Role of neutrophil extracellular traps and oxidative stress as targets of short-chain fatty acid effects in the exacerbation of SARS-CoV-2-induced chronic obstructive pulmonary disease in mice.

• Grant number: 25/01766-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: December 01, 2025
• End date: November 30, 2028
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Flávio Aimbire Soares de Carvalho
• Grantee: Fabiana Regina da Silva Olímpio
• Host Institution: Instituto de Ciência e Tecnologia (ICT). Universidade Federal de São Paulo (UNIFESP). Campus São José dos Campos. São José dos Campos , SP, Brazil
• Associated research grant: 23/11973-1 - Role of pro-inflammatory response and antiviral dysfunction as a target of butyrate in murine and human macrophages exposed to cigarette smoke and infected with SARS-CoV-2: Relevance to exacerbation of chronic obstructive pulmonary disease, AP.R

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory airway disease that affects millions of people worldwide and represents one of the leading causes of morbidity and mortality. Its exacerbation by respiratory infections, especially SARS-CoV-2, intensifies the inflammatory response and oxidative stress, contributing to clinical deterioration and poor outcomes. Recent evidence suggests that short-chain fatty acids (SCFAs), particularly butyrate a metabolite derived from bacterial fermentation in the gut, exhibit anti-inflammatory, antioxidant, epigenetic, and immunomodulatory properties. However, the molecular mechanisms by which butyrate modulates pulmonary inflammation exacerbated by viral infection in hosts with COPD remain poorly understood. Thus, this project aims to investigate the beneficial effects of butyrate on neutrophil extracellular traps (NETs), oxidative stress, and pulmonary and intestinal inflammatory responses, focusing on the GPR43/¿-arrestin signaling pathway, the Nrf2-HO-1 antioxidant axis, and histone deacetylase (HDAC) inhibition. To achieve this, an in vivo model of COPD exacerbation caused by SARS-CoV-2 will be used, along with an in vitro model using neutrophils derived from human bronchoalveolar lavage stimulated with cigarette smoke and exposed to SARS-CoV-2.It is expected that butyrate will act as an immunomodulatory agent by reducing NETs formation, activating the antioxidant axis, repressing pro-inflammatory signaling via NF-kB, and preserving the integrity of the pulmonary and intestinal epithelial barriers. The results will contribute to understanding the mechanism of action of butyrate on pulmonary inflammation, with emphasis on the role of neutrophils and the alterations in gut microbiota in a murine model of viral COPD exacerbation. Therefore, the findings from this proposal may support the development of new therapeutic strategies for COPD and other respiratory diseases associated with viral infection and gut dysbiosis. (AU)