Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to
therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of
sepsis from 30%, nor the mortality of
septic shock from greater than 50%. In the last decade only one new
drug for
sepsis has been brought to the market,
drotrecogin alfa-activated (Xigris™), and the success of this
drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the
systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic
therapy for
sepsis will only be successful if it addresses this pathophysiologic complexity; the
drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context,
therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that chemically modified tetracycline-3,
CMT-3 (or COL-3), a non-antimicrobial modified
tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of
sepsis and its associated complication of the
acute respiratory distress syndrome (ARDS). The purpose of this review is threefold: (1) to examine the shortcomings of current approaches to treatment of
sepsis and ARDS in light of their pathophysiology, (2) to explore the application of
COL-3 in ARDS and
sepsis, and finally (3) to elucidate the mechanisms of
COL-3 that may have potential therapeutic benefit in ARDS and
sepsis.