Parimal Chowdhury

Pathophysiological effects of nicotine on the pancreas: an update.

Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic diseases. It is well recognized that nicotine, a major component in cigarette smoke, is an addictive agent and, therefore, reinforces smoking behavior. The current review update focuses on the genetics of nicotine dependence and its role on the development of pancreatic diseases. The role of smoking and nicotine in pancreatitis and pancreatic cancer development is also discussed. Exposure of laboratory animals to nicotine clearly supports the notion that nicotine can induce pancreatic injury. The mechanism by which nicotine induces such effects is perhaps mediated via signal transduction pathways in the pancreatic acinar cell, leading to enhanced levels of intracellular calcium release, resulting in cytotoxicity and eventual cell death. The induction of pancreatic injury by nicotine may also involve activation and expression of protooncogene, H-ras, which can increase cytosolic calcium via second messenger pathways. Development of pancreatic carcinoma in cigarette smokers as observed in human populations may be the result of activation and mutation of the H-ras gene. A possible pathogenetic mechanism of nicotine in the pancreas activating multiple signal transduction pathways is schematically summarized in Figure 1.

Metabolic and pathologic effects of nicotine on gastrointestinal tract and pancreas of rats

We examined in male Sprague-Dawley rats the effects of nicotine at doses of 50 (0.31 mM) and 200 mg/L (1.23 mM) given for a period of 16 weeks on body weight gain, food and fluid intake, plasma CCK, glucose and insulin levels, amylase secretory responses of isolated pancreatic acinar cells to CCK 8 and carbachol, and histopathology (gross and light microscopy) of stomach and pancreas. These parameters were re-examined further in animals treated with nicotine at doses of 200 mg/L (1.23 mM) for 12 weeks and given tap water for an additional 4 weeks to evaluate the effects of nicotine withdrawal. Metabolic data suggest that decreases in body weight gain, food and fluid intake, and plasma levels of glucose and insulin by nicotine are dose dependent. Endocrinological studies showed that the plasma levels of CCK were significantly increased with nicotine but the amylase secretory response of pancreatic acinar cells was inhibited in response to CCK-8 and carbachol. Histopathologic data revealed that treatment of animals with a high dose of nicotine enhanced the appearance of numerous vacuoles in the pancreatic acinar cell cytoplasm. When the pancreatic acinar cell morphology was closely examined, it showed evidence of pyknotic nuclei and fusion of vacuoles. Prominent loss of gastric mucosal surface was found in nicotine-treated animals with gross microscopic evidence of bleeding ulcers. All of the metabolic parameters except body weight gain were reversed upon nicotine withdrawal. In addition, plasma CCK levels and pancreatic enzyme secretion were reversed upon nicotine withdrawal. Histopathologic data showed a partial but not a complete recovery of the pancreatic acinar cell morphology and gastric mucosal surface following 4 weeks of nicotine withdrawal. The data suggest that nicotine ingested chronically alters metabolic, endocrine, and pathologic factors that may be responsible, at least in part, for the development of gastrointestinal ulcers and pancreatitis. These alterations appear to have been substantially prevented by abstinence of nicotine ingestion.

Smoking and pancreatic disorders.

Cigarette smoking is a major risk factor for pancreatic cancer and probably pancreatitis. It has been reported that patients with chronic pancreatitis are 16 times more likely to develop pancreatic cancer than normal individuals. Nicotine, a major component of tobacco and an addicted drug of abuse in humans, appears to play a role in the aetiology of both pancreatic cancer and pancreatitis. This review discusses major published reports pertaining to the influence of nicotine on these diseases in humans and the probable effects of nicotine on the pathophysiology of the pancreas in animal models. A hypothetical pancreatic acinar cell model showing multiple signal transduction pathways is presented relating to possible mechanisms of action of nicotine on the pathophysiology of the pancreas.

Structural and functional changes of rat exocrine pancreas exposed to nicotine

SummaryNicotine, an addictive agent in cigaret smoking, has been implicated in the etiology of pancreatitis and pancreatic carcinoma. Very little experimental data are, however, available regarding the effects of nicotine on the structural and functional changes in the exocrine pancreas. Two groups of rats divided into control and nicotine exposed were used. The animals in the nicotine group were maintained for 28 d with ad libitum water containing 0.77 mM of nicotine. At term, the animals were sacrificed, and pancreas was examined for pathological and functional changes. Nicotine induced cytoplasmic vacuolation and cellular edema in the exocrine pancreas. Plasma levels of glucose and insulin and CCK-8-stimulated amylase release in isolated acini were significantly decreased by nicotine, whereas the total cellular amylase content was significantly increased. Analysis of competitive ligand binding data on membranes from isolated acini showed that theBmax andKd values for CCK receptors were not significantly changed by nicotine,p>0.05. These data indicate that a postreceptor mechanism is involved in the inhibition in stimulus-secretion coupling of enzyme secretion by nicotine. The increase in total cellular amylase content and decreased enzyme secretion by nicotine may be implicated in the induction of pancreatic pathology.

