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PRECLINICAL MODELS OF TRAUMATIC, HEMORRHAGIC SHOCK

Trauma is the leading cause of death between the ages 1 and 45. Between birth and age 36, trauma exceeds all other causes of death combined. Most ‘‘survivable’’ patients die when tissue trauma and shock act in concert to trigger inflammation that leads to organ failure or sepsis. Thus, clinical inflammation after injury is a major public health problem, and therapeutic advances in this field will depend upon animal models that predict the clinical effects of interventions accurately. Poor preclinical modeling will lead to therapeutic failure. Modeling traumatic, hemorrhagic shock (T/HS) in animal systems requires a precise understanding of clinical trauma and shock syndromes, as well as the mechanisms that transduce trauma and tissue ischemia into physiologic responses to injury, and of the animal models that can reconstitute these clinical responses accurately. The majority of clinical trauma results from blunt force injuries that result in extensive energy transfer to the patient. The resultant tissue injuries are accompanied to some degree by hemorrhage that can be rapid and exsanguinating, but more commonly, it is moderate in rate. Because tissue hemorrhage tends to be diffuse, however, it can be difficult to treat. Thus, shock from hemorrhage from blunt trauma tends to develop gradually, but tissue hypoperfusion and acidosis can persist for significant periods. Penetrating injury is more likely to cause direct injury to major blood vessels and rapid hemorrhagic shock. Conversely, penetrating injuries are seldom associated with major energy transfer and tissue destruction, but the operative procedures required to control bleeding do constitute a major tissue injury. Whereas tissue trauma is a mechanical event and hemorrhagic shock is a physiologic syndrome, the clinical entities that determine prognosis in patients who survive their initial insults are immune and inflammatory. This combination of mechanical tissue injury, hemorrhage, shock, ischemia, resuscitation, reperfusion, and later, sepsis, all interact to activate systemic immunity. Local tissue trauma and tissue necrosis are widely believed to unmask ‘‘pattern recognition’’ neo-antigens that lead to wound invasion by phagocytes that increase subsequent local mediator production. These events create an inflammatory wound environment that is a potent stimulus for systemic innate immune activation. The coagulation cascade is locally activated by tissue injury with hemorrhage and coagulation at injury sites. Activated platelets may represent an especially potent source of inflammatory lipids. Complement activation is mediated by soft-tissue trauma, burns, and local ischemia/reperfusion (I/R), and is an important determinant of later organ injury. Global I/R is also a key initiator of systemic inflammation. The mechanisms by which I/R leads to inflammation are complex. Gut ischemia may be important in initiating inflammation because the splanchnic circulation is preferentially hypoperfused during shock. Thus, the etiology, degree, duration, and location of tissue ischemia in shock models are all crucial. We are only now beginning to understand the cell-signaling mechanisms that transduce tissue injuries and shock syndromes into immune dysfunction syndromes. Effective preclinical models of human hemorrhagic shock and resuscitation must take into account many complex variables to create biologic systems that model the events and end points of interest in the most biologically relevant way possible. Successful models of T/HS require a detailed appreciation of all facets—mechanical, physiologic, cell biologic, and immunologic—of these complex relationships. Moreover, inflammatory responses to T/HS vary over time and models must take into account that the early and late responses tend to diverge. Response to t/HS can also be dichotomous, with decreased organ injury predicting increased susceptibility to sepsis. Thus, the appropriate time to study different end points of interest may vary substantially.