Nutritional depletion of essential nutrient s have implicated in the etiology of many
organ dysfunction. In the experimental rodents, L-arginine induced partial inhibition
of L-arginase enzyme, which converts L-arginine to L-ornithine and urea 21]. High dose of L-ornithine has also been implicated to cause acute pancreatitis 22]. L-arginine is precursor of nitric oxide and nitrate which are known to induce oxidative
stress. It was reported that L-arginine could induce pancreatitis through activation
of neurotransmitters synthesis. It was found that, i.p. administration of L-arginine resulted in metabolic acidosis and reduction of pH of
urine samples reaching the most acidic values (pH?=?5.5–6.0). The production of oxygen
free radicals occurs early in acute pancreatitis, overwhelming the antioxidant defense
system. The acinar cells significantly contribute to the generation of large amounts
of oxygen free radicals at the early stages of acute pancreatitis.

Our results demonstrated that i.p. injection of 400 mg/kg bw arginine induced acute
pancreatitis and neutrophil infiltration in the pancreas as indicated by elevations
in serum amylase, lipase, and transaminase activities, in addition the IL-6 level
compared with the control. Pre- or post-treatment with L-lysine reversed these changes
(P??0.01). Lysine is antagonistic to arginine and competes with arginine for absorption,
re-absorption, and transport across the cell membrane. In vitro, lysine inhibits the growth-promoting action of arginine as a potential benefit in
managing arginine pancreatitis 23].

L-lysine protected the pancreas from injury by inhibiting the release of the inflammatory
cytokine IL-6. The mechanism by which L-lysine exerts an anti-inflammatory effect
may be inhibition IL-6 expression, a key regulator of inflammatory mediator expression,
as an early event in experimentally induced pancreatitis, which correlates with the
inflammatory response. In addition, L-lysine inhibited lipid peroxidation by decreasing
MDA production through the release of IL-6. This observation is in agreement with
our results. MDA is a marker of lipid peroxidation, and NO levels were significantly
elevated while antioxidants were significantly decreased in arginine-injected mice
compared with the control group. While the activities of antioxidant enzymes, including
SOD, catalase, glutathione peroxidase, were significantly increased in response to
L-lysine, indicating that L-lysine is an indirect antioxidant. These results were
supported by the histological examination revealing an improvement in the arrangement
of cells, normal nuclei, and decreases in macrophage and neutrophil infiltration.

Recent study reported that cytokines as IL-6 released from the inflamed pancreas can
induce the synthesis of the inducible nitric oxide synthase, resulting in elevation
of free NO, which serve as a key cellular mediator of inflammation 22]. This finding is in accordance with our results showing a reversal of pancreatitis
by L-lysine administration.

In this study, the level of NO was significantly higher in the arginine-treated group
compared with that in the control group (P??0.001). NO is a highly reactive free radical that is produced from L-arginine by
a family of NO syntheses. Moreover, the released NO react with superoxide causes the
formation of peroxynitrite, which is a potent oxidant agent that play an important
role in the cellular damage. These findings are reflected by the decrease of SOD activity
in arginine-treated group and reversal by L-lysine treatment. The binding of peroxynitrite
with proteins led to nitration of tyrosine to form nitrotyrosine, which is a specific
a marker for peroxynitrite induced oxidative tissue damage. It is thus evident that
the increase of NO concentration is related to the lesion of pancreas and other organs.
In addition, the activity of SOD as an antioxidant was significantly decreased and
that of MDA as a lipid peroxidase was significantly increased, which further indicated
that free radical production and oxidation were intensified by arginine and reversed
by lysine administration.

Since cytokines are found to induce oxidative stress by the generation of oxygen free
radicals, iNOS expression, NO and superoxide production. Cytokine resulted in a large
increase in iNOS protein levels. This increment was inhibited by administration of
L-Lysine. As a consequence the amounts of NO was significant decreased. L-Lysine availability
was inversely proportional to superoxide production perhaps as a result in suppression
of pancreatitis.

