Endothelial Barrier Integrity Is Disrupted In Vitro by Heme and by Serum From Sickle Cell Disease Patients

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Gomes Santaterra, Vanessa Araujo ^[1] ; Luz Fiusa, Maiara Marx ^[1] ; Hounkpe, Bidossessi Wilfried ^[1] ; Chenou, Francine ^[1] ; Tonasse, Wouitchekpo Vincent ^[1] ; Gomes da Costa, Loredana Nilkenes ^{[2, 1]} ; Garcia-Weber, Diego ^[3] ; Domingos, Igor de Farias ^{[4, 5]} ; de Lima, Franciele ^[1] ; Borba-Junior, Ivanio Teixeira ^[1] ; Araujo, Aderson da Silva ^[6] ; Lucena-Araujo, Antonio Roberto ^[5] ; Cavalcante Bezerra, Marcos Andre ^[5] ; Nunes dos Santos, Magnun Nueldo ^[1] ; Costa, Fernando Ferreira ^{[1, 7]} ; Millan, Jaime ^[3] ; De Paula, Erich Vinicius ^{[1, 7]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Sch Med Sci, Campinas - Brazil

^[2] Univ Fed Piaui, Dept Biomed, Parnaiba - Brazil

^[3] Univ Autonoma Madrid, CSIC, Ctr Biol Mol Severe Ochoa, Madrid - Spain

^[4] Univ Fed Rio Grande do Norte, Dept Clin & Toxicol Anal, Natal, RN - Brazil

^[5] Univ Fed Pernambuco, Genet Postgrad Program, Recife, PE - Brazil

^[6] Fdn Pernambuco HEMOPE, Dept Internal Med Hematol & Hemotherapy, Recife, PE - Brazil

^[7] Univ Campirms, Hematol & Hemotherapy Ctr, Campinas - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 11, DEC 14 2020.
• Citações Web of Science: 0

Resumo

Free extracellular heme has been shown to activate several compartments of innate immunity, acting as a danger-associated molecular pattern (DAMP) in hemolytic diseases. Although localized endothelial barrier (EB) disruption is an important part of inflammation that allows circulating leukocytes to reach inflamed tissues, non-localized/deregulated disruption of the EB can lead to widespread microvascular hyperpermeability and secondary tissue damage. In mouse models of sickle cell disease (SCD), EB disruption has been associated with the development of a form of acute lung injury that closely resembles acute chest syndrome (ACS), and that can be elicited by acute heme infusion. Here we explored the effect of heme on EB integrity using human endothelial cell monolayers, in experimental conditions that include elements that more closely resemble in vivo conditions. EB integrity was assessed by electric cell-substrate impedance sensing in the presence of varying concentrations of heme and sera from SCD patients or healthy volunteers. Heme caused a dose-dependent decrease of the electrical resistance of cell monolayers, consistent with EB disruption, which was confirmed by staining of junction protein VE-cadherin. In addition, sera from SCD patients, but not from healthy volunteers, were also capable to induce EB disruption. Interestingly, these effects were not associated with total heme levels in serum. However, when heme was added to sera from SCD patients, but not from healthy volunteers, EB disruption could be elicited, and this effect was associated with hemopexin serum levels. Together our in vitro studies provide additional support to the concept of heme as a DAMP in hemolytic conditions. (AU)

• Processo FAPESP: 14/00984-3 - Doenças dos glóbulos vermelhos: fisiopatologia e novas abordagens terapêuticas
• Beneficiário: Fernando Ferreira Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/14172-6 - Investigação de aspectos fisiopatológicos e novas abordagens terapêuticas em doenças tromboembólicas
• Beneficiário: Joyce Maria Annichino-Bizzacchi
• Modalidade de apoio: Auxílio à Pesquisa - Temático