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International Journal of Experimental Pathology logoLink to International Journal of Experimental Pathology
. 1999 Dec;80(6):317–324. doi: 10.1046/j.1365-2613.1999.00126.x

Nitric oxide protects the ultrastructure of pancreatic acinar cells in the course of caerulein-induced acute pancreatitis

Anna Andrzejewska *, Grazyna Jurkowska †
PMCID: PMC2517840  PMID: 10632781

Abstract

Nitric oxide (NO) as a unique biologicalmediator that has been implicated in many physiological and pathophysiological processes may have a significant influence on the course of acute pancreatitis and the recovery process. The aim of the study was to evaluate the effect of a NO synthase inhibitor or a substrate for NO endogenous production on the ultrastructural features of the acinar cells in the course of caerulein-induced acute pancreatitis. Acute pancreatitis was induced in the rats by a supramaximal dose of caerulein. During acute pancreatitis induction, the rats were treated with l-arginine (the substrate for NO synthesis), NG-nitro-l-arginine (L-NNA, NO synthase inhibitor), l-arginine + L-NNA or saline. Light and electron microscopy examinations were performed in all groups after pancreatitis induction and additionally after 7 and 14 days of recovery. The study demonstrated that the NO synthase inhibitor given during pancreatitis induction in rats enhances the damage to the acinar cells, detected ultrastructurally, and increases the cellular inflammatory infiltration. In the later period, the considerable damage to the mitochondria and the changes in secretory compartment were observed, including dilated cisternae of Golgi apparatus, focal degranulation of rough endoplasmic reticulum, and reduced number of zymogen granules and condensing vacuoles. l-arginine reversed to some extent the deleterious effect of L-NNA, although when administered alone it had no apparent effect on the ultrastructure of pancreatic acinar cells compared with untreated animals. The obtained results indicate that the NO synthase inhibitor enhances the ultrastructural degenerative alterations in the pancreatic acinar cells in the course of caerulein-induced acute pancreatitis and confirm the protective role of endogenous nitric oxide in this disease.

Keywords: acute pancreatitis, nitric oxide, ultrastructure

Nitric oxide (NO) is a molecule with many biological activities which may exert a beneficial effect on the course of acute pancreatitis. Satoh et al. (1994) set up a hypothesis on the protective role of NO in caerulein-induced pancreatitis according to which, NO acts as an agent preserving proper perfusion and as a mediator of cytoprotection in the early phases of caerulein acute pancreatitis. Nitric oxide produced by endothelial cells is an important regulator of vascular tone increasing capillary blood flow (Moncada & Higgs 1993; Kuo & Schroeder 1995; Rodeberg et al. 1995). This effect is of particular importance for the course of acute pancreatitis, since pancreatic blood flow in the caerulein model of acute pancreatitis may be reduced by 50% (Konturek et al. 1993). A beneficial effect of NO can be also exerted by the inhibition of adhesion and aggregation of platelets (Radomski et al. 1990; Bodzenta-Lukaszyk et al. 1994) and a decrease in neutrophil accumulation in the pancreas in acute pancreatitis (Inagaki et al. 1997). Nitric oxide donors or the substrate for NO synthesis were able to exert beneficial effects in mild and severe forms of acute pancreatitis and opposite effects after nitric oxide synthesis inhibition were found (Liu et al. 1995; Dobosz et al. 1997; Werner et al. 1997, 1998). Nitric oxide also regulates pancreatic secretion mainly through the modulation of pancreatic blood flow (Konturek et al. 1993, 1994) and according to Patel et al. (1995) it has a direct effect on the pancreatic acinar cells. However, some investigators do not confirm neither the detrimental influence of nitric oxide synthase (NOS) inhibitors nor the beneficial effects of l-arginine on the development of changes in the course of acute pancreatitis (Weindenbach et al. 1995). According to Abe et al. (1995) nitric oxide even promotes the pancreatic oedema in the mild form of acute pancreatitis. These contradictory results indicate that the role of nitric oxide in the course of acute tissue damage has not been clearly elucidated as yet (Anggard 1994; Billiar & Harbrecht 1997). It has also not been determined if modulation of NO synthesis can affect the ultrastructure of pancreatic acinar cells in acute pancreatitis.

Thus, the aim of the present study was to determine whether a nitric oxide synthase inhibitor or the substrate for its endogenous synthesis, administered during the induction of acute pancreatitis, affects the pancreas ultrastructure in the course of acute pancreatitis and recovery process after inflammatory damage.

Materials and methods

Animals

Male Wistar rats (n = 78) weighing 190–215 g were used in the study. The animals were given a standard chow diet. Care was provided in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals (NIH publication 85–23 1985).

