Department of Physiology, Wayne State University, Detroit, Michigan 48201, USA.
Department of Physics and Astronomy, Wayne State University, Detroit, Michigan 48201, USA.
Phys Rev E. 2019 Nov;100(5-1):052407. doi: 10.1103/PhysRevE.100.052407.
Medical conditions due to acute cell injury, such as stroke and heart attack, are of tremendous impact and have attracted huge amounts of research effort. The biomedical research that seeks cures for these conditions has been dominated by a qualitative, inductive mind-set. Although the inductive approach has not been effective in developing medical treatments, it has amassed enough information to allow construction of quantitative, deductive models of acute cell injury. In this work we develop a modeling approach by extending an autonomous nonlinear dynamic theory of acute cell injury that offered new ways to conceptualize cell injury but possessed limitations that decrease its effectiveness. Here we study the global dynamics of the cell injury theory using a nonautonomous formulation. Different from the standard scenario in nonlinear dynamics that is determined by the steady state and fixed points of the model equations, in this nonautonomous model with a trivial fixed point, the system property is dominated by the transient states and the corresponding dynamic processes. The model gives rise to four qualitative types of dynamical patterns that can be mapped to the behavior of cells after clinical acute injuries. The nonautonomous theory predicts the existence of a latent stress response capacity (LSRC) possessed by injured cells. The LSRC provides a theoretical explanation of how therapies, such as hypothermia, can prevent cell death after lethal injuries. The nonautonomous theory of acute cell injury provides an improved quantitative framework for understanding cell death and recovery and lays a foundation for developing effective therapeutics for acute injury.
由于急性细胞损伤引起的医学病症，如中风和心脏病发作，具有巨大的影响，已经吸引了大量的研究工作。寻求这些病症治疗方法的生物医学研究一直以来都受到定性、归纳思维模式的主导。尽管归纳法在开发医疗方法方面并不有效，但它已经积累了足够的信息，可以构建急性细胞损伤的定量、演绎模型。在这项工作中，我们通过扩展急性细胞损伤的自主非线性动力学理论来开发一种建模方法，该理论为概念化细胞损伤提供了新的思路，但存在降低其有效性的局限性。在这里，我们使用非自治形式研究细胞损伤理论的全局动力学。与模型方程的稳态和平衡点决定的非线性动力学的标准情况不同，在这个具有平凡固定点的非自治模型中，系统特性由瞬态状态和相应的动态过程主导。该模型产生了四种定性类型的动力学模式，可以映射到临床急性损伤后细胞的行为。非自治理论预测了受损细胞具有潜在应激反应能力（LSRC）。LSRC 为治疗方法（如低温）如何在致命损伤后预防细胞死亡提供了理论解释。急性细胞损伤的非自治理论为理解细胞死亡和恢复提供了一个改进的定量框架，并为急性损伤的有效治疗方法的开发奠定了基础。
