AUTHOR=López-Cortés Andrés , Guerrero Santiago , Ortiz-Prado Esteban , Yumiceba Verónica , Vera-Guapi Antonella , León Cáceres Ángela , Simbaña-Rivera Katherine , Gómez-Jaramillo Ana María , Echeverría-Garcés Gabriela , García-Cárdenas Jennyfer M. , Guevara-Ramírez Patricia , Cabrera-Andrade Alejandro , Puig San Andrés Lourdes , Cevallos-Robalino Doménica , Bautista Jhommara , Armendáriz-Castillo Isaac , Pérez-Villa Andy , Abad-Sojos Andrea , Ramos-Medina María José , León-Sosa Ariana , Abarca Estefanía , Pérez-Meza Álvaro A. , Nieto-Jaramillo Karol , Jácome Andrea V. , Morillo Andrea , Arias-Erazo Fernanda , Fuenmayor-González Luis , Quiñones Luis Abel , Kyriakidis Nikolaos C. 

TITLE=Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.833174

DOI=10.3389/fphar.2022.833174

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood.</p><p><bold>Methods:</bold> Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth <italic>in silico</italic> analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials.</p><p><bold>Results:</bold> Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-<italic>κ</italic>B, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis.</p><p><bold>Conclusion:</bold> We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.</p>