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Doxycycline or leukocyte secretory protease inhibitor (SLPI) as potential therapy for acute distress syndrome in a murine model in the presence or absence of diabetes mellitus

Grant number: 22/13258-5
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): April 01, 2023
Effective date (End): July 31, 2024
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Stephen Fernandes de Paula Rodrigues
Grantee:Andressa Assunção dos Santos
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute respiratory distress syndrome (ARDS) is a disease with rapid onset and is featured by an excessive acute inflammatory process in the lung, resulting in alveolar edema and subsequent tissue hypoxia. It is often observed in diseases like pneumonia, sepsis, and more recently, the coronavirus disease 19 (COVID-19). The pathogenesis of ARDS involves the neutrophils and monocytes trafficking to the lung tissue, massive release of inflammatory and oxidant mediators, and proteases, including matrix metalloproteinases (MMPs), which contribute to the loss of surfactant, epithelial and endothelial cells apoptosis, alveolar edema, impairing gas exchange, and high rate of morbidity and mortality. Furthermore, the gut-lung axis seems to play a role in the pathophysiology of ARDS as well, possibly due to the bacterial translocation that occurs as result of the increased intestinal permeability. Despite the use of artificial ventilation and corticosteroids as only strategies to combat ARDS, part of patients does not respond to this treatment. In this context, we will test doxycycline (Dox), tetracycline with MMPs inhibitory activity, and the leukocyte secretory protease inhibitor (SLPI), a protein with known anti-inflammatory effects, in an experimental model of ARDS induced in C57Bl/6 mice. In addition, knowing that individuals with diabetes mellitus (DM) are at greater risk of being affected by respiratory infections, such as bacterial and viral pneumonia, influenza, and COVID-19, we will evaluate the possible therapeutic effect of Dox and SLPI in animals with DM and ARDS combined. ARDS induction will be performed by intratracheal injection of peptidoglycan (PPG) and lipoteichoic acid (LTA), Treatment will be performed 2h and 24h after injection of PPG and LTA. DM will be induced in adult mice by injecting streptozotocin (STZ) for five consecutive days, and ARDS will be obtained the same way described above, starting on the 15th day, i.e., after confirmation of hyperglycemia. The following parameters will be measured 48h after ARDS induction: respiratory mechanics, permeability of alveolar-capillary and intestinal vascular barriers, leukocyte adherence in intestinal blood vessels, cell count in bronchoalveolar lavage fluid and bone marrow, circulating leukocyte count, histological study of the lung, MMP-9/-2 activities, and expression of inflammatory/edematogenic proteins in the lung and intestine.

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