Nonautonomous dynamics of acute cell injury

Abstract

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 quantitative theoretical 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 * , emerges from the nonautonomous theory. A continuous transition across the four qualitative patterns has been observed, which sets a natural range for initial conditions. Under these initial conditions in the parameter space tested, the total induced stress response can be increased to 2.5-11 folds of S max * . This result indicates that cells possess a reserve 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.