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We have read with interest the article by Frossard et al (
) entitled “Both thermal and non-thermal stress protect against caerulein induced pancreatitis and prevent trypsinogen activation in the pancreas”. We have a few comments with regard to the interpretation of the data that were obtained in this experiment.
Previous experimental work by Frossard and others have implicated HSP70 as playing a protective role in caerulein induced acute pancreatitis. In the present study Frossard et al showed that thermal and non-thermal stress induced by injection of the β agonist isoproterenol upregulated HSP70 in the pancreas which is associated with amelioration of subsequently induced caerulein pancreatitis. The authors hypothesise that the protective effects on pancreatitis severity caused by thermal and non-thermal stress may by mediated by HSP70. We believe however that both heat shock stress and non-thermal stress can stimulate several other anti-inflammatory pathways which were not discussed in this study, all of which could be alternative explanations for the observations that were made.
It is widely established that catecholamines, both endogenously released during heat shock stress or by injection of isoproterenol, can influence activation of inflammatory pathways during inflammation and infection1 (reviewed by van der Poll2). Evidence exists that catecholamines exert anti-inflammatory effects on a number of host mediator systems, such as the cytokine network and neutrophils, all of which are implicated in the pathogenesis of acute pancreatitis and the pancreatitis associated systemic inflammatory response syndrome. Catecholamines, either endogenously produced or exogenously administered, may act to dampen excessive proinflammatory pathways by mechanisms not related to enhanced production of heat shock proteins. Firstly, catecholamines exert anti-inflammatory effects on the cytokine network by inhibiting the production of proinflammatory cytokines such as tumour necrosis factor (TNF), interleukin (IL)-1β, IL-12, and interferon γ (IFN-γ), of which TNF and IL-1β have been implicated as mediators that play a proinflammatory role in acute pancreatitis.3,4 Secondly, in animal models of endotoxaemia, pretreatment with isoproterenol enhances the production of the anti-inflammatory cytokine IL-10 which has been shown to be protective in acute pancreatitis.5,6 Thirdly, in endotoxaemia models, β adrenergic stimulation results in reduction of levels of CC chemokines.7 Fourthly, neutrophil migration to the pancreas, one of the hallmarks of acute pancreatitis, towards chemotactic stimuli such as C5a and lipopolysaccharide (LPS) is reduced by administration of β agonists but also affects LPS induced neutrophil degranulation in vivo. Fifthly, with regard to the hypothesis that HSP70 prevents the activation of trypsinogen in the pancreas, it must be noted that recent evidence suggests that neutrophils and possibly cytokines can also influence trypsinogen activation. Therefore, the reduction in trypsinogen activation shown in their study might be unrelated to HSP expression and may be explained by the reduction of inflammation due to β adrenergic effects.8,9
Therefore, we believe that the conclusion by Frossard et al that the protective effects of thermal and non-thermal stress might be mediated by HSP70 is only one possible explanation and that their observations might also be explained by the immunomodulatory effects of catecholamines.
We thank van Westerloo et al for their interest in our paper and their comments on the interpretation of our data. They are of the opinion that besides heat shock proteins both thermal and non-thermal stress can stimulate several other anti-inflammatory pathways that in turn could be responsible for the protective effects observed in the study. Secondly, catecholamines can exert anti-inflammatory effects independent of heat shock proteins.
When we embarked on this project, we were also concerned that all the stresses that result in the induction of HSP70 may have other non-HSP related effects and did mention this in our discussion. At that point we did not have the tools to show the crucial protective role played by HSP70.
To prove that a cause-effect relationship exists between HSP70 expression and protection against pancreatitis, we adopted the antisense oligonucleotide approach in another recently published experimental study1 to indicate unequivocally that the thermal stress induced protection of intrapancreatic trypsinogen activation and protection against caerulein induced pancreatitis are mediated by HSP70. Furthermore, our studies have shown that HSP70 induction that occurs during the evolution of pancreatitis in non-thermally stressed rats acts to limit the severity of pancreatitis.
Using antisense oligonucleotides to HSP70, Nisoli and colleagues2 have also shown that the protective effects of noradrenaline against tumour necrosis factor α induced apoptosis in cultured rat brown adipocytes is due to nitric oxide induced HSP70 expression. In fact, catecholamines have been used in the past to induce heat shock proteins in several experimental systems.3,4
Westerloo et al have cited examples wherein exogenous or endogenous catecholamines inhibit the production of inflammatory cytokines and enhance the production of interleukin 10 (IL-10), an anti-inflammatory cytokine that has been shown to limit the severity of pancreatitis. Unfortunately, in the studies cited expression of HSP70 was not monitored. It is entirely possible that prior thermal or non-thermal stress induce HSP70 which may in turn lead to the enhanced production of anti-inflammatory factors and attenuation of proinflammatory cytokines. Indeed this has been shown to be the case in many experimental systems, including animal models of sepsis (reviewed by Bruemmer-Smith and colleagues5). Moreover, mycobacterial HSP70 has been shown to prevent adjuvant arthritis and induce IL-10 producing T cells.6
The mechanism(s) by which HSP70 might protect against caerulein induced pancreatitis is not yet known. Experiments examining the relationship between HSP70 and the inflammatory cascade induction during caerulein induced pancreatitis are currently underway.
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