Materials

Caerulein was purchased from Farmitalia Carlo Erba (Milan, Italy), soluble starch from Merck (Darmstadt, Germany). All other reagents were purchased from Sigma Chemical Co. (St. Louis, Mo.).

Experimental design

Acute pancreatitis was induced by subcutaneous (sc.) injections of caerulein (12 μg/kg body weight) every 8 h (t.i.d.) for 2 days. This analogue of cholecystokinin (CCK) was dissolved in gelatin (16% w/v) to prolong its absorption (Jurkowska et al. 1992). The control animals (n = 6) were injected instead of caerulein with saline in gelatin sc. in equivalent volumes; two of them were killed either after 2 days of experiment or after the next 7 and 14 days.

Acute pancreatitis rats were divided into the following treatment groups:

Group I. Acute pancreatitis rats given saline (n = 18);

Group II. Acute pancreatitis rats treated with l-arginine 200 mg/kg t.i.d. sc. (n = 18);

Group III. Acute pancreatitis rats treated with NG-nitro-l-arginine/L-NNA/10 mg/kg t.i.d. sc. (n = 18);

Group IV. Acute pancreatitis rats treated with L-NNA + l-arginine (n = 18).

These different treatment patterns were performed during the 2 days of caerulein injections. The experiment was terminated after either pancreatitis induction or after 7 or 14 days of recovery (6 rats in each group at each time point).

The animals were fed ad libitum with a standard diet during whole experiment, with a 12-h light-dark cycle. After an overnight fast, with free access to water, rats were sacrificed by decapitation. Representative specimens of pancreatic tissue from 5 rats from each acute pancreatitis group and from 2 rats of control group in respective time interval were fixed in 10% buffered formalin, embedded in paraffin and stained with haematoxylin and eosin (H & E) for histological examination. Small specimens of pancreatic tissue (3 from each animal) were fixed in 3,6% glutaraldehyde in 0.1 mol/l cacodylate buffer (pH 7.4) for 3 h and after washing in a buffer, postfixed in 2% osmium tetroxide for 1 h. The samples were dehydrated in alcohol and propylene oxide and then embedded in Epon 812. The ultrathin sections were cut from each block on a Reichert ultramicrotome, stained with lead citrate and uranyl acetate, and studied under a Opton 900 PC transmission electron microscope field by field. Fifty to 60 electron micrographs of most characteristic changes for each group was made. The determination of pathology was made blind.

Results

Light microscopy

After the induction of acute pancreatitis the distinct interstitial oedema accompanied by the inflammatory infiltration with granulocytes and macrophages was found in all experimental groups. Moreover, some acinar cells displayed the features of vacuolar degeneration and occasionally disintegration. These changes were similar in all groups with acute pancreatitis with a tendency to a more profuse inflammatory infiltration and degenerative changes in the L-NNA treated animals. After 7 days of recovery the oedema and inflammatory infiltration were maintained in the L-NNA group, being less pronounced in the remaining groups. After 14 days of recovery the histological picture of the pancreas in all experimental groups did not differ significantly from the pancreas of the control rats.

Electron microscopy

Control group

Ultrastructural picture of pancreatic acinar cells did not show any abnormalities (Figure 1a).

Figure 1.

Figure 1

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a. Numerous zymogen granules in the cytoplasm of the acinar cells. Control group — 2 days of the experiment. Bar = 2.5 μm; Mag. × 3000. b. The characteristics of acinar cells — dilated cisternae of Golgi apparatus (G) and rare zymogen granules accumulated around the acinar lumen (AL). Group I — acute pancreatitis, 2 days after first caerulein injection. Bar = 1.1μm; Mag. × 7000.

Group I Acute pancreatitis rats given saline

After acute pancreatitis induction the majority of acinar cells showed slight dilatation and focally irregular arrangement of rough endoplamic reticulum (RER) channels. Golgi apparatus was distinct and frequently formed new arrangements in the cell; some of the cisternae were markedly dilated and filled with amorphous material. Zymogen granules were less numerous than in the control group (Figure 1b). Some mitochondria displayed rarification of the matrix. Small phagosomes were seen occasionally. After 7 days following acute pancreatitis induction the ultrastructural picture of the acinar cells resembled that described above. However, after 14 days it was almost normal — only some acinar cells contained phagosomes or showed the increased rarification of the mitochondrial matrix, and sporadically myelinic structures within the mitochondria.

Group II Acute pancreatitis treated with l-arginine

The ultrastructure of the acinar cells in early phase of acute pancreatitis in the group of l-arginine treated animals resembled that observed in rats with the untreated acute pancreatitis. After 7 days, the features of acinar cells damage were slightly more pronounced — the numerous mitochondria were swollen and contained myelinic structures. Focal degranulation of RER was frequently observed (Figure 2). Cisternae of Golgi apparatus were distended and contained amorphous material. Zymogen granules were scarce. After 14 days the ultrastructural picture of most acinar cells was nearly normalized (Figure 3).

