Toward computational identification of multiscale "tipping points" in acute inflammation and multiple organ failure

Sepsis accounts annually for nearly 10% of total U.S. deaths, costing nearly $17 billion/year. Sepsis is a manifestation of disordered systemic inflammation. Properly regulated inflammation allows for timely recognition and effective reaction to injury or infection, but inadequate or overly robust inflammation can lead to Multiple Organ Dysfunction Syndrome (MODS). There is an incongruity between the systemic nature of disordered inflammation (as the target of inflammation-modulating therapies), and the regional manifestation of organ-specific failure (as the subject of organ support), that presents a therapeutic dilemma: systemic interventions can interfere with an individual organ system's appropriate response, yet organ-specific interventions may not help the overall system reorient itself. Based on a decade of systems and computational approaches to deciphering acute inflammation, along with translationallymotivated experimental studies in both small and large animals, we propose that MODS evolves due to the feedforward cycle of inflammation fi damage fi inflammation. We hypothesize that inflammation proceeds at a given, "nested" level or scale until positive feedback exceeds a "tipping point." Below this tipping point, inflammation is contained and manageable; when this threshold is crossed, inflammation becomes disordered, and dysfunction propagates to a higher biological scale (e.g., progressing from cellular, to tissue/organ, to multiple organs, to the organism). Finally, we suggest that a combination of computational biology approaches involving data-driven and mechanistic mathematical modeling, in close association with studies in clinically relevant paradigms of sepsis/MODS, are necessary in order to define scale-specific "tipping points" and to suggest novel therapies for sepsis.