THE IMMUNOLOGY OF TRAUMA

Published on 10/03/2015 by admin

Last modified 10/03/2015

Print this page

This article have been viewed 3281 times

CHAPTER 95 THE IMMUNOLOGY OF TRAUMA

Following trauma, the immune system is called into action by signals from injured tissues. Injuries, hypoxia, and hypotension, as well as secondary insults such as ischemia/reperfusion injuries, compartment syndromes, operative interventions, and infections induce a host response that is characterized by local and systemic release of proinflammatory cytokines, arachidonic acid metabolites, and activation of complement factors, kinins, and coagulation as well as hormonal mediators. Clinically, this is the systemic inflammatory response syndrome (SIRS). Paralleling SIRS is an anti-inflammatory response referred to as the compensatory anti-inflammatory response syndrome (CARS). An imbalance between these responses appears to be responsible for increased susceptibility to infection and organ dysfunction. The aim of this chapter is to provide an overview of the immune response following trauma.

In this chapter we will discuss the two-hit model, SIRS, CARS, cytokine response, cell-mediated response, leukocyte recruitment, proteases and reactive oxygen species, and acute phase reaction.

TWO-HIT MODEL

In the two-hit model, the inciting injury induces a systemic inflammatory response (Figure 1). This “first hit” primes the immune system for an exaggerated and potentially lethal inflammatory reaction to a secondary, otherwise nonlethal, stimulus (“second hit”). This secondary stimulus may be either endogenous or exogenous. Endogenous second hits include cardiovascular instability, respiratory distress, metabolic derangements, and ischemia/reperfusion injuries. In contrast, exogenous second hits include surgical interventions, blood product transfusions, and missed injuries. The two-hit model proposes that this second hit results in destructive inflammation leading to multiple organ failure (MOF) and potentially death. This model has been supported by the work of Moore and colleagues who linked postinjury opportunistic infections to SIRS and MOF.

Figure 1 Pathogenesis of postinjury multiple organ failure.

SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

In 1991, a consensus conference of the American College of Chest Physicians and the American Society of Critical Care Medicine (ACCP/SCCM) defined SIRS as a generalized inflammatory response triggered by a variety of infectious and noninfectious events. They arbitrarily established clinical parameters through a process of consensus. Table 1 summarizes the diagnostic criteria for SIRS. At least two of the four criteria must be present to fulfill the diagnosis of SIRS. Note that this definition emphasizes the inflammatory process regardless of the presence of infection. The term sepsis is reserved for SIRS when infection is suspected or proven. Subsequent studies have validated these criteria as predictive of increased intensive care unit (ICU) mortality, and that this risk increases concurrent with the number of criteria present.

Table 1 Clinical Parameters of Systemic Inflammatory Response Syndrome

Heart rate > 90 beats/min

Respiratory rate > 20 breaths/min, or Paco₂ < 32 mm Hg

Temperature > 38° C < 36° C

Leukocytes > 12,000/mm³ or < 4000/mm³ or ≥10% juvenile neutrophil granulocytes

PaCO₂, Arterial CO₂ partial pressure.

Systemic inflammatory response syndrome is characterized by the local and systemic production and release of multiple mediators, including proinflammatory cytokines, complement factors, proteins of the contact phase and coagulation system, acute-phase proteins, neuroendocrine mediators and an accumulation of immunocompetent cells at the local site of tissue damage. The severity of trauma, duration of the insult, genetic factors, and general condition of the individual determine the local and systemic release of proinflammatory cytokines and phospholipids.

COMPENSATORY ANTI-INFLAMMATORY RESPONSE SYNDROME

Trauma not only stimulates the release of proinflammatory mediators, but also the parallel release of anti-inflammatory mediators. This compensatory anti-inflammatory response is present concurrently with SIRS (Figure 2). When these two opposing responses are appropriately balanced, the traumatized individual is able to effectively heal the injury without incurring secondary injury from the autoimmune inflammatory response. However, overwhelming CARS appears responsible for post-traumatic immunosuppression, which leads to increased susceptibility to infections and sepsis. With time, SIRS ceases to exist and CARS is the predominant force.

