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*This chapter is dedicated to its previous author, Dr. Stephen Lowry, my mentor and friend.

  1. Endogenous damage-associated molecular patterns (DAMPs) are produced following tissue and cellular injury. These molecules interact with immune and nonimmune cell receptors to initiate a “sterile” systemic inflammatory response following severe traumatic injury.

  2. In many cases, DAMP molecules are sensed by pattern recognition receptors (PRRs), which are the same receptors that cells use to sense invading pathogens. This explains, in part, the similar clinical picture of systemic inflammation observed in injured and/or septic patients.

  3. The central nervous system receives information with regard to injury-induced inflammation via soluble mediators as well as direct neural projections that transmit information to regulatory areas in the brain. The resulting neuroendocrine reflex plays an important modulatory role in the immune response.

  4. Inflammatory signals activate key cellular stress responses (the oxidative stress response, the heat shock protein response, the unfolded protein response, autophagy, and programmed cell death), which serve to mobilize cellular defenses and resources in an attempt to restore homeostasis.

  5. The cells, mediators, signaling mechanisms, and pathways that compose and regulate the systemic inflammatory response are closely networked and tightly regulated by transcriptional events as well as by epigenetic mechanisms, posttranslational modification, and microRNA synthesis.

  6. Nutritional assessments, whether clinical or laboratory guided, and intervention should be considered at an early juncture in all surgical and critically ill patients.

  7. Management of critically ill and injured patients is optimized with the use of evidence-based and algorithm-driven therapy.


The inflammatory response to injury or infection occurs as a consequence of the local or systemic release of “pathogen-associated” or “damage-associated” molecules, which use similar signaling pathways to mobilize the necessary resources required for the restoration of homeostasis. Minor host insults result in a localized inflammatory response that is transient and in most cases beneficial. Major host insults, however, may lead to amplified reactions, resulting in systemic inflammation, remote organ damage, and multiple organ failure in as many as 30% of those who are severely injured. Recent data support this idea and suggest that severely injured patients who are destined to die from their injuries differ from survivors only in the degree and duration of their dysregulated acute inflammatory response.1,2

This topic is highly relevant because systemic inflammation is a central feature3 of both sepsis and severe trauma. Understanding the complex pathways that regulate local and systemic inflammation is necessary to develop therapies to intervene during overwhelming sepsis or after severe injury. Sepsis, defined by a systemic inflammatory response to infection, is a disease process with an incidence of over 900,000 cases per year. Further, trauma is the leading cause of mortality and morbidity for individuals under age 45.

In this chapter, we will review what is known about the soluble and cellular effectors of the injury-induced inflammatory response; how ...

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