Butylated hydroxytoluene induces type-V collagen and overexpression of remodeling genes/proteins in experimental lung fibrosis

Autor(es)

Martins, Vanessa ^[1] ; Teodoro, Walcy Rosolia ^[2] ; Velosa, Ana Paula Pereira ^[2] ; Andrade, Priscila ^[2] ; Farhat, Cecilia ^[1] ; Fabro, Alexandre Todorovic ^[3] ; Capelozzi, Vera Luiza ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Pathol, Fac Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Rheumatol Discipline, Fac Med, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: HISTOLOGY AND HISTOPATHOLOGY; v. 33, n. 10, p. 1111-1123, OCT 2018.
• Citações Web of Science: 1

Resumo

Anomalous histoarchitecture with increased levels of type-V collagen (Col V) in lungs of human idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM) airway-centered interstitial fibrosis suggest that this collagen can be a possible trigger involved in the pathogenesis of these diseases. Butylated hydroxytoluene (BHT) injury model revealed a distal involvement of lung parenchyma with significant endothelial injury and fibrotic response, contrasting with the BLM airway-centered insult. We undertook this study to analyze whether BHT alters distal airway/alveolar epithelial cells (AECs) and extracellular matrix (ECM) signaling involved in the initiation and progression of pulmonary fibrosis in a different pathway concerning overexpression of Col V. Female mice C57BL/6 (n=6) were instilled intraperitoneally with 400mg/kg of BHT dissolved in 1 mL of corn oil and euthanized at day 14 or 21 after BHT administration. Morphometry, immunohistochemistry and transmission electron microscopy were performed to characterize microscopic and submicroscopic changes of AECs and endothelial cells through transforming growth factor beta (TGF-beta) basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) expression. Immunofluorescence and immunogold electron microscopy were performed to characterize Col V. Quantitative polymerase chain reaction (qPCR) was used to confirm differential levels of RNA messenger. BHT lungs showed marked fibrotic areas and hyperplastic AECs. The alveolar damage caused destruction of elastic fibers and a critical increase of Col V in ECM of distal lung parenchyma. Fibrogenesis-promoting markers TGF-beta, bFGF and VEGF were also overexpressed in situ, coinciding with up-regulation in remodeling enzymes, growth factors, cytokines, transduction and transcription genes. BHT alters distal lung parenchyma signaling involved in pulmonary fibrosis highlighted similarities to human IPF in a pathway involving Col V arising as a promissory model to identify effective therapeutic targets. (AU)

• Processo FAPESP: 11/09181-2 - RELEVÂNCIA DO FIBROBLASTO NO REMODELAMENTO PARENQUIMATOSO PULMONAR EM MODELOS EXPERIMENTAIS DE FIBROSE INDUZIDA POR BLEOMICINA E 3-5-di-tert-4-hidroxitolueno (BHT)
• Beneficiário: Vanessa Martins da Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/03543-2 - Relevância do fibroblasto no remodelamento parenquimatoso pulmonar em modelos experimentais de fibrose induzida por bleomicina e 3-5-di-tert-4-hidroxitolueno (BHT)
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/07040-5 - Análise por imunofluorescência dos colágenos I, III, IV e V no modelo experimental de Fibrose Pulmonar induzido por Bleomicina
• Beneficiário: Deborah Bernardo Lopes
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica