa and Hospital São Paulo, both in Ribeirão Preto, between June 2020 and January 2021 were analyzed. We also included 13 critically ill volunteers hospitalized, but for different clinical conditions, for the control group, in addition to proteome data from lung biopsies of individuals who died as a result of the disease.

“We found that metalloproteinases act by two mechanisms in the lung: by tissue injury and by modulating immunosuppression through the release of inflammatory mediators existing in the cell membrane, such as sHLA-G, an important mediator of immune response”, he explains to the Agency. Fapesp Carlos Arterio Sorgi, professor in the Department of Chemistry at the Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo (FFCLRP-USP), and one of the corresponding authors of the study.

Injury is caused when the tissue detects a noxious external stimulus or a foreign body. In these circumstances, inflammation occurs and, during this process, the scenario changes with the emergence of defense cells producing mediators that lead to uncontrolled oxidative stress.

On the USP campus in Ribeirão Preto, Sorgi is one of the coordinators of the ImunoCovid research consortium, a multidisciplinary coalition of 11 researchers from USP and the Federal University of São Carlos (UFSCar) who work collaboratively, sharing data and samples.

The consortium, supported by Fapesp, is led by Lúcia Helena Faccioli, a professor at 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 and 21/04590-3).

In addition, the group had the participation of Professor Raquel Fernanda Gerlach, from the Faculty of Dentistry of Ribeirão Preto, a specialist in metalloproteinases who shares the article’s correspondence. “The consortium sought this partnership to be able to answer the most complex questions that appeared in this case”, says Sorgi.

Results

By analyzing the samples, the researchers found that the rates of MMP-2 and MMP-8 were significantly higher in the tracheal aspirate of patients with Covid-19 compared to those not contaminated by SARS-CoV-2. In addition, individuals who died had a higher level of these active enzymes than those who survived.

During the action of metalloproteinases in the lung, molecules of the immune system are released from cell membranes, including sHLA-G and sTREM-1, responsible for causing immunosuppression in the organ. That is, instead of stimulating antiviral immunity, the virus ends up not facing resistance from the body.

In the research, the data demonstrated that sHLA-G and sTREM-1 levels were elevated in patients with Covid-19 and, after a series of tests, it was shown that MMP-2 was involved in the release of sHLA-G.

In 2020, another study by the ImunoCovid consortium had pointed out that monitoring the rates of sTREM-1 protein in plasma, from the first symptoms, would serve as an important tool to assist in the decision-making of health teams and as a predictor of evolution. and outcome of Covid-19 (read more).

According to the results published in Biomolecules, patients with the disease also showed an increase in the count of neutrophils (a type of leukocyte responsible for the body’s defense, capable of producing some metalloproteinases and reactive oxygen species) in the lung.

Although the molecular basis of SARS-CoV-2 immunopathology is still unknown, it is established that lung infection is associated with hyperinflammation and tissue damage. MMPs are crucial components of the processes that lead to pneumonia and the worsening of Covid-19 cases.

Until then, metalloproteinases had been studied as biomarkers for the disease, as was the case of an article published last year by another team of researchers from USP in Ribeirão Preto in the journal Biomedicine & Pharmacotherapy.

In the work published now, these molecules appear in the pathogenesis of the lung, as a potential therapeutic target. According to Sorgi, the idea is to continue the work by testing a metalloproteinase inhibitor associated with anti-inflammatory drugs in animal models to try to reverse the serious condition of Covid-19. One of these drugs is doxycycline, an antibiotic available in the Brazilian market and currently used to treat diseases such as typhoid fever and pneumonia.

“We will need to start from scratch. The idea is to set up a new project, including partnerships with international groups, to work with the animal model and then the clinical application”, says the professor.

The article 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 can be read at www.mdpi.com/2218-273X/12 /5/604/htm#.