Editorial

 

Role of the peritoneum in the pathogenesis of acute pancreatitis-associated lung injury

 

Acute pancreatitis is an unpredictable, potentially severe disease with an incidence of around 30 cases per 100,000 inhabitants and year (1,2). In the USA, acute pancreatitis results in about 300,000 hospital admissions every year and a direct mortality of 3,200 deaths in that same period (3), which involves almost exclusively the 15-20% of patients who develop necrotic pancreatitis. Two periods of maximum mortality exist in the course of this disease - the first week, in which deaths most commonly result from multiple organ failure, and within a number of weeks, when infectious complications predominate (4).

The pathologic phenomenon that initiates pancreatitis is intrapancreatic activation of trypsinogen. This relevant piece of knowledge has provided insight into the pathogenesis of hereditary pancreatitis. Thus, a single-nucleotide mutation in the gene coding for cationic trypsinogen induces an amino acid substitution in the protein gene product, which may give rise to structural changes rendering the resulting trypsin extremely resistant to autolysis (5,6) in an inappropriate time and place, since they allow for trypsin and protease co-localization (7) thus setting off the process of pancreatic self-digestion. Acinar cells undergo modifications (8), the expression of nuclear transcription factors such as NFκB becomes activated (9), and a complex proinflammatory cascade ensues, with synthesis and release of Th1 and Th2 cytokines, and phagocytic cell mobilization. Shortly afterwards this process goes beyond the anatomic limits of the pancreas and results in multisystem involvement, which is mostly responsible for the commonly serious outcome of this disease (4,10).

The early stages of acute pancreatitis develop in a very short time within the pancreas, an organ whose deep anatomic location makes it virtually inaccessible for sample collection. Therefore, our knowledge on these early vital stages stems from a number of established experimental models that may not be extrapolated to human pancreatitis from an etiologic standpoint. The intraperitoneal injection of supramaximal doses of cerulein, a decapeptide analog of cholecystokinin, induces a mild, self-limited pancreatitis that is similar to human edematous pancreatitis (11). Severe necrotic pancreatitis is obtained by providing an experimental animal with a choline-deficient, ethionine-supplemented diet (12). The intraductal injection of taurocholate induces a fulminant pancreatitis that results in death in a few hours (13). Other models exist, but these have been most widely used.

Lung injury commonly develops early in acute pancreatitis, which may result in severe adult respiratory distress syndrome (ARDS). This disorder may be seen even in the cerulein-induced model (11,14,15), and basically consists of increased permeability across the pulmonary endothelial barrier with hemorrhage, edema and interstitial infiltration by phagocytic cells (16), as well as oxygen desaturation (17). The human counterpart of such disturbances is well known (10), and its most obvious manifestation is an early development of pulmonary infiltrates, which may be detected in one fourth of patients (18) and definitely impairs prognosis (19).

Why does the lung become involved so much early and severely in acute pancreatitis? The inflammatory response triggered by pancreatitis rapidly reaches beyond pancreatic limits, and pancreatic enzymes, proinflammatory cytokines, chemokines, growth factors, and other inflammation mediators escape from the pancreas into the blood and onto the peritoneum. It is a long-acknowledged fact that amylase, lipase and other pancreatic enzymes are present in increased concentrations in pancreatic ascites and pleural effusion secondary to pancreatitis (20). However, the presence of such enzymes does not imply pathogenicity, and elastase alone -maybe also trypsin- is seemingly responsible for lung damage through the activation of NFκB and the ensuing expression of the TNFα gene in the lung (21). Phospholipase A₂ also plays a role in lung injury as it induces the release of arachidonic acid, thromboxanes, kinines, and platelet activating factor; the fact that this enzyme is of extrapancreatic origin is however somewhat enigmatic (20).

The role played by the peritoneum to extend this pathologic process is difficult to elicit, and procedures allowing the exclusion of phenomena directly depending on pancreas involvement should be put to good use therefore. This has been the goal of the paper by Mozo et al. in this issue of our journal (15). Their experimental model included the intraperitoneal injection of rat pancreas homogenate; one group of animals received enterokinase-activated homogenate, whereas the other group received a non-activated extract. A third -control- group received a saline solution. IL-ß1 concentration increased in both homogenate groups, more obviously so in the group receiving the activated form. However, only in the latter was observed a significantly more severe lung injury in comparison with the control group. The conclusion drawn by the authors is that peritoneal macrophages are the source of IL-1ß, and that this cytokine then reaches the lung and plays a role in injury mechanisms there. The role of peritoneal macrophages in triggering lung injury had already been demonstrated by Mikami et al. (22), who showed that peritoneal macrophage depletion reduced serum cytokines and lung damage in experimental pancreatitis in the rat.

An aspect left out by Mozo et al. is the role that the liver may play in the production and release of proinflammatory cytokines as a result of both Kupffer cell and sinusoid endothelium activation by products originating in the inflamed pancreas. This potential mechanism is actually supported by the fact that portal-cava shunting prevents increased pulmonary synthesis of prostacyclin and thromboxane B₂, increased phospholipase A₂ concentrations, and increased superoxide dismutase activity (23) in experimental pancreatitis. In addition, Kupffer cell blockage using ClGa improves survival and reduces cytokine plasma concentrations in experimental models of severe pancreatitis (24).

The pathogenesis of acute pancreatitis-associated lung injury is very complex and remains to be fully understood; an in-depth analysis falls out of the scope of this editorial. The lung is invaded by a wide variety of proinflammatory mediators that in turn stimulate in situ production (25). Advances in the understanding of these mechanisms of injury will no doubt provide therapeutic strategies more selective and effective than those currently available. Such is the case of RANTES blocks using met-RANTES, an antagonist of C-C chemokine receptors (26), or C-x-C chemokine inhibition (27,28). Other potential therapeutic goals include adhesion molecules VCAM-1 (29) and ICAM-1 (30), and macrophage migration inhibitory factor (MIF) (31). Interfering with NFκB (32) and platelet activating factor (PAF) expression may be of use in earlier stages of the disease, one of the latter' functions being macrophage activation (33); lexipafant, an antagonist of PAF, notably reduces lung injury in experimental pancreatitis, but clinical results are discouraging to this day (34) and seem to be restricted to patients who receive treatment within the first 48 hours of the disease (35). The therapeutic manipulation of both pro- and anti-inflammatory cytokines may also be of practical use (36).

The clinical applicability of these and other experimental findings remains in the future, since in most cases their preventive potential but not their therapeutic capability for an already existant pancreatitis is assessed. However, the contribution by Moro et al., who confirm the active role of the peritoneum and its resident macrophages in the pathogenesis of acute pancreatitis-associated lung injury, must be considered a further advance in the still long path towards eliciting the pathogenesis of this severe complication.

J. M. Ladero Quesada

Service of Digestive Diseases. Hospital Clínico San Carlos.
Universidad Complutense. Madrid, Spain

 

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