Внутриклеточное содержание белков теплового шока 70 кДа и его взаимосвязь с продукцией активных форм кислорода в нейтрофилах человека при старении - Диссертация

В настоящее время старение рассматривается как сложный биологический процесс, который протекает на фоне разнообразных молекулярных и функциональных изменений в организме. Самая известная из теорий, объясняющих причины старения, утверждает, что чрезмерное образование свободных радикалов, особенно активных форм кислорода (АФК), совместно с нарушением защитной системы клеток от клеточного стресса, способствует старению организма [Harman D., 1956]. С одной стороны АФК осуществляют элиминацию патогена и клиренс поврежденных тканей, а с другой стороны, интенсивная продукция АФК усугубляет воспалительные реакции, оказывая повреждающее влияние не только на мишени, но и на собственные ткани организма. Нейтрофилы, клетки врожденной иммунной системы, представляют основной источник как внутриклеточных, так и внеклеточных АФК в организме и могут играть значительную роль в процессе старения. Известно, что нейтрофилы прямо или косвенно участвуют в патогенезе многих заболеваний, связанных с возрастом.Учитывая, что устойчивость к стрессу, опосредованная системой белков семейства HSP70, является важным фактором, влияющим на процессы клеточного старения, на первом этапе была поставлена задача оценить содержание HSP70 в нейтрофилах в разных возрастных группах: 20-59 (молодые), 60-89 (пожилые) и 90 и более лет (долгожители). Об этом свидетельствует отсутствие достоверных отличий в содержании некрозных (PI-позитивных) клеток между образцами, содержащими интактные либо подвергнутые гипертермии нейтрофилы после их часовой инкубации, а также в содержании апоптозных нейтрофилов между образцами, содержащими интактные либо подвергнутые ТШ клетки после их четырехчасовой инкубации. Для изучения динамики внутриклеточных HSP70 в нейтрофилах под действием ТШ уровень HSP70 определяли методом проточной цитометрии в интактных клетках и сразу после тепловой обработки, затем анализировали изменение этого уровня через каждый час до 7 ч., а также в более поздние сроки (15-17 ч после окончания ТШ). Сравнительный анализ экспрессии Hsp70 в лимфоцитах и нейтрофилах в нашей модели клеточного стресса показал, что в нейтрофилах индукция этих белков существенно слабее, чем в лимфоцитах, или, у некоторых доноров, отсутствует. На основании полученных цитометрических результатов можно заключить, что: 1) используемый в данной работе метод проточной цитометрии позволяет регистрировать изменение экспрессии HSP70; 2) увеличение экспрессии HSP70 зависит от температуры и времени воздействия ТШ; 3) индукция Hsp70 в лимфоцитах происходит существенно слабее, чем в моноцитах; 4) использование антител BRM22 позволяет регистрировать ярко выраженное (более чем в десять раз) стресс-индуцируемое увеличение содержания HSP70, вероятно, за счет преимущественного связывания антител с превалирующим в клетках белком Hsc70, количество которого под действием стресса практически не изменяется.В нейтрофилах человека не обнаружено достоверных возрастных изменений в общем внутриклеточном содержании HSP70. В то же время, разница между уровнем HSP70 после теплового шока и исходным внутриклеточным уровнем HSP70 увеличивалась с возрастом. Индуцированное тепловым шоком кратковременное возрастание внутриклеточного уровня HSP70 в нейтрофилах, измеренного методом проточной цитометрии, не связано с синтезом белка de novo, а обусловлено временными конформационными изменениями белка, сопровождающимися усилением доступности эпитопов субстрат-связывающего домена к специфичным антителам.

3.1 Внутриклеточное содержание HSP70 в интактных нейтрофилах в разных возрастных группах

В настоящее время старение рассматривается как сложный биологический процесс, который протекает на фоне разнообразных молекулярных и функциональных изменений в организме. Самая известная из теорий, объясняющих причины старения, утверждает, что чрезмерное образование свободных радикалов, особенно активных форм кислорода (АФК), совместно с нарушением защитной системы клеток от клеточного стресса, способствует старению организма [Harman D., 1956]. С одной стороны АФК осуществляют элиминацию патогена и клиренс поврежденных тканей, а с другой стороны, интенсивная продукция АФК усугубляет воспалительные реакции, оказывая повреждающее влияние не только на мишени, но и на собственные ткани организма.

