Tác động của các họa chất liên quan đến mầm bệnh vi khuẩn và virus (PAMPs) lên các bơm kháng đa thuốc (MDR) trong các tế bào nội mô não của hàng rào máu-não đang phát triển ở người

Springer Science and Business Media LLC - Tập 20 Số 1 - Trang 1-17 - 2023
Lye, Phetcharawan1,2, Bloise, Enrrico3, Matthews, Stephen G.1,2,4,5
1Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
3Departamento de Morfologia, Instituto de Ciências Biológicas, N3-292, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
4Department of Obstetrics & Gynaecology, University of Toronto, Toronto, Canada
5Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

Tóm tắt

Các bơm kháng đa thuốc (MDR), cụ thể là P-glycoprotein (P-gp, được mã hóa bởi ABCB1) và protein kháng ung thư vú (BCRP/ABCG2) đóng vai trò quan trọng trong hàng rào máu-não (BBB), bảo vệ não khỏi sự tiếp xúc với thuốc. Tác động của nhiễm trùng đến MDR trong hàng rào máu-não đang phát triển ở người vẫn chưa được xác định. Chúng tôi giả thuyết rằng sự tiếp xúc với các họa chất liên quan đến vi khuẩn và virus (PAMPs) sẽ làm thay đổi sự biểu hiện và hoạt động của MDR trong các tế bào nội mô não thai nhi (hfBECs) thu được từ các mạch mao mạch não ở giai đoạn đầu và giữa thai kỳ. Chúng tôi đã mô phỏng nhiễm trùng (4 giờ và 24 giờ) bằng các PAMP vi khuẩn, lipopolysaccharide (LPS; một ligand của thụ thể toll-like [TLR]-4) hoặc các PAMP virus, polyinosinic polycytidylic acid (Poly I:C; ligand TLR-3) và RNA đơn chuỗi (ssRNA; ligand TLR-7/8). Sự biểu hiện mRNA được đánh giá bằng qPCR, trong khi sự biểu hiện protein được đánh giá bằng Western blot hoặc miễn dịch huỳnh quang. Hoạt động của P-gp và BCRP được đánh giá bằng các thử nghiệm Calcein-AM và Chlorin-6. Các TLR-3, 4 và 8 được tìm thấy có biểu hiện trong các hfBECs thu được. Các tác nhân gây nhiễm đã mô phỏng tạo ra các phản ứng pro-inflammatory cụ thể cũng như những thay đổi trong sự biểu hiện P-gp/ABCB1 hoặc BCRP/ABCG2 (P < 0.05). LPS và ssRNA đã làm giảm đáng kể hoạt động P-gp ở 4 và 24 giờ trong giai đoạn đầu và giữa thai kỳ (P < 0.03 - P < 0.001), nhưng lại làm tăng đáng kể hoạt động BCRP trong hfBECs theo kiểu phụ thuộc vào liều (P < 0.05 - P < 0.002). Ngược lại, Poly-IC đã giảm đáng kể hoạt động P-gp sau 4 giờ trong giai đoạn đầu (P < 0.01) và giữa thai kỳ (P < 0.04), nhưng không phải ở 24 giờ, và không có tác động tổng thể lên hoạt động BCRP, mặc dù hoạt động BCRP đã tăng lên với liều cao nhất ở 24 giờ trong giai đoạn giữa thai kỳ (P < 0.05). Các PAMP gây nhiễm có tác động đáng kể đến sự biểu hiện và chức năng của các bơm MDR trong hfBECs, mặc dù các tác động là cụ thể về PAMP, thời gian và liều lượng. Kết luận, các nhiễm trùng vi khuẩn và virus trong thai kỳ có thể có những tác động sâu sắc đến sự tiếp xúc của não thai nhi với các cơ chất sinh lý và dược lý của P-gp và BCRP, dẫn đến việc thay đổi quỹ đạo phát triển não thai nhi.

Từ khóa

#kháng đa thuốc #bơm kháng đa thuốc #hàng rào máu-não #nội mô não thai nhi #mầm bệnh vi khuẩn #mầm bệnh virus #PAMPs #P-glycoprotein #protein kháng ung thư vú #nhiễm trùng #phản ứng sinh học.

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