It has long been understood that reperfusion of the ischemic gut can lead to lung injury.36 Because gut ischemia/reperfusion is an established phenomenon in the injured patient with hemorrhagic shock, this remains a tantalizing hypothesis for the development of inflammatory injury to the lung. Curiously, however, convincing evidence of inflammatory mediators leaving the gut into the portal circulation has been lacking in humans. This led Deitch37 to hypothesize that the egress of proinflammatory substances from the gut may be via lymph, not venous blood. This intriguing hypothesis has substantial support in animal models, including the finding that diversion of gut lymph abrogates lung injury. While the precise mediators of this phenomenon are as yet unknown, changes in posthemorrhagic shock lymph flow, lipid content, and protein content are an active area of investigation.38,39
Mediators and Markers of Acute Respiratory Distress Syndrome
Systemic complement activation secondary to trauma or sepsis is considered a major early factor in ARDS.40 C5a, a product of complement activation, is a powerful neutrophil chemoattractant. Moreover, C5a induces neutrophil aggregation and activation leading to pulmonary neutrophil sequestration and lung injury. Clinically, plasma and bronchoalveolar C3a levels correlate with the development of ARDS.41
Phospholipids are potent inflammatory mediators that are formed by the action of phospholipase A2 (PLA2) on membrane phospholipids. PLA2 contributes to the inflammatory response by two separate pathways, catalyzing the production of both platelet-activating factor (PAF) and arachidonic acid. Arachidonic acid metabolism results in release of eicosanoids such as leukotrienes, thromboxane, and prostaglandins. Each of these is a pivotal mediator in the inflammatory cascade and has been implicated in the pathogenesis of ARDS.42
PAF is a phospholipid with potent vasoactive and inflammatory properties. It is produced by a number of cell types including macrophages, neutrophils, endothelial cells, and type II pneumocytes. PAF production is stimulated by endotoxin, tumor necrosis factor (TNF), and leukotrienes, and exerts diverse biologic actions, including neutrophil activation and adherence, platelet aggregation and degranulation, and macrophage production of inflammatory mediators. Infusion of PAF in animals results in increased vascular permeability and neutrophil-mediated ALI.43
Lysophosphatidyl cholines are another class of bioactive lipids that may play a significant role in lung injury after trauma. These compounds accumulate during routine storage of packed red blood cells and have been shown to cause lung injury in isolated perfused rodent lungs.44 These or related compounds from transfusion of banked red cells may provide a second insult leading to inflammatory organ injury in the injured patient.
As mentioned above, the pulmonary endothelium is recognized as an active participant in the development of ALI. As such, markers of endothelial activation or injury have been investigated as predictors of the development of ARDS. von Willebrand factor antigen (vWF:Ag) has been studied fairly extensively as a marker of endothelial dysfunction. vWF:Ag is synthesized largely by vascular endothelial cells and has been shown to be a sensitive marker of endothelial injury or activation.45 This antigen was studied prospectively in 45 patients to determine whether elevated levels of vWF:Ag are predictive for the development of ALI.46 Only patients with nonpulmonary sepsis were included, and one third developed ALI. Elevated plasma levels of vWF:AG (>45% above controls) were 87% sensitive and 77% specific for development of ALI. Positive predictive value was 65%.
Following activation, endothelial expression of adhesion molecules, including ICAM-1, VCAM-1, E-selectin, and P-selectin, is upregulated. These compounds are susceptible to proteolytic cleavage and may exist in the circulation in a soluble form. Therefore, these molecules represent a measure of endothelial activation or damage. We and others have demonstrated elevated ICAM-1 levels in severely injured patients who subsequently developed MOF.47,48 In contrast, plasma levels of soluble E- and P-selectins measured at admission were not useful in predicting ALI.
The maintenance of a functioning alveolar epithelium is important for recovery from ALI.49 Unlike the endothelium, there is a lack of specific histologic markers of alveolar epithelial injury. Surfactant abnormalities have been noted in the earliest reports of ARDS. Surfactant lipids and proteins are synthesized and released by alveolar epithelial type II cells. The surfactant-associated proteins SP-A and SP-B are decreased in BAL fluid from patients with ARDS and at risk for ARDS.50
Markers of leukocyte activation have also been measured in plasma and BAL fluid of patients in an attempt to predict development of ARDS. Gordon et al. noted markedly elevated plasma elastase levels very early after multisystem trauma.51 Subsequent studies supported a causative role for neutrophil elastase in ARDS,52 and have led to the clinical development of human elastase inhibitor.53 Increased expression of β2 integrins has been observed on the surface of circulating pulmonary artery neutrophils in patients at risk for postinjury ARDS.54
Circulating and BAL fluid levels of cytokines are also inherently attractive as predictors of ARDS; whether they are markers or mediators remains an important question. TNF-α, IL-1β, IL-6, and IL-8 have been the most intensely investigated in relation to the development of ARDS. Studies examining the predictive value of cytokines central to sepsis (TNF-α, IL-1β) levels in ARDS have had negative or mixed results.55 IL-8 is a neutrophil chemoattractant that has been studied in both plasma and BAL fluid. It is elevated in the plasma following injury but does not appear to consistently predict development of ARDS. Donnelly et al. studied 29 patients at risk for developing ARDS and observed that IL-8 levels in BAL fluid were significantly higher in patients who later progressed to ARDS.56