THE TWO-EVENT CONSTRUCT OF POSTINJURY MULTIPLE ORGAN FAILURE

INTRODUCTION The two-event construct of postinjury multiple organ failure (MOF) is based on the fundamental concept that injury primes the innate immune system such that a second insult, during this vulnerable window, provokes unbridled systemic inflammation, resulting in organ dysfunction (Fig. 1) (1, 2). Because the neutrophil (PMN) is a pivotal early effector cell in the pathogenesis of postinjury MOF (3-5), PMN priming/activation is typically studied as the in vitro surrogate of the two-event phenomenon (6). Priming is defined as an enhanced response to a stimulus that is from previous exposure of the cell to a different agonist (7). PMN priming for cytotoxicity encompasses a wide range of physiologic responses, including superoxide anion generation, degranulation of enzymes, cytokine (IL8) and lipid mediator (LTB4) production, enhanced integrin expression (CD11b/CD18), decreased selectin expression (L selectin), reduced deformability, cellular elongation, and delayed apoptosis (8). Physiologically relevant priming agents are diverse and include platelet-activating factor (PAF), LTB4, C5a, substance P, TNF, IL8, granulocyte-macrophage-colony-stimulating factor, interferon, lipopolysaccharide (LPS), influenza virus, and L selectin cross-linking and CD18 cross-linking. The objectives of this brief overview are to provide some historic perspective on the two-event hypothesis and to present supporting evidence from the clinical arena as well as the bench.FIG. 1: Postinjury MOF is typically produced by multiple insults (two-event model) that can be characterized as priming (systemic inflammatory response) and activation (secondary event).THE TWO-EVENT HYPOTHESIS: A FORTUITOUS TRANSLATION A number of investigators have contributed to the development and refinement of the two-event construct in studying the underlying mechanisms of autodestructive or dysfunctional immune response to injury. Because of time restraints, we will briefly describe how our interests were stimulated to examine this concept. In the mid 1980s, several of the authors, while conducting surgical intensive care unit (ICU) rounds, encountered a young patient who had undergone an uncomplicated emergent splenectomy in a rural hospital after a motor vehicle accident, and was transferred to our facility for intramedullary femoral fixation at 18 h postinjury. The patient arrived alert, hemodynamically stable, and breathing comfortably on supplemental nasal oxygen. He was taken directly to the operating room for what appeared to be an uncomplicated femoral fixation, but developed hypoxia at the end of the procedure. He arrived in the surgical ICU with rapidly progressive acute respiratory distress syndrome (ARDS) and succumbed to MOF within 72 h. At the same time in the trauma research laboratory, intrigued by the growing interest in pathologic priming (9-11) and the implications of PMN in ARDS (4, 5), we observed that hemorrhagic shock provoked transient, inconsequential PMN sequestration in rodents (12). We then documented that otherwise innocuous low-dose LPS, introduced at the time of this lung PMN sequestration, precipitated lethal ARDS (Fig. 2) (13). Our ensuing laboratory work focused on the mechanisms responsible for shock-induced priming of systemic PMN, and identified postischemic gut PLA2 activation as an early pivotal event (Fig. 3) (14). Our recent in vivo work has shown that mesenteric lymph is the conduit for proinflammatory lipids generated in the ischemic/reperfused splanchnic bed.FIG. 2: Sequential insults of hemorrhagic shock and IP LPS result in (a) acute lung injury at 12 h (a) and mortality at 24 h (b).FIG. 3: The reperfused mesenteric circulation serves as a priming bed for circulating PMNs that provoke distant organ injury after secondary activation. Gut PLA2 activation is a key proximal step, occurring during ischemia, and PMN CD11b/CD18-dependent interaction with pulmonary endothelium is a critical distal event.To further understand the role of priming in PMN-mediated tissue injury, we conducted in vitro studies with isolated PMN from healthy volunteers, using PAF as a priming agent and fMLP to simulate activation (6). We selected PAF as a priming agent because our collective animal experiments invoked a PLA2-dependent polar lipid as the dominant agent generated in ischemic gut (15). The selection of fMLP as the activating agent was