The role of transforming growth factor β in COVID-19 lung injury: clinical and diagnostic parallels

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Abstract

BACKGROUND: Severe acute respiratory syndrome causes complex immune responses of hyperactivation of immunocompetent cells, including increased degranulation activity of mast cells and release of their secretome products. Mast cell granules may contain a lot of profibrotic enzymes and cytokines (chymase, tryptase, interleukin-4, 10, and 13) as well as growth factors. The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the body and the subsequent strong immune and inflammatory response and dysregulation of coagulation and fibrinolytic pathways cause massive activation of latent (inactive) transforming growth factor β (TGF-β) in the lungs and the latent pool of TGF-β in the blood of patients with coronavirus disease 2019 (COVID-19).

AIM: To evaluate the role of TGF-β in lung involvement in patients with COVID-19 by examining autopsy lung material, determining the quantitative level of TGF-β with further correlation analysis of clinical and laboratory parameters.

MATERIALS AND METHODs: The study included autopsy lung samples from patients who died from severe COVID-19. Autopsies were performed 2 days after the patients died. Autopsy material was collected for histology. Correlation analysis was performed between the number of TGF-β-positive cells and clinical and laboratory parameters.

RESULTS: Extensive representation of TGF-β positive cells was found in autopsy tissues. A negative correlation was found between the number of TGF-β-positive cells and the blood concentration of band neutrophils (r=−0.617; p=0.033); between the number of TGF-β-positive cells and the concentration of C-reactive protein according to blood chemistry (r=–0.491; p=0.013). A positive correlation was found between the number of TGF-β-positive cells and blood platelet concentration (r=0.384; p=0.012); the number of TGF-β-positive cells and erythrocyte sedimentation rate (r=0.409; p=0.025). A positive correlation was also found between the number of TGF-β-positive cells and the presence of a cough in the patient at the beginning of the hospital stay (r=0.367; p=0.046).

CONCLUSION: A correlation was found between the number of TGF-β-positive cells, neutrophil concentration, platelet concentration, erythrocyte sedimentation rate, C-reactive protein concentration, and the presence of cough in patients who died from severe COVID-19. These correlations suggest the negative role of TGF-β and the therapeutic possibilities of regulating its activation. Further studies in a larger number of patients are required.

About the authors

Andrey V. Budnevsky

Voronezh State Medical University

Email: budnev@list.ru
ORCID iD: 0000-0002-1171-2746
SPIN-code: 7381-0612

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Voronezh

Sergey N. Avdeev

The First Sechenov Moscow State Medical University

Email: serg_avdeev@list.ru
ORCID iD: 0000-0002-5999-2150
SPIN-code: 1645-5524

MD, Dr. Sci. (Medicine), Professor, Academician of the Russian Academy of Sciences

Russian Federation, Moscow

Evgeniy S. Ovsyannikov

Voronezh State Medical University

Email: ovses@yandex.ru
ORCID iD: 0000-0002-8545-6255
SPIN-code: 7999-0433

MD, Dr. Sci. (Medicine), Associate Professor, Professor

Russian Federation, Voronezh

Nadezhda G. Alekseeva

Voronezh State Medical University

Author for correspondence.
Email: nadya.alekseva@mail.ru
ORCID iD: 0000-0002-3357-9384
SPIN-code: 2284-2725

MD

Russian Federation, Voronezh

Oleg N. Choporov

Voronezh State Medical University

Email: onchoporov@vrngmu.ru
ORCID iD: 0000-0002-3176-499X
SPIN-code: 4294-9831

Dr. Sci. (Engineering), Professor

Russian Federation, Voronezh

Viktoria V. Shishkina

Voronezh State Medical University

Email: 4128069@gmail.ru
ORCID iD: 0000-0001-9185-4578
SPIN-code: 9339-7794

MD, Cand. Sci. (Medicine), Associate Professor

Russian Federation, Voronezh

Elena E. Ivanova

Voronezh State Medical University

Email: 89155888871@mail.ru
ORCID iD: 0000-0001-8920-8059
SPIN-code: 9608-2647

MD, Cand. Sci. (Medicine)

Russian Federation, Voronezh

Inna M. Perveeva

Voronezh State Medical University; Voronezh Regional Clinical Hospital No. 1

Email: perveeva.inna@yandex.ru
ORCID iD: 0000-0002-5712-9302
SPIN-code: 5995-6533

MD, Cand. Sci. (Medicine)

Russian Federation, Voronezh; Voronezh

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Supplementary files

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2. Fig. 1. Histotopographic features of TGF-β-positive cells in the bronchial wall (a) and in the alveolar septa (b, c) of patients with COVID-19: a — cells with positive expression of TGF-β are observed in the bronchial lumen, the bronchial mucosa is also infiltrated by TGF-β-positive cells; b — positive immune reaction of TGF-β by numerous macrophages; c — perivascularly localized TGF-β-positive cell; d — focal fibrotic areas of the lung (connective tissue fibers are colored blue); e, f — cellular representatives of fibroblastic differon in lung stroma remodeling sites. Staining techniques: a–c — immunohistochemical reaction with antibodies to transforming growth factor (anti-TGF-β; #ab215715; dilution 1:500; Abcam, UK), specific brown staining, nuclei were stained with Mayer’s hematoxylin, bar — 20 µm; d, f — staining by picro method Mallory, bar: d — 50 µm and f — 20 µm; e — staining by hematoxylin and eosin, bar — 20 µm.

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