Figure 2.

Figure 2

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A large area of degranulated rough endoplasmic reticulum channels (RER) and mitochondria (M) with focal rarification of their matrix in the cytoplasm of an acinar cell. Group II — acute pancreatitis treated with l-arginine, 7 days of recovery. Bar = 1.1 μm; Mag. × 7000.

Figure 3.

Figure 3

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Nearly normal ultrastructural appearance of pancreatic acinar cells. AL, acinar lumen. Group II, acute pancreatitis treated with l-arginine, 14 days of recovery. Bar = 2.5 μm; Mag. × 3000.

Group III Acute pancreatitis treated with NG-nitro-l-arginine/L-NNA/

Following acute pancreatitis induction the presence of numerous, frequently large autophagosomes in the acinar cells cytoplasm was the predominant ultrastructural feature in the group of L-NNA treated animals. The number of autophagosomes observed in the cells was increased (both in the number of phagosomes per affected cell and in the total number of cells with phagosomes) when compared with untreated and l-arginine treated acute pancreatitis groups. These structures contained components of cytoplasm, membranous formations or amorphous masses (Figure 4). Zymogen granules were irregular in shape and diverse in diameter (Figure 5). Changes in the remaining organelles were similar to those in the untreated or l-arginine treated groups.

Figure 4.

Figure 4

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Large autophagosomes (Aph) in the cytoplasm of an acinar cell. Group III, acute pancreatitis treated with L-NNA, 2 days after first caerulein injection. Bar = 1.1 μm; Mag. × 7000.

Figure 5.

Figure 5

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Zymogen granules (ZG) irregular in shape and diverse in diameter accumulated in the vicinity of Golgi apparatus (G). Group III, acute pancreatitis treated with L-NNA, 2 days after first caerulein injection. Bar = 1.1 μm; Mag. × 7000.

After 7 days, compared with changes observed directly following acute pancreatitis induction, the damage to the mitochondria was considerably more pronounced — the most of these organelles showed features of swelling and focal destruction of the cristae. The number of phagosomes was decreased — they were rare and randomly dispersed in the cytoplasm. Areas of the RER degranulation were focally observed. Golgi apparatus was distinct and its cisternae contained floccular substance of intermediate electron density. In the Golgi area, in addition to normal condensing vacuoles, the large vacuoles with masses of amorphous material were seen (Figure 6). Zymogen granules and condensing vacuoles were quite numerous.

Figure 6.

Figure 6

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Various acinar cells with rare zymogen granules, damaged mitochondria (M) and large cisternae of Golgi apparatus (G). AL, acinar lumen. Group III, acute pancreatitis treated with L-NNA, 7 days of recovery. Bar = 1.7 μm; Mag. × 4400.

After 14 days of recovery, the damage to the mitochondria persisted — they varied in shape and size. The increased rarification of the matrix and destruction of the cristae were found. Numerous mitochondria contained the myelinic figures. The RER channels were numerous and densely arranged; however, large areas of degranulation were seen. Golgi apparatus was very large, with sometimes distortedly distended cisternae containing floccular or microgranular material. Rare zymogen granules and condensing vacuoles accumulated around the acinar lumen (Figure 7). Only scarce autophagosomes were observed.

Figure 7.

Figure 7

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Large vacuoles with masses of amorphous material (X) in the Golgi area, swollen mitochondria (M) with destruction of the cristae, myelinic figures and rarification of their matrix in the cytoplasm of an acinar cell. Group III, acute pancreatitis treated with L-NNA, 14 days of recovery. Bar = 1.1 μm; Mag. × 7000.

Group IV Acute pancreatitis treated with L-NNA + l-arginine

After acute pancreatitis induction acinar cells showed relatively numerous autophagosomes. Mitochondria displayed considerable pleomorphism, although only some of them showed the increased matrix rarification. The RER channels were numerous, sometimes dilated. Golgi apparatus revealed no significant changes. Zymogen granules and condensing vacuoles were numerous, varied in size and usually accumulated around the acinar lumen.

After 7 days, ultrastructural picture showed considerable damage to the mitochondria similar to that observed in acute pancreatitis + L-NNA group. Areas of RER degranulation were also visible. The cisternae of Golgi apparatus were dilated. The quantity of zymogen granules and condensing vacuoles compared with the group after 2 days was significantly reduced. Autophagosomes were small and rare.

After 14 days the damage to mitochondria was not so pronounced as after 7 days. Golgi apparatus cisternae were less dilated and less deformed compared with acute pancreatitis + L-NNA group (Figure 8). The number of zymogen granules was variable: from numerous to almost lacking in some acinar cells.