Один из механизмов, обеспечивающих защиту клеток от неблагоприятных последствий действия АФК, связан с участием высоко консервативных белков теплового шока семейства 70 КДА (HSP70). Белки HSP70 обладают широким спектром шаперонных функций и способствуют нормальному протеканию многих внутриклеточных процессов. Они обеспечивают устойчивость клеток к стрессу, участвуя в процессах дезагрегации, репарации и элиминации поврежденных в условиях стресса белков.

Нейтрофилы, клетки врожденной иммунной системы, представляют основной источник как внутриклеточных, так и внеклеточных АФК в организме и могут играть значительную роль в процессе старения. Известно, что нейтрофилы прямо или косвенно участвуют в патогенезе многих заболеваний, связанных с возрастом. В нейтрофилах, несмотря на их низкую биосинтетическую активность, как и во всех эукариотических клетках, экспрессируются белки HSP70. В то же время, работ, в которых бы изучались особенности экспрессии и роль HSP70 в функционировании нейтрофилов, мало. Нет информации о возрастных изменениях, связанных с уровнем внутриклеточных HSP70 в нейтрофилах. До сих пор не ясно, участвуют ли HSP70 в регуляции процессов продукции АФК нейтрофилами.

Таким образом, актуальным является изучение в рамках одной работы вопросов, связанных с возрастными изменениями экспрессии HSP70 и генерации АФК в популяции нейтрофилов, а также анализ взаимосвязи внутриклеточного уровня HSP70 с продукцией АФК. Немаловажным также представляется оценка способности нейтрофилов продуцировать внеклеточные формы HSP70, играющие важную иммунорегуляторную роль [Calderwood et al., 2005; Pockley, 2002]. Изучение этих вопросов может способствовать более глубокому пониманию процесса старения, а также позволить сформулировать стратегию коррекции патологических состояний, ассоциированных с возрастом, в которых нейтрофилы играют важную роль.

Цель исследования - изучение возрастных особенностей внутриклеточного уровня HSP70 и динамики стресс-индуцированных изменений содержания HSP70, а также анализ взаимосвязи этих изменений с продукцией АФК в нейтрофилах человека.

Исходя из цели исследования поставлены следующие задачи: O Проанализировать содержание HSP70 в нейтрофилах человека в трех возрастных группах: молодые, пожилые и долгожители.

O Исследовать динамику изменения внутриклеточного уровня HSP70 в нейтрофилах в ответ на тепловой шок и выявить факторы, влияющие на эту динамику.

O Сравнить динамику изменения внутриклеточного содержания HSP70 в нейтрофилах в ответ на тепловой шок в разных возрастных группах.

O Оценить спонтанную и индуцированную продукцию активных форм кислорода в нейтрофилах в разных возрастных группах.

O Изучить взаимосвязь содержания HSP70 и продукции АФК, а также ее возрастные особенности. белок тепловой шок возрастной

1. В нейтрофилах человека не обнаружено достоверных возрастных изменений в общем внутриклеточном содержании HSP70. В то же время, разница между уровнем HSP70 после теплового шока и исходным внутриклеточным уровнем HSP70 увеличивалась с возрастом.

2. Индуцированное тепловым шоком кратковременное возрастание внутриклеточного уровня HSP70 в нейтрофилах, измеренного методом проточной цитометрии, не связано с синтезом белка de novo, а обусловлено временными конформационными изменениями белка, сопровождающимися усилением доступности эпитопов субстрат-связывающего домена к специфичным антителам.

3. Вызванные тепловым шоком изменения внутриклеточного уровня HSP70 характерны для конститутивного (Hsc70) и индуцированного (Hsp70) белков семейства HSP70.

4. В нейтрофилах в условиях гипертермии реализуется активный механизм высвобождения как Hsp70, так и Hsc70, сопряженный с процессом дегрануляции лизосом.

5. В группе пожилых доноров спонтанная внутриклеточная и внеклеточная продукция АФК в нейтрофилах увеличивается, а индуцированная - уменьшается. В группе долгожителей величины спонтанной внутриклеточной и индуцированной продукции АФК ниже, чем в группе пожилых, и достоверно не отличаются от аналогичных параметров, определенных в группе молодых добровольцев.

6. С помощью корреляционного анализа в группе пожилых выявлена положительная взаимосвязь внутриклеточного уровня HSP70 и индуцированной продукции АФК в нейтрофилах, аналогичная взаимосвязь отсутствовала в группах молодых и долгожителей. Указанное различие между группами пожилых и долгожителей может быть связано с высоким риском смертности в пожилом возрасте до 90 лет.

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