The role of aging in the development of lung inflammation and fibrosis in COVID-19

• Grant number: 20/10281-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2021
• End date: January 31, 2023
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Thais Mauad
• Grantee: Thais Mauad
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Amaro Nunes Duarte Neto ; Ellen Caroline Toledo do Nascimento ; Fernanda Degobbi Tenorio Quirino dos Santos Lopes ; Leila Antonangelo ; Luiz Fernando Ferraz da Silva ; Luiz Vicente Ribeiro Ferreira da Silva Filho ; Marilia Cerqueira Leite Seelaender ; Marisa Dolhnikoff ; Paulo Hilário Nascimento Saldiva

Abstract

The elderly is disproportionately affected by the severe form of COVID-19, with increasing mortality according to the age group, reaching 20% in individuals over eighty years. The greater susceptibility is credited not only to the higher frequency of comorbidities, but also to the immunological changes associated with aging, such as activation of the innate immune system and deficiencies in the lymphocytic responses. The response to fibrotic and reparative stimuli is also altered in the elderly, with a higher collagen production after injuries. These changes appear to be mediated by several subcellular mechanisms, such as the lower expression of sirtuins, activation of the NLRP3 inflammasome and dysregulation in the mechanisms involved in the response to hypoxia. Changes in the viral receptors ACE2 and TMPRSS-2 that occur during different age groups also seem to influence the severity of the response to infection by COVID-19. Little is known about pulmonary aging and inflammatory cell changes in non-diseased lungs, and how these changes could affect COVID-19 severity. In this project we will study lung tissue obtained through minimally invasive autopsy in adult and elderly patients who died from COVID-19, from the Hospital das Clínicas of FMUSP, from March to June 2020. As controls we will study fragments of lung tissue from elderly patients and adults, who died due to non-pulmonary causes and lung tissue of patients who died from Acute Respiratory Discomfort Syndrome, also matched for age and duration of mechanical ventilation. The expression of viral receptors will be compared with lung tissue obtained through pediatric autopsies of deceased children without lung disease. Cellular and extracellular matrix markers will be studied by immunohistochemical method in lung tissue of patients who died from COVID-19. Using the Luminex technique on frozen fragments of lung tissue COVID-19, cytokines, chemokines, growth factors and matrix metallopreoteases will be quantified. By the PCR technique, the genes involved in the NLRP3 inflammasome route and hypoxia-inducible factor 1 (HIF-1) will be quantified. This data set will allow a better understanding of COVID's inflammatory and fibrotic processes and the influence of lung aging on these processes. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

JOÃO CARLOS GEBER JÚNIOR; RENATA APARECIDA DE ALMEIDA MONTEIRO; JOÃO WILSON PEDRO DA ROCHA; EDSON LUIZ TÁRSIA DUARTE; ELIZABETE NICODEMO; OLAVO MUNHOZ; EDISON FERREIRA DE PAIVA; THAIS MAUAD; LUIZ FERNANDO FERRAZ DA SILVA; PAULO HILARIO NASCIMENTO SALDIVA; et al. What else in times of COVID-19? The role of minimally invasive autopsy for the differential diagnosis of acute respiratory failure in a case of kala-azar. Revista do Instituto de Medicina Tropical de São Paulo, v. 65, 2023-06-02. (20/10281-0)