Septic shock: desperately seeking treatment

Septic shock results from the dysregulation of the innate immune response following infection. Despite major advances in fundamental and clinical research, patients diagnosed with septic shock still have a poor prognostic outcome, with a mortality rate of up to 50%. Indeed, the reasons leading to septic shock are still poorly understood. First postulated 30 years ago, the general view of septic shock as an acute and overwhelming inflammatory response still prevails today. Recently, the fact that numerous clinical trials have failed to demonstrate any positive medical outcomes has caused us to question our fundamental understanding of this condition. New and sophisticated technologies now allow us to accurately profile the various stages and contributory components of the inflammatory response defining septic shock, and many studies now report a more complex inflammatory response, particularly during the early phase of sepsis. In addition, novel experimental approaches, using more clinically relevant animal models, to standardize and stratify research outcomes are now being argued for. In the present review, we discuss the most recent findings in relation to our understanding of the underlying mechanisms involved in septic shock, and highlight the attempts made to improve animal experimental models. We also review recent studies reporting promising results with two vastly different therapeutic approaches influencing the renin–angiotensin system and applying mesenchymal stem cells for clinical intervention. Abbreviations: ACE, angiotensin-converting enzyme; AngI etc., angiotensin I etc.; ARDS, acute respiratory distress syndrome; AT1R, AngII type 1 receptor; AT2R, AngII type 2 receptor; CARS, contra anti-inflammatory response syndrome; CLP, caecal ligation puncture; ICU, Intensive Care Unit; IFNγ, interferon γ; IL, interleukin; LPS, lipopolysaccharide; MARS, mixed anti-inflammatory response syndrome; MOFS, multiple organ failure syndrome; MSC, mesenchymal stem cell; NF-κB, nuclear factor κB; PARS, primary anti-inflammatory response syndrome; PRR, pattern recognition receptor; RAS, renin–angiotensin system; SIRS, systemic inflammatory response syndrome; TNFα, tumour necrosis factor α