Молекулярно-генетические особенности патогенеза идиопатического легочного фиброза

Идиопатический легочный фиброз – тяжелая прогрессирующая интерстициальная болезнь л ких с распространенностью 2–29 случаев на 100 000 человек населения в мире. Значимым фактором риска заболевания является старение, механизмы развития которого задействованы в патогенезе идиопатического легочного фиброза. К ним относятся истощение теломер, геномная нестабильность, дисфункция митохондрий и потеря протеостаза. Важную роль в развитии идиопатического легочного фиброза играют также эпителиально-мезенхимальный переход, активация TGF-β и снижение экспрессии сиртуина SIRT7. Молекулярно-генетические исследования показали, что в патогенезе идиопатического легочного фиброза имеют значение мутации и полиморфизмы в генах муцина (MUC5B), в генах, ответственных за целостность теломер (TERC, TERT, TINF2, DKC1, RTEL1, PARN), генов сурфактанта (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2) и иммунной системы (IL1RN, TOLLIP), а также гаплотипы генов HLA (DRB1*15:01, DQB1*06:02). Перспективно изучение влияния на развитие болезни обратимых эпигенетических факторов, которые могут быть скорректированы таргетной терапией. Среди них с идиопатическим легочным фиброзом ассоциированы специфические микроРНК и длинные некодирующие РНК. Сделано предположение, что драйверным событием для идиопатического легочного фиброза служит дисрегуляция транспозонов, которые являются ключевыми источниками некодирующих РНК и влияют на механизмы старения. Это обусловлено тем, что при патологической активации транспозонов происходит нарушение регуляции генов, в эпигенетическом управлении которых участвуют происходящие от этих транспозонов микроРНК (в связи с комплементарностью нуклеотидных последовательностей). Анализ базы данных MDTE (miRNAs derived from Transposable Elements) позволил выявить 12 различных микроРНК, гены которых в эволюции возникли от транспозонов и ассоциированы с идиопатическим легочным фиброзом (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). Описаны взаимосвязи мобильных элементов с TGF-β, сиртуинами и теломерами, дисфункция которых вовлечена в патогенез идиопатического легочного фиброза. Новые данные об эпигенетических механизмах развития патологии могут стать основой для улучшения результатов таргетной терапии болезни с использованием в качестве мишени некодирующих РНК.

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