Роль ММП-2 и ММП-9 в реализации связи процессов воспаления, фиброза и апоптоза при прогрессировании неалкогольной жировой болезни печени и диагностическая значимость плазменного уровня их активных форм

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Матриксные металлопротеиназы ММП-2 и ММП-9 играют важную роль в патогенезе хронических заболеваний печени, участвуя в процессах воспаления и фиброза. Их роль в прогрессировании неалкогольной жировой болезни печени (НАЖБП) мало изучена. Проведен анализ уровней ММП-2, -9 в плазме крови пациентов с разными формами НАЖБП (стеатозом печени (СП) и неалкогольным стеатогепатитом (НАСГ) слабой (-СА), умеренной (-УА), высокой (-ВА) активности без выраженного фиброза), оценены корреляционные связи между уровнями ММП-2, -9 и мРНК генов MMP2, MMP9, ADAM17, NLRP3, активности каспазы 3 в лейкоцитах периферической крови (ЛПК), ФНОα, ИЛ-6, рИЛ-6Р, фрагментов цитокератина-18 в плазме. При СП уровни мРНК гена MMP2 в ЛПК и ММП-2 в плазме ниже, чем в контроле, и повышена экспрессия гена NLRP3 в ЛПК относительно других групп. При НАСГ-СА уровень ММП-9 выше, чем у контроля, СП, НАСГ-УА, что можно связать с активацией воспаления при трансформации СП в НАСГ. Плазменный уровень ММП-9 более 389,50 пг/мл диагностически значим для выявления НАСГ-СА среди пациентов СП (AUC ROC = 0,818; 95%-ный доверительный интервал равен 0,689–0,948; p < 0,001). При НАЖБП уровень ММП-9 может быть связан не только с воспалением, но и с апоптозом. Вероятно, определенную роль в этой связи играет ADAM17. При более высокой активности НАСГ усилен апоптоз гепатоцитов, повышен уровень активности каспазы 3 в ЛПК, уровень ММП-9 в крови снижен до уровня контроля и СП. При НАСГ-ВА уровень мРНК гена ADAM17 в ЛПК повышен по сравнению с контролем, НАСГ-СА и НАСГ-УА. Таким образом, ММП-2 и ММП-9 включены в патогенез НАЖБП уже на ранних стадиях, и их уровень в крови может быть связан с наличием и активностью воспаления в паренхиме печени.

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И. В. Курбатова

Карельский научный центр РАН

Автор, ответственный за переписку.
Email: irina7m@yandex.ru
Россия, 185910, Петрозаводск, Республика Карелия

Л. В. Топчиева

Карельский научный центр РАН

Email: irina7m@yandex.ru
Россия, 185910, Петрозаводск, Республика Карелия

О. П. Дуданова

Петрозаводский государственный университет

Email: irina7m@yandex.ru
Россия, 185910, Петрозаводск, Республика Карелия

А. А. Шиповская

Петрозаводский государственный университет

Email: irina7m@yandex.ru
Россия, 185910, Петрозаводск, Республика Карелия

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2. Рис. 1. Концентрация ММП-2 в плазме крови пациентов с НАЖБП и в контрольной группе. Данные представлены в виде: Q1–Q3, медиана, минимум, максимум. Указаны значения p, согласно U-критерию Манна–Уитни с поправкой Бонферрони

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3. Рис. 2. Концентрация ММП-9 в плазме крови пациентов с НАЖБП и в контрольной группе. Данные представлены в виде: Q1–Q3, медиана, минимум, максимум. Указаны значения p, согласно U-критерию Манна–Уитни с поправкой Бонферрони

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4. Рис. 3. ROC-кривая для концентрации ММП-9 в плазме пациентов НАСГ-СА относительно пациентов СП. AUC = 0,818 (95%-ный доверительный интервал 0,689–0,948); p < 0,001

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5. Рис. 4. Схема, отражающая предполагаемую связь изменения уровней ММП-2 и -9 и разных стадий НАЖБП. Объяснения в тексте; ↑ – увеличение; ↓ – уменьшение

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