PATHOPHYSIOLOGICAL EFFECTS OF NICOTINE ON THE PANCREAS

Nicotine, a major component of tobacco and cigarette smoking is an addictive agent and has been characterized as a drug of abuse by the US Surgeon General (1–3). The economic burden due to abuse of this drug is substantial because of the well-documented pathophysiological effects of nicotine on organs in the cardiovascular, respiratory, hepatic, renal, and nervous systems (3). Association of nicotine through cigarette smoking with the increased incidence of pancreatitis and pancreatic cancer has also been reported (4–18). A survey on the association between cigarette smoking and pancreatic cancer showed that cigarette smokers had a significant 70% higher risk of pancreatic cancer in comparison to nonsmokers (8–16). When compared with nonsmokers, subjects who smoke filtered cigarettes had a 50% elevated risk. The proportion of pancreatic cancer attributable to cigarette smoking was 29% in blacks and 26% in whites (10). Most of the data that link cigarette smoke/nicotine to pancreatic diseases were gathered in humans. Recent studies with animals have also shown that nicotine or its metabolites could induce pathological and functional changes in the pancreas (17–25). This review will present and discuss the current understanding of the pathophysiology induced by nicotine in the exocrine pancreas and the possible mechanism of action of nicotine. Effects of Nicotine and its Metabolites on the Structural and Functional Changes of the Exocrine Pancreas Cotinine and nornicotine are natural metabolites of nicotine. About 80%-90% of the dose of nicotine consumed can be accounted for in human urinary metabolites. In rodents, hepatic nicotine metabolism is found to involve cytochrome p450s that catalyze the first step of this pathway (26, 27). It has been demonstrated that pancreatitis could be induced in mice fed a caerulein and choline-deficient ethionine (CDE) supplemented diet (28–33).

Effect of L364718, a new CCK antagonist, on amylase secretion in isolated rat pancreatic acini

We examined the effect of L364718, a new cholecystokinin (CCK) receptor antagonist, on amylase release stimulated by CCK or different secretagogues in isolated rat pancreatic acini. L364718 caused a parallel rightward shift of the dose-response curve of CCK8. Schild plots showed a slope of 1.05 ± 0.15 and a pA2 value of 10.01 ± 0.31. L364718 inhibited maximally stimulated amylase release by CCK in a dose-dependent manner, with half maximal inhibition (ID5,) at 1.7 nM and complete inhibition at 30 nM. Asperlicin, a prototype compound of L3M718, also caused dose-dependent inhibition, but L364718 was approximately 400 times more potent than asperlicin (ID50 = 761 nM). L364718 significantly inhibited amylase release in response to CCK33 and CCK8 but had no effect on amylase release stimulated by other receptor secretagogues or agents bypassing receptors. The results indicate that L364718 acts as an extremely potent, competitive, and specific antagonist of CCKs action on pancreatic acini.

Induction of pancreatic acinar pathology via inhalation of nicotine

Abstract This study was conducted to determine the effects of nicotine inhalation on the onset, progression, and sequential development of pancreatic lesions. Male Sprague-Dawley rats in groups of five were exposed to saline or nicotine aerosol twice daily for 15, 30, 45, and 60 min for 21 days. After sacrifice, blood samples were analyzed for plasma levels of nicotine, glucose, gastrin, and cholecystokinin. Pancreatic tissues were examined for pathological lesions. While there were no significant differences in plasma levels of glucose, gastrin, and cholecystokinin in all groups, there was a steady increase in plasma levels of nicotine with increased exposures to nicotine. Histopatho-logical examination of pancreatic tissue revealed definitive pancreatic injuries that also appeared to be directly correlated with increased duration of nicotine exposure. The pathological changes of the pancreas were confined only to acinar cells of the exocrine pancreas. Two main types of cellular changes were observed: cellular swelling/vacuolation and nuclear condensation/cellular pyknosis. Both of these changes indicated tissue injuries in the pancreas. Transformation of the glandular acini to solid masses of epithelial cells was also observed. The results from our present study strongly suggest that the exocrine pancreas is very sensitive and susceptible to nicotine toxicity. Our data further indicate that early morphological changes in the pancreas induced by nicotine may occur without functional or metabolic alterations; however, such changes could occur at a later stage, when tissue and cellular changes become more extensive.

