© 2003 American Thoracic Society
Compartments That Cause the Real Damage in Severe Acute PancreatitisDepartment of Surgery University of Liverpool Liverpool, United Kingdom Cytokines exert a major influence on the outcome of acute pancreatitis, in particular by triggering the systemic inflammatory response and multisystem organ failure, the latter being a marked feature of severe acute pancreatitis and responsible for most of the associated mortality (1). A number of researchers have, therefore, endeavored to ameliorate the severity of the disease by instigating anticytokine therapies in one form or another (1).
The initial injury occurs within the pancreatic acinar cells themselves, involving the premature activation of digestive enzymes (2) and the expression and release of chemokines by the acini (3). This results in the early recruitment and activation of inflammatory cells; systemic dissemination and amplification of this process are believed to be the basis of multisystem organ dysfunction (1). The mechanism by which the initial pancreatic insult results in the systemic amplification of the inflammatory response is poorly understood. Although active digestive enzymes are potent stimulators of macrophages and can induce the local production of proinflammatory cytokines such as tumor necrosis factor- A subsequent rise in cytokine levels in plasma is a well recognized phenomenon, but elevated levels have also been reported in other body fluid compartments such as ascites and lymph. Ascitic fluid has consistently been shown to be rich in cytokines in a number of conditions including congestive cardiac failure (6), sterile and infected cirrhotic ascites (7), and malignant ascites (8) in addition to severe acute pancreatitis (3). Ascites from experimental animals with severe acute pancreatitis has been shown to stimulate macrophage activation (9) and induce the production of additional proinflammatory cytokines (10). This amplification is likely to be caused by the proinflammatory cytokines themselves rather than by activated digestive zymogens within the ascitic fluid (4).
Although increased levels of cytokines have been demonstrated within the lymphatic system in acute pancreatitis, previous studies have not shown any consistent pattern of cytokine elevation in the thoracic duct lymph (11, 12). The phenomenon of differential cytokine expression in different compartments has been noted in conditions other than acute pancreatitis (13). In this issue of AJRCCM (pp. 148–157), the study by Dugernier and colleagues (14) investigates compartmentalization of the cytokine response in 60 patients with severe acute pancreatitis. The levels of 11 pro- or antiinflammatory cytokines were measured in three fluid compartments, namely ascitic fluid, thoracic duct lymph, and plasma, in patients with acute pancreatitis and at least one established end-organ failure. In addition, the proinflammatory activity of each sample was assessed by a biological assay of the degree of upregulation of intercellular adhesion molecule-1 (ICAM-1) on cultured A549 cells (human Type II alveolar epithelial cells), and the antiinflammatory activity was assessed by the degree of inhibition of this process when induced by recombinant IL-1ß and TNF-
One of the two key findings of the study was a consistent gradient of cytokine concentration, with the highest levels found in ascitic fluid followed by lymph and then plasma. This is especially true of the interleukins in general (IL-6, IL-8, IL-10, IL-1ß, IL-1 receptor antagonist, and anti–IL-1) but less apparent for the TNF-related measurements (TNF- The globally parallel time course in lymph and plasma is not surprising given that one compartment empties directly into the other. The fact, however, that plasma levels remain high and essentially unaltered, despite 6 days of thoracic duct drainage, implies that the plasma cytokines are derived from sources other than simple lymphatic drainage of the pancreas. Mediators and/or activated cells themselves could cross the peritoneal membrane directly (and in either direction) as well as being produced in extrapancreatic sites—the distant damaged organs being the obvious source. The sustained and predominant plasma antiinflammatory response probably reflects the relative inefficiency of this mechanism in resolving this self-sustaining distant organ damage and explains the failure of blood cleansing approaches to treating acute pancreatitis such as hemofiltration as well as peritoneal lavage, or even the simpler approach of early total pancreatectomy. The technique of thoracic duct drainage to treat severe acute pancreatitis is based on the hypothesis that cytokines and other proinflammatory substances produced in the inflamed pancreas are carried to the circulation via the thoracic duct and that interrupting this flow will reduce the likelihood of multiorgan failure and ameliorate the severity of disease. This notion was developed in the late 1980s and early 1990s but has not gained widespread acceptance in the treatment of severe acute pancreatitis, as there seems to be little evidence that it conveys any clinical benefit (15, 16). The fact that continued thoracic duct drainage over a period of 6 days, as done by Dugernier and colleagues (14), did not appear to affect the circulating levels of cytokines goes some way in explaining the lack of therapeutic effect of this approach. Given the findings of this study and others (14–16), a more productive therapeutic strategy may be to address the local release of cytokines from the pancreas and to interrupt the system of inflammatory amplification that appears to be driven by extrapancreatic sources. REFERENCES
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