Ronald V. Maier, MD
Professor and Surgeon-in-Chief, Department of Surgery
Trauma remains a major cause of death and disability in America. The major cause of late death following trauma is organ dysfunction, including acute pulmonary failure, leading to multiple organ failure syndrome (MOFS) and death. The primary etiology of MOFS is the systemic inflammatory response syndrome causing disseminated tissue injury and organ dysfunction. The long-lived, highly diverse tissue-fixed macrophage is a crucial central coordinator of both the normal and aberrant host excessive inflammatory responses responsible for the systemic inflammatory response syndrome. The present proposal investigates the intracellular signaling mechanisms involved in the control of inflammatory gene up-regulation in the tissue-fixed macrophage. The macrophage is both “primed” and activated by a multitude of stimuli in the inflammatory milieu. Until now, therapeutic approaches have focused on controlling single components of the inflammatory response. However, since the inflammatory response is so replete with redundancy in feedback amplification, it is more appealing to broaden our focus to a more global control of inflammatory injury. The elucidation of the intracellular signal transduction pathways in the macrophage will allow us to target potential therapeutic interventions to control the aberrant macrophage response and the overall host response to severe stress and critical illness. The ability to develop rational therapies for clinical use to safely ameliorate the aberrant inflammatory response will, hopefully, prevent the sequential multiple organ injury and failure and the associated excessive mortality seen in these disease states.