A cell-based approach to study changes in the pancreas following nicotine exposure in an animal model of injury

BackgroundCigarette smoking is a recognized risk factor for the induction of pancreatic diseases and is suspected to play a major role in the development of pancreatic cancer in smokers.Materials and methodsThis study was designed to characterize the mechanisms of nicotine-induced injury to the pancreas. AR42Jcells, a stable mutant pancreatic tumor cell line, was chosen for the study because of its stability in culture media and also because of its known secretory capacity, which is like that of a normal pancreatic acinar cell. It is hypothesized that nicotine-induced effects on the pancreas are triggered by oxidative stress induced in pancreatic acinar cell via oxidative stress signaling pathways.ResultsThe results from our study showed that, in vitro, nicotine induced generation of oxygen free radicals measured as malondialdehyde, an end product of lipid peroxidation. Treatment of AR42J cells with nicotine induced p-ERK 1/2 activation as confirmed by Western blot and immunofluorescence imaging of cytoplasmic localization of mitogen-activated protein kinase (MAPK) signals. Nicotine enhanced AR42J cell proliferation and cholecystokinin-stimulated amylase release in AR42J cells. These effects of nicotine were confirmed by simultaneous studies conducted on the same cells by hydrogen peroxide, a known oxidative biomarker. Allopurinol, a XOD inhibitor, suppressed these effects induced by nicotine and H2O2 with the exception that cholecystokinin-stimulated amylase release by H2O2 remained unaltered when AR42J cells were preincubated with allopurinol. These results suggest that nicotine-induced effects on pancreatic acinar cells were associated with generation of oxyradical mediated via the XOD pathway. The results have a direct impact on cell proliferation, MAPK signaling, and acinar cell function.ConclusionWe conclude that nicotine induces oxidative stress in pancreatic acinar cells and that these events trigger pathophysiological changes in the pancreas, leading to increased cell proliferation and injury.

L-364,718, a new CCK antagonist, inhibits postprandial pancreatic secretion and PP release in dogs.

The effects of L-364,718, a new CCK receptor antagonist, on food-stimulated exocrine pancreatic secretion and plasma levels of PP, insulin, CCK, and gastrin were examined in four conscious dogs with pancreatic fistulas. Intravenous injections of L-364,718 (20 nmol/kg) significantly inhibited pancreatic protein and enzyme responses by food (33% inhibition) but not juice volume output. Both rapid and secondary prolonged postprandial rises of plasma PP were also significantly suppressed by L-364,718 (50% inhibition); however, plasma levels of insulin were not altered. Postprandial levels of gastrin were not affected by L-364,718 administration, whereas 3-hr integrated CCK response was significantly enhanced by L-364,718. This study indicates that L-364,718 inhibits pancreatic protein and enzyme secretion and the release of pancreatic polypeptide stimulated by food in conscious dogs. This inhibition might be due to the selective blockage of receptor binding of circulating CCK molecules. The results suggest that L-364,718 may be useful for the physiological and pathophysiological studies associated with CCK.

Inhibition of CCK or carbachol- stimulated amylase release by nicotine

This study was undertaken to investigate the mechanisms of action of nicotine on receptor mediated enzyme secretion in isolated rat pancreatic acini. Acinar cells were isolated from untreated and nicotine treated rats by collagenase digestion and differential centrifugation. Cells from the untreated animals were incubated with either varying concentrations of nicotine (range 10 microM to 30 mM) or with a fixed dose of 10 mM nicotine with varying concentrations of carbachol(10nM to 100 microM). Cells from the nicotine treated animals(16 weeks in drinking water) were incubated with either a fixed dose of CCK-8(10(-10) M) or carbachol(10(-5) M). All incubations were conducted at 37 C for 30 min. Amylase released in the media was measured by spectrophotometry. In pancreatic acinar cells isolated from control rats, amylase release stimulated by carbachol was inhibited by nicotine. Acinar cells isolated from rats treated with nicotine at nicotine concentrations of 1.23 mM also showed significant inhibition of amylase release in response to CCK-8 and carbachol compared to their identical controls. Nicotine induced inhibition curves of amylase release stimulated by carbachol were non-parallel suggesting that the effect of nicotine on acinar cells is regulated by mechanisms other than carbachol receptors. Nicotine may have a direct inhibitory effect on the intracellular mechanisms of pancreatic enzyme secretion. We conclude that the mechanism by which nicotine inhibits pancreatic enzyme secretion is complex.