The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis

Premature activation of digestive enzymes within the pancreas which leads to autodigestion of the gland is an early step in the pathogenesis of pancreatitis. Pancreatic injury is followed by other manifestations of inflammation including plasma extravasation, edema, and neutrophil infiltration which constitute the features of pancreatitis. Recent studies indicate that neural innervation of the pancreas may play an important role in the initiation and maintenance of the inflammatory response to injury. The pancreas is innervated by vagal, sympathetic and parasympathetic neurons, as well as sensory neurons. Activation of pancreatic primary sensory neurons causes the release of inflammatory neuropeptides both in the spinal cord to signal pain and in the pancreas itself where they produce plasma extravasation and neutrophil infiltration. Recent studies indicate that primary sensory neurons of the pancreas express transient receptor potential V1 (TRPV1) channels whose activation induces pancreatic inflammation. Moreover, blockade of these TRP channels significantly ameliorates experimental pancreatitis. This review describes our current understanding of the role of TRPV1 channels in pancreatitis and illustrates how this mechanism might be used to direct future treatments of pancreatic diseases.     

Glucagon secretion in chronic pancreatitis.

Plasma insulin, pancreatic glucagon and immunoreactive glucagon-like polypeptide of intestinal origin (enteroglucagon) have been measured in 10 patients with chronic pancreatitis and 5 normal subjects. Basal levels and changes following oral glucose (50 g) and an intravenous infusion of arginine (25 g in 30 min) have been studied. In patients with chronic pancreatitis the plasma insulin response to oral glucose and intravenous arginine was reduced. Basal pancreatic glucagon was increased in the patients and increased further with oral glucose. During an arginine infusion the pancreatic glucagon showed a brisk early increase greater than that seen in the normal subjects. Basal enteroglucagon levels were significantly increased in chronic pancreatitis but response to orla glucose and arginine infusion were little different from those seen in the normal subjects.     

Receptor tyrosine kinases.

A major process through which environmental information is transmitted into cells is via activation of protein tyrosine kinases. Receptor tyrosine kinases contain extracellular ligand recognition, single membrane spanning, and cytoplasmic protein tyrosine kinase domains. The cytoplasmic kinase core is flanked by regulatory segments, which in some family members are also inserted into the core kinase domain. Ligand binding initiates receptor signaling from the cell surface. Activated receptors autophosphorylate to remove alternate substrate/inhibitory constraints and to provide loci for assembly of proteins that contain SRC homology regions. Information is transmitted and diffused by tyrosine phosphorylation of the assembled proteins and of cellular substrates that include protein kinases with specificity for serine/threonine residues. Signaling, which is strictly ligand-dependent, is attenuated by down-regulation of receptors and by feed-back inhibitory loops that involve receptor phosphorylation by cellular kinases. The tyrosine kinase receptors are essential for normal growth, development, and reparative processes. Mutations that remove normal regulatory constraints on the approximately 290 amino acid kinase core of these large proteins result in constitutive function and cell transformation.     

Indications for surgery in necrotizing pancreatitis.

The decision to operate on a patient with severe acute pancreatitis is often difficult and requires mature clinical judgment. Indications that are widely accepted include to establish the differential diagnosis, when the surgeon is concerned that the symptoms are due to a disease other than pancreatitis for which an operation is mandatory; in persistent and severe biliary pancreatitis, when an obstructing gallstone is lodged in the ampulla of Vater and cannot be managed endoscopically; in the presence of infected pancreatic necrosis; and to drain a pancreatic abscess, if percutaneous drainage does not produce the desired result. Other indications that are less well defined and somewhat controversial are the presence of sterile pancreatic necrosis involving 50% or more of the pancreas, when the pancreatitis persists despite maximal medical therapy, and when a patient''s condition deteriorates. For these last three indications, guidelines have been presented that permit a logical approach to management, although uncertainty remains. Surgeons should strive to describe in detail and precisely the clinical state of their patients at the time that an operation is done, as well as the findings and technical details of the operation. This should allow further refinement in the management of this vexing problem.     

Patterns of incidence in acute pancreatitis.

A review of acute pancreatitis occurring over a 20-year period in the Bristol clinical area is reported. A total of 590 cases were available for analysis. The yearly incidence was 53-8 per million population at risk, with a mortality of 9-0 per million. This compares favourably with 11-4 deaths per million for England and Wales as a whole during the same period but the difference is not statistically significant. When the deaths occurring in the Bristol clinical area were expressed in terms of case mortality rate the figure was 17%. In contrast the mortality for recurrent acute pancreatitis was only 1-5%, and the benign nature of this second condition is confirmed. Aetiological factors and age and sex distribution were also analysed in relation to each other and to mortality. An increase in acute pancreatitis secondary to chronic alcoholism was confirmed and steroid pancreatitis also emerged as a definite entity in this survey. The pattern of recurrence in patients with idiopathic pancreatitis was studied in detail and is analysed on an actuarial basis.     

Anti-cytokine strategies.

Although antibiotics and support systems have reduced the mortality due to bacterial infections, 40-50% mortality is still an unacceptable statistic. Anti-LPS (anti-lipid A) passive immunotherapy has reduced this mortality but only in patients with documented Gram-negative bacteriemia. However, anti-cytokine therapy such as monoclonal antibodies to TNF and the IL-1ra have reduced mortality to all infectious causes. IL-1ra is presently in Phase III trials as is monoclonal anti-TNF. Two other strategies are soluble (extracellular domains) receptors to TNF and IL-1. These are now entering Phase I trials but animal data strongly support that similar to antibodies to TNF and IL-1ra, these anti-cytokine therapies will also be effective.     

