Evaluation of the effects of administering a specific IL-17 inhibitor on the inflammatory process and the distribution of collagen types I, III, and V in the lung tissue of mice exposed to cigarette smoke.

• Grant number: 25/12894-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Fernanda Degobbi Tenorio Quirino dos Santos Lopes
• Grantee: Luan Henrique Vasconcelos Alves
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 24/13808-0 - The immunogenic role of type V collagen in the imbalance of Th17 and Treg responses in Chronic Obstructive Pulmonary Disease (COPD), AP.R

Abstract

There is evidence supporting the importance of autoimmune mechanisms in the progression of chronic obstructive pulmonary disease (COPD), as a consequence of the chronic inflammatory process induced by exposure to cigarette smoke. As the inflammatory process advances, the adaptive immune response mediated by Th17 lymphocytes plays a significant role, and its activation has been partly attributed to a failure in the regulation of inflammation by regulatory T cells (Tregs), through the release of the anti-inflammatory cytokine IL-10. Type V collagen (Col V) is a fibrillar collagen of the extracellular matrix (ECM), found in the lung interstitium and incorporated into heterotypic fibrils composed of types I and III collagens. These two types are the most abundant in lung tissue and are primarily responsible for the physical properties that determine the tissue's elasticity. Due to its location and its immunogenic and antigenic properties, Col V is considered a sequestered antigen, remaining hidden from the immune system under normal conditions. However, in cases of tissue damage, such as lung ECM injury induced by cigarette smoke exposure and the resulting chronic inflammation, Col V epitopes may become exposed to the immune system, potentially turning them into autoantigens. Some studies have already demonstrated that the use of a specific IL-17 inhibitor, a cytokine produced by Th17 lymphocytes, can attenuate damage to the lung parenchyma, a structural alteration that characterizes the presence of COPD.In order to better understand how Th17 response inhibition may interfere with the Th17/Treg imbalance and consequently with the process of pulmonary destruction and remodeling of the different collagen types in COPD, we will use C57BL/6 mice (6-8 weeks old), which will be exposed to cigarette smoke to induce COPD and will receive a neutralizing antibody against IL-17 (R&D Systems, Abingdon, UK). Four experimental groups will be established: the Smoke group, consisting of animals exposed to cigarette smoke; the Smoke + Anti-IL-17 group, consisting of animals exposed to cigarette smoke and treated with the IL-17 neutralizing antibody; the Control group, consisting of animals maintained under filtered room air; and the Control + Anti-IL-17 group, consisting of animals kept in filtered air and treated with the IL-17 neutralizing antibody. Respiratory mechanics will be evaluated, and histological analyses will be performed to assess the presence of enlargement in the distal airspaces and to quantify the expression of collagen types I, III, and V in both proximal and distal lung parenchyma. Additionally, flow cytometry will be used to assess the different populations of inflammatory cells involved in the Th17 and Treg responses in lung tissue homogenates. Part of these cells will also be analyzed in lung tissue sections by histology, especially in the peribronchovascular regions, where a higher density of inflammatory cells is known to occur in this experimental model.