Figure 2 Postinjury multiple organ failure occurs as a result of a dysfunctional inflammatory response. CARS, Compensatory anti-inflammatory response syndrome; MOF, multiple organ failure; SIRS, systemic inflammatory response syndrome.

CYTOKINE RESPONSE

Cytokines exert their effects in both a para- and auto-crine manner. Proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) are released within 1–2 hours. Secondary proinflammatory cytokines are released in a subacute fashion and include IL-6, IL-8, macrophage migratory factor (MMF), IL-12, and IL-18. Clinically, IL-6 levels correlate with injury severity score (ISS) and the development of MOF, acute respiratory distress syndrome (ARDS), and sepsis.

Interleukin-6 also acts as an immunoregulatory cytokine by stimulating the release of anti-inflammatory mediators such as IL-1 receptor antagonists and TNF receptors which bind circulating proinflammatory cytokines. IL-6 also triggers the release of prostaglandin E2 (PGE2) from macrophages. Prostaglandin E2 is potentially the most potent endogenous immunosuppressant. Not only does it suppress T-cell and macrophage responsiveness, it also induces the release of IL-10, a potent anti-inflammatory cytokine that deactivates monocytes. Serum IL-10 levels correlate with ISS as well as the development of post-traumatic complications.

Following trauma, IL-12 production is decreased, stimulating a shift in favor of T_H2 cells and the subsequent production of antiinflammatory mediators IL-4, IL-10, IL-13, and transforming growth factor beta (TGF-β). This decrease in IL-12 and resultant increase in T_H2 cells correlates with adverse outcomes. A listing of pro and anti-inflammatory mediators appears in Tables 2 and 3.

Table 2 Proinflammatory Mediators

Mediator	Action
IL-1	IL-1 is pleiotropic. Locally, it stimulates cytokine and cytokine receptor production by T cells as well as stimulating B-cell proliferation. Systemically, IL-1 modulates endocrine responses and induces the acute phase response.
IL-6	Il-6 induces acute-phase reactants in hepatocytes and plays an essential role in the final differentiation of B cells into Ig-secreting cells. Additionally, IL-6 has antiinflammatory properties.
IL-8	IL-8 is a major mediator of the inflammatory response. It functions as a chemoattractant and is also a potent angiogenic factor.
IL-12	IL-12 regulates the differentiation of naive T cells into TH1 cells. It stimulates the growth and function of T cells and alters the normal cycle of apoptotic cell death.
TNF-α	TNF-α is pleiotropic. TNF-α and IL-1 act alone or together to induce systemic inflammation as above. TNF-α is also chemotactic for neutrophils and monocytes, as well as increasing neutrophil activity.
MIF	MIF forms a crucial link between the immune and neuroendocrine systems. It acts systemically to enhance the secretion of IL-1 and TNF-α

Ig, Immunoglobulin; IL, interleukin; MIF, migration inhibitory factor; TNF, tumor necrosis factor.

Table 3 Anti-Inflammatory Mediators

Buy Membership for Critical Care Medicine Category to continue reading. Learn more here

Mediator	Action
IL-4	IL-4, IL-3, IL-5, IL-13, and CSF2 form a cytokine gene cluster on chromosome 5q, with this gene particularly close to IL-13.
IL-10	IL-10 has pleiotropic effects in immunoregulation and inflammation. It downregulates the expression of T_H1 cytokines, MHC class II antigens, and costimulatory molecules on macrophages. It also enhances B-cell survival, proliferation, and antibody production. In addition, it can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway.
IL-11	IL-11 stimulates the T-cell–dependent development of immunoglobulin-producing B cells. It is also found to support the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells.
IL-13