Are genetically modified mice useful for the understanding of acute pancreatitis?

Abstract

Treatment of patients with acute pancreatitis has greatly improved due to a better understanding of the pathophysiology of the disease. This pathophysiology includes the activation and release of pancreatic enzymes in the interstitium, the autodigestion of the pancreas, and a multiple organ dysfunction after their release into the systemic circulation. Moreover, significant evidence exists that synthesis and release of proinflammatory cytokines and chemokines are also responsible for the local injury and systemic dispersion of the inflammation. The use of knockout mice devoid of active pro-or anti-inflammatory mediators allows examination of the effects of a specific cytokine without any drawbacks induced by pharmacological manipulations. The results obtained from these genetically modified mice show that numerous mediators have a major role in the pathophysiology of acute pancreatitis. They also clearly demonstrate that a single genetic deletion cannot completely prevent the occurrence of pancreatic or distant organ injury. However, the fact that the immune system is characterized by redundancies of ligands and receptors complicates the full understanding of each report. The utility of such experimental models might have limitations, and a full extrapolation of experimental data from genetically modified mice to humans must be done with caution.

In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury

“…They account for significant morbidity and mortality in patients with this disease (31). Recent studies, most of which have employed experimental models of pancreatitis, have indicated that a number of inflammatory factors regulate the coupling of pancreatic to lung injury (9,26). Those studies have shown that neutrophils (2, 10), T lymphocytes (10,22), adhesion molecules (10), platelet-activating factor (18), TNF-␣ (13,14), substance P (1), and chemokines acting via the CCR-1 receptor (13) are each involved in this process.…”

“…The use of knockout mice devoid of active proor anti-inflammatory mediators allows examination of the effects of a specific cytokine without the drawbacks induced by pharmacological manipulations (26), but one must keep in mind that the specific mutation has been present in the mouse from the time of its conception. This may result in phenotypic changes due to the mutation itself, but it may also result in changes caused by adaptation to and compensation for the mutation (26). This latter possibility would seem unlikely, however, in our studies, in view of our observation that deletion of GM-CSF alters neither lung morphology nor circulating leukocyte levels at 3 mo of age.…”

“…Several models of acute pancreatitis in experimental animals have been shown to be accompanied by measurable lung injury (9,14,15,37), and a number of recent studies have focused on identifying the factors that couple pancreatic inflammation to lung injury in those models (1,2,10,26). In the current communication, we have utilized the secretagogue (caerulein)-induced model of acute pancreatitis (20) in mice to examine the role played by granulocyte-macrophage colony-stimulating factor (GM-CSF) in mediating acute lung injury in this model.…”

Time-course proteomic analysis of taurocholate-induced necrotizing acute pancreatitis

“…The complexity of the interactions between these different pathways makes it difficult to understand which are the key factors in controlling disease course. In order to investigate pathobiological processes of AP, different experimental models of the disease have been developed in mammals [2][3][4]. These experimental models differ in the mechanisms of disease induction, the nature and extent of the pancreatic injury, the importance of the systemic response.…”

Carbon monoxide-bound hemoglobin vesicles ameliorate multiorgan injuries induced by severe acute pancreatitis in mice by their anti-inflammatory and antioxidant properties

“…43,44 For example, a marked attenuation of the severity of acute pancreatitis is observed when receptors for TNF-α and IL-1β are blocked, and the mortality is dramatically reduced in TNF-α and IL-1β knockout mice after the development of severe acute pancreatitis. [45][46][47] Moreover, anti-cytokine therapies against TNF-α and IL-1β showed protective effects in experimental animal models with severe acute pancreatitis. 48 Since the serum levels of TNF-α and IL-1β during the course of severe acute pancreatitis were decreased by a CO-HbV treatment (Figure 4), the therapeutic effect of CO-HbV could be modulated by the production of systemic cytokines.…”