Figure 8.

Figure 8

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Part of acinar cell — note much less damage of mitochondria (M) than in group III presented at Figure 7. G, Golgi apparatus. Group IV, acute pancreatitis treated with L-NNA + l-arginine, 14 days of recovery. Bar = 1.1 μm; Mag. × 7000.

Discussion

Our results indicate that the inhibition of NO synthase (NOS) worsens the ultrastructural picture of acute pancreatitis. The presence of the numerous, large autophagosomes in the cytoplasm of acinar cells was the major feature in the NOS inhibitor treated group 2 days after the first caerulein injection. These structures appear in consequence of focal cytoplasm degradation and damage to the membranes of cell organelles. In the groups not treated with L-NNA, autophagosomes were small and rare, suggesting much less damage to the acinar cells. These findings, evident in the electron microscopy examination were not revealed in the light microscopy. The role of various NOS inhibitors in the aggravation of pancreatic damage or the converse protective effect of nitric oxide in acute pancreatitis has been reported by other investigators (Liu et al. 1995; Molero et al. 1995; Dobosz et al. 1997; Werner et al. 1997, 1998; Vaquero et al. 1998). The main mechanism of the beneficial NO effect in acute pancreatitis is probably dependent on the improvement of the microcirculation and inhibition of neutrophil adhesion and accumulation in small vessels (Inagaki et al. 1997). Leucocytes and macrophages can initiate or aggravate cell damage through different mechanisms, including reactive oxygen species, cytokines and a large quantity of nitric oxide produced by the inducible form of NOS (Feigl 1988; Billiar 1995; Rodeberg et al. 1995; Brown et al. 1998). We suggest that in the L-NNA treated group these mechanisms were more intense compared with the other groups resulting in more severe damage to the acinar cells and a more profuse inflammatory infiltration in the early phase of acute pancreatitis. This damage was mainly to the mitochondria, which after 7, and particularly after 14 days displayed characteristic features of injury: pleomorphism, marked swelling, partial destruction of the cristae, rarification of matrix and formation of numerous myelinic figures. These changes, although pronounced, do not always indicate irreversible degeneration, but may reflect sublethal changes due to ATP deficiency in acute pancreatitis (Halangk et al. 1997). Structural mitochondrial lesions usually lead to energy deficiency in the cells. Thus, the lack of sufficient energy supply may induce the morphological abnormalities found in L-NNA treated group 7 and 14 days after acute pancreatitis induction. These changes include considerable dilatation of Golgi cisternae, large areas of the RER degranulation and the reduced number of zymogen granules and condensing vacuoles.

The data concerning the connection between morphological alterations of pancreatic mitochondria and nitric oxide in acute pancreatitis are lacking. Immunocytochemical examinations have revealed an inducible form of NOS in the internal mitochondrial membranes of the rat liver and brain (Bates et al. 1995). Giulivi et al. (1998) demonstrated that liver mitochondria are the source of large quantities of NO, the production of which may affect energy metabolism, oxygen consumption, and reactive oxygen species formation. It is known that NO reversibly inhibits mitochondrial respiration by competing with oxygen at the level of cytochrome oxidase (Brown 1995, 1997; Poderoso et al. 1996; Richter 1997). The presence of any form of NOS in the pancreatic acinar cells has not been shown in immunomorphological studies, however, biochemical assays indicate that NOS activity is present (Gukovskaya & Pandol 1994; Molero et al. 1995).

The administration of l-arginine concomitantly with L-NNA partly prevented the ultrastructural changes found in the acinar cells of the NOS inhibitor treated animals. Our results indicate that l-arginine applied alone did not affect the ultrastructure of the acinar cells in the course of acute pancreatitis, compared with the untreated animals. However our former biochemical studies suggest the beneficial effect of the substrate for NO synthesis on the course and recovery after acute pancreatitis (Jurkowska et al. 1999).

The obtained results indicate that:

•the inhibitor of NO synthase (L-NNA) given during acute pancreatitis induction in rats enhances damage to the acinar cells detected in ultrastructural examination;

•the administration of L-NNA during acute pancreatitis induction leads to the damage of mitochondria and induces changes in the secretory compartment of acinar cells during recovery following acute pancreatitis;

•l-arginine partly prevents the deleterious effect of L-NNA on the ultrastructural changes in the rat pancreas in acute pancreatitis.

In conclusion we suggest that undisturbed synthesis of endogenous NO plays an essential role in the limitation of destructive mechanisms in caerulein acute pancreatitis, both in the early phase and in the recovery period.

Acknowledgments

This study was supported by the Medical Academy of Bialystok within the project nr 3-12854.

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