Effect of doxycycline, secretory leukocyte protease inhibitor (SLPI), inhaled aldosterone or gold nanoparticles treatment in a murine model of acute respiratory distress syndrome

• Grant number: 20/07212-7
• Support Opportunities: Regular Research Grants
• Duration: August 01, 2021 - July 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Stephen Fernandes de Paula Rodrigues
• Grantee: Stephen Fernandes de Paula Rodrigues
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Joilson de Oliveira Martins ; Wothan Tavares de Lima

Abstract

The acute respiratory distress syndrome (ARDS) is a disease that progresses quickly and is characterized mainly by pronounced lung edema and hypoxemia that lead to high morbidity and mortality rates. It is in great part caused by sepsis, pneumonia and, most recently, by the coronavirus disease 19 (COVID-19). Patients with ARDS require artificial ventilatory support in about 80% of the cases, enhancing then the hospitalization time. The pathophysiology of ARDS is complex and involves excessive inflammatory response, which leads to alveolar-capillary barrier damage and a consequent lung fluid accumulation (edema). Moreover, it is observed neutrophil, monocytes and epithelial cells infiltration in the lung parenchyma and release of proinflammatory mediators, such as cytokines, proteinases (including matrix metalloproteinases MMPs), reactive oxygen and nitrogen species (RONS) and coagulation factors, which are greatly responsible for the endothelial and lung epithelial cells death, enhancing then the alveolar-capillary barrier permeability. The gut-lung axis seems to play a role in the pathophysiology of ARDS as well, probably by enhancing the intestinal permeability and bacterial translocation. Those pulmonary alterations fully compromise the lung function of gas exchange. Today, there is no efficacious pharmacological treatment to manage the ARDS. Once doxycycline (Dox) is an antibiotic that also inhibits MMPs, the secretory leukocyte protease inhibitor (SLPI) is a modulator of the proteases activity and mitigates inflammation, aldosterone is a hormone which controls tissue fluid transport, and it was demonstrated 20 nm size citrate-capped gold nanoparticles (cit-AuNP) reduce inflammation and oxidative stress, we aim to test the efficacy of those drugs in diminishing the pulmonary alterations in a murine model of ARDS. Besides, it was demonstrated Dox, SLPI or cit-AuNP reduce intestinal permeability or bacterial translocation in experimental models of local acute insult. Thus, we will test the effect of those drugs in intestinal inflammatory parameters in mice with ARDS as well. Furthermore, once diabetes mellitus (DM) increases the risk of respiratory infections (e.g., measles, COVID-19, bacterial and fungal infections) and Dox owns potential of immediate reposition in the clinical practice, this drug will be also assayed in a group of animals with ARDS and DM combined. To do all that, C57BL/6 mice will be intratracheally injected with peptidoglycan (PPG) and lipoteichoic acid (LTA) solution. Mice will be randomly divided into different groups, according to the treatment, as follows: Dox, SLPI, aldosterone, or cit-AuNP. Those drugs will be given 2h after the PPG/LTA. DM will be induced by five consecutive days injection of streptozotocin (STZ) two weeks before induction of ARDS, and Dox treatment performed as mentioned above. The following parameters will be measured 24h after the PPG/LTA injection: respiratory mechanics, permeability of both the alveolar-capillary barrier and intestinal blood vessels, leukocyte adhesion in intestinal blood vessels, bronchoalveolar lavage cell count, histology of the lung, MMP-9 and MMP-2 activities, and lung and intestinal expression of pro-inflammatory and edematous proteins. Glucose blood levels will be measured in STZ-injected mice before induction of ARDS. (AU)