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. 2022 Apr:148:112753.
doi: 10.1016/j.biopha.2022.112753. Epub 2022 Feb 25.

Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19

Jordana Grazziela A Coelho Dos Reis  1 , Geovane Marques Ferreira  2 , Alice Aparecida Lourenço  2 , Ágata Lopes Ribeiro  2 , Camila Pacheco da Silveira Martins da Mata  3 , Patrícia de Melo Oliveira  2 , Daisymara Priscila de Almeida Marques  2 , Linziane Lopes Ferreira  2 , Felipe Alves Clarindo  2 , Murillo Ferreira da Silva  4 , Heitor Portella Póvoas Filho  5 , Nilson Roberto Ribeiro Oliveira Jr  5 , Maisah Meyhr D'Carmo Sodré  6 , Sandra Rocha Gadelha  4 , George Rego Albuquerque  7 , Bianca Mendes Maciel  4 , Ana Paula Melo Mariano  4 , Mylene de Melo Silva  6 , Renato Fontana  4 , Lauro Juliano Marin  8 , Renata Santiago Alberto Carlos  9 , Amanda Teixeira Sampaio Lopes  6 , Fabrício Barbosa Ferreira  6 , Uener Ribeiro Dos Santos  10 , Íris Terezinha Santos de Santana  6 , Hllytchaikra Ferraz Fehlberg  6 , Rachel Passos Rezende  10 , João Carlos T Dias  10 , Eduardo Gross  10 , Gisele Assis Castro Goulart  11 , Marie Gabriele Santiago  11 , Ana Paula Motta Lavigne de Lemos  5 , Aline O da Conceição  10 , Carla Cristina Romano  5 , Luciana Debortoli de Carvalho  10 , Olindo Assis Martins Filho  12 , Claudio Almeida Quadros  13 , David L Morris  14 , Sarah J Valle  15
Affiliations

Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19

Jordana Grazziela A Coelho Dos Reis et al. Biomed Pharmacother. 2022 Apr.

Abstract

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation.

Method: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed.

Results: BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg.

Conclusion: These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.

Keywords: BromAc; COVID-19; Mucolytic therapy; SARS-CoV-2; Tracheal aspirate.

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Figures

Fig. 1
Fig. 1
Effect of BromAc® in tracheal aspirate samples from eight COVID-19 patients using flow through method. Volume of flow through in microliters is represented in scatter plots with median and interquartile range for a curve with 0, 125 and 250 µg of Bromelain in addition to 2% NAC (A). Visual aspect of tracheal aspirate sample before and after treatment BromAc® 250 μg (B). Correlation of mucolytic effect of BromAc® with tracheal aspirate sample cellularity. XY dispersion graphs demonstrate the results for cellularity including total cell count (C) and live cell count (D) according to volume of flow through in microliters. Tables on the right display the results of Pearson r coefficient, 95% confidence Interval as well as P value and P value summary.
Fig. 2
Fig. 2
Rheological measurements of tracheal aspirate samples from COVID-19 patients untreated (UN) and after treatment with N-Acetylcysteine (NAC), BromAc® 250 μg. Results plotted as scatter graphs over floating bars expressing minimum and maximum as well as the average line (A). Effect on viscosity as function of shear rate expressed in sec-1 (B) and along time expressed in minutes (C). Data are expressed as mean ± SEM. A value of p < 0.05 was considered to indicate statistically significant difference. Heatmap analysis demonstrating viscosity intensity in individual samples. Color key is provided in the figure showing highest (red) and lowest (blue) viscometry (cP) and Speed (rpm) (D). Asterisks identify statistical differences at p values: * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0,0001.(For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Effect of BromAc® in Chemokines present in tracheal aspirate sample from COVID-19 patients. Chemokine results were measured by Luminex and are plotted as scatter graphs over bars expressing average and standard deviation. Sputum from 10 COVID-19 patients were examined. Results are expressed in pg/mL and statistical differences at p < 0.05 were expressed as connecting lines and ( * ).
Fig. 4
Fig. 4
Effect of BromAc® in pro-inflammatory cytokines present in tracheal aspirates from COVID-19 patients. Cytokine results were measured by Luminex and are plotted as scatter graphs over bars expressing average and standard deviation. Sputum from 10 COVID-19 patients was examined. Results are expressed in pg/mL and statistical differences at p < 0.05 were expressed as connecting lines and ( * ).
Fig. 5
Fig. 5
Effect of BromAc® on growth factors present in tracheal aspirates from COVID-19 patients. The results for growth factors were measured by Luminex and are plotted as scatter graphs over bars expressing average and standard deviation. Sputum from 10 COVID-19 patients were assessed. Results are expressed in pg/mL and statistical differences at p < 0.05 were expressed as connecting lines and ( * ).
Fig. 6
Fig. 6
Effect of BromAc® in regulatory cytokines present in tracheal aspirates from COVID-19 patients. Cytokine results were measured by Luminex and are plotted as scatter graphs over bars expressing average and standard deviation. Data from 10 COVID-19 patients were tested. Results are expressed in pg/mL and statistical differences at p < 0.05 were expressed as connecting lines and ( * ).
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