Adipose-derived stem cells and adipose-derived stem cell-conditioned medium modulate in situ imbalance between collagen I-and collagen V-mediated IL-17 immune response recovering bleomycin pulmonary fibrosis

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Felix, Renato Goncalves ^[1] ; Carvalho Bovolato, Ana Livia ^[1] ; Cotrim, Ondina Silvia ^[1] ; Leao, Patricia dos Santos ^[2] ; Batah, Sabrina Setembre ^[2] ; Golim, Marjorie de Assis ^[1] ; Velosa, Ana Paula ^[3] ; Teodoro, Walcy ^[3] ; Martins, Vanessa ^[4] ; Cruz, Fernanda Ferreira ^[5] ; Deffune, Elenice ^[1] ; Fabro, Alexandre Todorovic ^[2] ; Capelozzi, Vera Luiza ^[4]

Afiliação do(s) autor(es)

^[1] Sao Paulo State Univ, Botucatu Med Sch, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med, Rheumatol Div, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Dept Pathol, Av Dr Arnaldo 455, Sala 1143, BR-01246903 Sao Paulo, SP - Brazil

^[5] Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Lab Pulm Invest, Rio De Janeiro, RJ - Brazil

• Tipo de documento: Artigo Científico
• Fonte: HISTOLOGY AND HISTOPATHOLOGY; v. 35, n. 3, p. 289-301, MAR 2020.
• Citações Web of Science: 0

Resumo

The immunogenic collagen V (Col V) and the proinflammatory cytokine interleukin (IL)-17 have been implicated in the pathogenesis of multiple autoimmune diseases. Col V is also up-regulated during adipogencsis and can stimulate adipocyte differentiation in vitro. Conditioned medium (CM) generated from adipose-derived mesenchymal stem cells (MSCs) reduces bleomycin (BLM)-induced lung injury in rats, suggesting a crucial role in situ of immunomodulatory factors secreted by MSCs in these beneficial effects. In the present work, we investigated this hypothesis, analyzing levels of plasma inflammatory mediators and inflammatory and fibrotic mediators in the lung tissue of BLM-injured rats after treatment with MSCs and CM. Pulmonary fibrosis was intratracheally induced by BLM. After 10 days, BLM animals were further randomized into subgroups receiving saline, MSCs, or CM intravenously. On days 14 and 21, the animals were euthanized, and the lungs were examined through protein expression of nitric oxide synthase (NOS), IL-17, transforming growth factor-beta (TGF-beta), vascular endothelial growth factor, endothelin-1, and the immunogenic Col V through histological quantitative evaluation and plasma levels of fibrinogen, Von Willebrand factor, and platelet-derived growth factor (PDGF). Rats that had been injected with MSCs and CM showed a significant increase in weight and significant improvements at 14 and 21 days after intravenous injection at both time points of analysis of plasma fibrinogen, PDGF, and Von Willebrand factor and NOS-2 expression, supporting an early anti-inflammatory action, thus reducing TGF-beta and collagen I fibers. In contrast, intravenous injection of CM was able to significantly increase the deposition of Col V fibers and IL-17 on both day 14 and day 21 as compared with the amount observed in rats from the BLM group and MSC groups. In conclusion, this study reinforces previous observations on the therapeutic properties of MSCs and CM and is the first report to demonstrate the association of its actions with immunomodulatory biomarkers on lung tissue. We concluded that adipose-derived stem cells and adipose-derived stem cells-CM modulate an in situ imbalance between collagen I- and Col V-mediated IL-17 immune response, emerging as a promising therapeutic option for recovering from BLM pulmonary fibrosis. (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: 18/20403-6 - Marcadores biomoleculares de proliferação e remodelamento em doenças respiratórias agudas e crônicas: promissores alvos terapêuticos
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/14277-4 - Prognóstico e evolução clínica de novos e vigentes biomarcadores genéticos e protéicos em câncer de pulmão
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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