Clinically-relevant forms of acute cell injury, which include stroke and myocardial infarction, have been of long-lasting challenge in terms of successful intervention and treatments. Although laboratory studies have shown it is possible to decrease cell death after such injuries, human clinical trials based on laboratory therapies have generally failed. We suggested these failures are due, at least partially, to the lack of a quantitativetheoretical framework for acute cell injury. Here we provide a systematic study on a nonlinear dynamical model of acute cell injury and characterize the global dynamics of a nonautonomous version of the theory. The nonautonomous model gives rise to four qualitative types of dynamical patterns that can be mapped to the behavior of cells after clinical acute injuries. In addition, the concept of a maximum total intrinsic stress response, S_{max stress response capacity which provides a theoretical explanation of how therapies  can prevent cell death after lethal injuries. This nonautonomous theory of acute cell injury thus provides a quantitative framework for understanding cell death and recovery and  developing effective therapeutics for acute injury.
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 mindset. 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.
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which include stroke and myocardial infarction, have been of long-lasting challenge in terms of successful intervention and treatments. Although laboratory studies have shown it is possible to decrease cell death after such injuries, human clinical trials based on laboratory therapies have generally failed. We suggested these failures are due, at least partially, to the lack of a quantitativetheoretical framework for
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