Management of necrotizing pancreatitis.

A comprehensive management plan is presented for patients with severe acute pancreatitis. These patients may have pancreatic or peripancreatic necrosis or pancreatic fluid collections. Multiple organ failure often develops in patients with severe pancreatitis. We therefore recommend that all patients with acute pancreatitis be evaluated for pancreatic anatomy and function. If a patient is seriously ill, a computed tomographic (CT) scan with vascular enhancement should be done. Meanwhile, vigorous fluid replacement is necessary using Swan-Ganz monitoring. Patients with necrosis do not need surgical intervention unless the clinical course or CT scan-guided aspiration shows infection. The objective of an operation should be to remove all infected tissue and fluid. A preoperative CT scan with vascular enhancement should be used as a guide during the operation to ensure that all foci of infected necrosis or fluid are eliminated. We have found that open packing and irrigation with sodium oxychlorosene are helpful in patients with extensive necrosis or those who become infected early after the onset of symptoms. In all, 40% to 50% of patients treated by closed drainage will require reoperation because of incomplete debridement. Persistent sepsis is an indication for reoperation.     

Receptor binding of asialoerythropoietin.

The interaction of 125I-asialoerythropoietin (asialoepo) with receptors has been characterized both by binding assay and affinity cross-linking. Purified spleen cells from mice infected with the anemia strain of Friend virus (FVA cells) have receptors for 125I-asialoepo with two classes of affinity constant: one with Kd = 0.02-0.03 nM and 300-400 per cell, the other with lower affinity (Kd = 0.9-1.2 nM) and 1,000-1,200 per cell. The Kd value for the high affinity site is one-third of that for the binding of native 125I-erythropoietin (125I-epo) to the same FVA cells (Kd = 0.08-0.1 nM). Using 125I-asialoepo or 125I-epo affinity cross-linking methods, we find two components with apparent molecular weights of 88 kDa and 105 kDa in FVA cells, and in the transformed mouse cell lines, 201, IW32, and NN10, in agreement with earlier studies using 125I-epo. These results indicate that 125I-asialoepo binds to the same receptors as 125I-epo, but with greater affinity for the high affinity site. Since 201 cells contain only a single class of lower affinity receptors for erythropoietin (epo), finding the same two components as found for FVA cells by cross-linking experiment indicates that the two components do not represent the two classes of receptor.     

Receptor subtypes involved in tachykinin-mediated edema formation.

Intradermal (ID) injection of the natural tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) (0.3-30 nmol) resulted in a marked and dose-related rat paw edema, with mean ED50 values of 2.68 nmol, 1.17 nmol, and 0.80 nmol, respectively. The ID injection of the selective NK1, SP methyl-ester (1-30 nmol), NK2, [beta-Ala8]-neurokinin A4-10) (beta-Ala, 0.3-30 nmol), or NK3, senktide (1-10 nmol) agonists, caused extensive edema formation with mean ED50s of 0.48 nmol, 0.41 nmol, and 0.18 nmol, respectively. The ID injection of the selective NK1 antagonist FK888 (0.1-3 nmol) produced marked inhibition (94%, 52%, and 66%, respectively) of rat paw edema induced by SP, NKA, or SP methyl-ester. The ID co-injection of the NK2 receptor antagonist SR 48968 elicited a graded inhibition (52%, 67%, and 35%, respectively) of rat paw edema induced by NKA, beta-Ala and, to a lesser extent, the edema caused by SP. Finally, the ID co-injection of the NK, receptor antagonist SR 142801 significantly inhibited (53%, 76%, 53%, and 100%, respectively) the edema formation caused by NKB and NKA or by SP and senktide. Together, the data of the present study suggest that tachykinin-mediated rat paw edema depends on the activation of NK1, NK2 and NK3 receptor subtypes, with apparent major involvement of NK1 receptors subtypes.     

Evolutionary equilibrium strategies.

This paper re-examines the concept of evolutionary stability proposed by Maynard Smith.For any finite population it is shown that a strategy which is stable in the sense of Maynard Smith may have a lower fitness than a mutant strategy regardless of the proportion of contestants using the latter.Two alternative concepts of evolutionary stability are then proposed. A strategy is described as being strongly stable if no mutant is able to invade because of its higher fitness and weakly stable if it has a higher fitness whenever the contestants using any particular mutant strategy become sufficiently numerous.For the “war of attrition” between contestants of a given species Maynard Smith and others have argued that the evolutionarily stable strategy is for a contestant to bid (for food or territory) by attempting to wait out its opponent according to an exponential mixed strategy. This paper establishes that such a strategy is only weakly stable and that for any number n there exists a mutant strategy with a higher fitness until the number of mutants in the population exceeds n.The final section reconsiders the stability issue when a natural informational asymmetry is introduced. Each contestant is assumed to be uncertain as to the value its opponent places on the object over which they are competing. In contrast to the symmetric case it is shown that there is a strategy which is strongly stable with respect to any feasible mutant as long as the population is sufficiently large.