Механизмы защитного действия мезенхимальных мультипотентных стромальных клеток при экспериментальном остром пиелонефрите тема диссертации и автореферата по ВАК РФ 03.03.04, кандидат биологических наук Пулькова, Наталья Владимировна

• Пулькова, Наталья Владимировна
• кандидат биологических наук
• 2013

Оглавление диссертации кандидат биологических наук Пулькова, Наталья Владимировна

Введение.

Обзор литературы.

Пиелонефрит.

Медицинские аспекты пиелонефрита.

Моделирование пиелонефрита.

Механизмы развития пиелонефрита.

Цитокины, хемокины и молекулы клеточной адгезии в развитии пиелонефрита.

Роль толл-подобных рецепторов в развитии пиелонефрита.

Иммунологические реакции при пиелонефрите.

Активные формы кислорода и азота при воспалении.

Ишемическое и фармакологическое прекондиционирование.

Матриксные металлопротеиназы.

Применение стволовых клеток для лечения почечных патологий.

Биология стволовых клеток.

Типы стволовых клеток, используемых для нефропротекции.

Влияние ММСК на воспалительный процесс.

Общая характеристика ММСК.

Миграционная способность ММСК.

Иммуномодулирующие свойства ММСК.

Влияние ММСК на активность матриксных металлопротеиназ.

Материалы и методы исследования.

Материалы.

Методы.

Эксперименты на культурах клеток.

Получение и ведение культуры мезенхимальных мультипотентных стромальных клеток.

Выделение лейкоцитов из периферической крови.

Инкубация культуры ММСК с лейкоцитами и ЛПС или LiCI.

Микроскопическое исследование клеток.

Оценка продукции активных форм кислорода.

Проточная цитофлуориметрия.

Оценка продукции оксида азота.

Оценка митохондриального трансмембранного потенциала.

Иммуноцитохимия (адгезивные и суспензионные клетки).

Определение активности матриксных металлопротеиназ.

Мечение клеток кальцеином зеленым и микрочастицами оксида железа

Оценка миграции клеток in vitro.

Эксперименты на животных.

Моделирование острого пиелонефрита у крыс.

Приготовление инокулята фекальных бактерий крыс.

Определение количества малонового диальдегида в тканях почек.

Определение продукции фактора некроза опухоли и нитрата/нитрита.

Определение активности миелопероксидазы в тканях почек.

Оценка интенсивности флуоресценции кальцеина в тканях почек.

Гистологическое исследование почек.

Гематологический и биохимический анализ крови крыс.

Определение числа лейкоцитов в суточной моче крыс.

Определение концентрации белка.

Иммуноблоттинг.

Статистика.

Результаты.

Влияние ММСК на окислительный стресс и развитие воспаления при экспериментальном остром пиелонефрите.

Влияние ММСК на морфологические изменения в почке после индукции острого пиелонефрита у крыс.

Миграция экзогенных ММСК в ткани поврежденной почки.

Влияние активированных лейкоцитов на ММСК в культуре.

Сокультивирование с лейкоцитами индуцирует в ММСК запуск сигнальных путей, аналогичных фармакологическому прекондиционированию ЫС1.

Влияние ММСК, прекондиционированных ионами лития или воспалением, на течение острого пиелонефрита у крыс.

Обсуждение.

Выводы.

Заключение диссертации по теме «Клеточная биология, цитология, гистология», Пулькова, Наталья Владимировна

Выводы

1. При введении инокулята из смешанной культуры фекальных бактерий в мочевой пузырь у крыс развивается острый пиелонефрит, который характеризуется диффузной и очаговой, преимущественно нейтрофильной, воспалительной инфильтрацией, развитием окислительного стресса и повышением содержания провоспалительного цитокина ТЫРа в тканях почки. После введения ММСК костного мозга указанные показатели воспалительного процесса снижаются.

2. При экспериментальном остром пиелонефрите трансплантированные ММСК накапливаются в почке более интенсивно, чем в почке животных контрольной группы. Усилению миграции ММСК способствует высокий уровень ТМРа.

3. В условиях сокультивирования с лейкоцитами, активированными липополисахаридом, в ММСК происходит запуск сигнальных путей, обеспечивающих иммуносупрессорные свойства этих клеток, признаками которых является повышение количества трансформирующего ростового фактора (Т6Р1) и индуцибельной 1\Ю-синтазы (¡N08), а также усиление активности матриксной металлопротеиназы (ММП-2).

4. Сокультивирование с лейкоцитами и липополисахаридом индуцирует в ММСК сигнальные пути, аналогичные путям, активируемым при фармакологическом прекондиционировании 1Ю1, о чем свидетельствует повышение количества фосфорилированной формы киназы гликогенсинтазы (ввК-Зр), ключевого фермента, определяющего устойчивость клеток к окислительному стрессу.

5. Трансплантация ММСК костного мозга после сокультивирования с активированными лейкоцитами снижает признаки воспаления при экспериментальном остром пиелонефрите, что выражается в уменьшении числа лейкоцитов в крови, уровня TNFa и активности миелопероксидазы (МПО) в тканях почки.

6. Инкубация с ЫС1 не приводит к увеличению в ММСК количества Т6(31, ¡N03 и активности ММП-2, однако повышает количество фосфорилированной формы СвК-Зр. Влияние таких ММСК на число лейкоцитов в крови и активность МПО в тканях почки при остром пиелонефрите не отличается от действия на эти показатели интакных ММСК. ММСК, сокультивированные с активированными лейкоцитами, вызывают более выраженное уменьшение числа лейкоцитов в крови по сравнению с эффектом нативных ММСК и ММСК, обработанных ЫС1.

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