consistent with our findings following in vivo LPS activation. Other laboratories had studied these agents well (7-9) and characterized dosing and time courses applicable for clinical investigation. THE TWO-EVENT HYPOTHESIS: CLINICAL EVIDENCE IN TRAUMA In parallel studies in the surgical ICU, we developed an anatomic/physiologic profile to identify injured patients at risk for MOF (15). Using this risk stratification, we then obtained blood samples from seriously injured patients during the first 24 h postinjury to assess circulating PMN priming status and the priming capacity of circulating plasma (17). A consistent pattern of systemic priming was evident; PMN became primed for superoxide release within 3 h of injury, peaked at 6 to 18 h postinjury, and resolved at 36 h (Fig. 4). Furthermore, injured patients' plasma primed normal PMN (healthy volunteers) at the same time intervals, and this priming capacity was markedly attenuated with a PAF-like receptor antagonists (WEB 2170). In subsequent studies, we documented the same time pattern for increased CD11b on the surface of PMN in circulating whole blood of patients at high risk for MOF, and observed a precipitous fall in the number of circulating PMN in those patients who developed MOF (18). We also found that postinjury PMN priming includes increased elastase release, IL8 production, and delayed apoptosis (19, 20).FIG. 4: PMN superoxide release (fMLP activated) in injured patients at risk for MOF.A number of other investigators worldwide have reported evidence of PMN priming in severely injured patients at risk for ARDS/MOF (21-25). Other groups have suggested that circulating monocytes and tissue macrophages also become primed after severe injury (26-28). Finally, most authorities agree that microvascular endothelium has an integral role in postinjury priming of the innate inflammatory response (29-31). There is some confusion in terminology, however, because well-recognized PMN priming agents (LPS and TNF) stimulate the expression of adhesion molecules on endothelium (ICAM and VCAM); this is typically referred to as endothelial activation. IN VIVO MODELS OF THE POSTINJURY TWO-EVENT CONSTRUCT A number of investigators have improvised useful two event models in small animals to stimulate a specific trauma-related scenario (Table 1). It is challenging to identify these models via a literature search; consequently, my list will be representative of the concept. The Toronto group (32) has devised an excellent two event rodent model of ARDS using hemorrhagic shock followed by intratracheal LPS. The San Diego group (33) has developed a reproducible two-event model of MOF in mice: hemorrhagic shock followed by CLP. The Rhode Island group (34) has also used hemorrhagic shock followed by CLP as a two-event model in mice. We have recently described the abdominal compartment syndrome as a second insult after hemorrhagic shock in rats, provoking MOF (35). As in our original description (13), the Hannover group (36) has used superior mesenteric artery occlusion followed by intraperitoneal LPS to induce MOF in rodents. Not surprisingly, there have been few two-event models described in large animals. The Edmonton group (37) outlined a clinically relevant model in swine with hemorrhagic shock under anesthesia followed in 72 h with intravenous LPS under anesthesia.Table 1: Small animal models of the postinjury two-event constructMODELING EARLY VERSUS LATE ONSET MOF Faist and Baue (38) were the first to recognize disparate patterns of postinjury MOF depending on the time of onset. We subsequently confirmed this observation by analyzing patients with early versus late onset MOF (39). Clearly, the underlying pathophysiology and predominant mechanisms are different and will demand specific models to interrogate relevant therapeutic strategies (40). Most of the experimental design in investigating MOF has focused on the innate immune system, but Mannick et al. (41) provide compelling evidence that the adaptive immune system is an independent but integral part of the maladaptive response to injury. Consequently, the two-event hypothesis of postinjury MOF is complex (Fig. 5) and must be considered in developing future clinically relevant models.FIG. 5: The innate and adaptive immune systems responses to severe injury culminate in a dysfunction immune state, rendering the patient at risk for MOF.

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