The positive actions of L-lysine on antioxidant status is likely to reflect, in large
part, enhancement of GSH and/peroxidase systems as the main line of antioxidant defense.
GSH,may regenerate it from GSSG via a GSSG reductase catalyzed reaction. The net action
of L-Lysine is to remove free radicals and protect against oxidative damage of these
radicals.

Lysine treatment significantly decreased the histopathological scores and protected
against elevation of serum amylase, ALT, AST activities, and IL-6 level. Pancreatic
injury and hydrolytic enzyme release activate pro-inflammatory cells, resulting in
the production of inflammatory mediators as cytokines, which cause a systemic multiple
organ injury 24], 25].

Nutritional depletion of essential nutrient s have implicated in the etiology of many
organ dysfunction. In the experimental rodents, L-arginine induced partial inhibition
of L-arginase enzyme, which converts L-arginine to L-ornithine and urea 21]. High dose of L-ornithine has also been implicated to cause acute pancreatitis 22]. L-arginine is precursor of nitric oxide and nitrate which are known to induce oxidative
stress. It was reported that L-arginine could induce pancreatitis through activation
of neurotransmitters synthesis. It was found that, i.p. administration of L-arginine resulted in metabolic acidosis and reduction of pH of
urine samples reaching the most acidic values (pH?=?5.5–6.0). The production of oxygen
free radicals occurs early in acute pancreatitis, overwhelming the antioxidant defense
system. The acinar cells significantly contribute to the generation of large amounts
of oxygen free radicals at the early stages of acute pancreatitis.

Our results demonstrated that i.p. injection of 400 mg/kg bw arginine induced acute
pancreatitis and neutrophil infiltration in the pancreas as indicated by elevations
in serum amylase, lipase, and transaminase activities, in addition the IL-6 level
compared with the control. Pre- or post-treatment with L-lysine reversed these changes
(P??0.01). Lysine is antagonistic to arginine and competes with arginine for absorption,
re-absorption, and transport across the cell membrane. In vitro, lysine inhibits the growth-promoting action of arginine as a potential benefit in
managing arginine pancreatitis 23].

L-lysine protected the pancreas from injury by inhibiting the release of the inflammatory
cytokine IL-6. The mechanism by which L-lysine exerts an anti-inflammatory effect
may be inhibition IL-6 expression, a key regulator of inflammatory mediator expression,
as an early event in experimentally induced pancreatitis, which correlates with the
inflammatory response. In addition, L-lysine inhibited lipid peroxidation by decreasing
MDA production through the release of IL-6. This observation is in agreement with
our results. MDA is a marker of lipid peroxidation, and NO levels were significantly
elevated while antioxidants were significantly decreased in arginine-injected mice
compared with the control group. While the activities of antioxidant enzymes, including
SOD, catalase, glutathione peroxidase, were significantly increased in response to
L-lysine, indicating that L-lysine is an indirect antioxidant. These results were
supported by the histological examination revealing an improvement in the arrangement
of cells, normal nuclei, and decreases in macrophage and neutrophil infiltration.

Recent study reported that cytokines as IL-6 released from the inflamed pancreas can
induce the synthesis of the inducible nitric oxide synthase, resulting in elevation
of free NO, which serve as a key cellular mediator of inflammation 22]. This finding is in accordance with our results showing a reversal of pancreatitis
by L-lysine administration.

In this study, the level of NO was significantly higher in the arginine-treated group
compared with that in the control group (P??0.001). NO is a highly reactive free radical that is produced from L-arginine by
a family of NO syntheses. Moreover, the released NO react with superoxide causes the
formation of peroxynitrite, which is a potent oxidant agent that play an important
role in the cellular damage. These findings are reflected by the decrease of SOD activity
in arginine-treated group and reversal by L-lysine treatment. The binding of peroxynitrite
with proteins led to nitration of tyrosine to form nitrotyrosine, which is a specific
a marker for peroxynitrite induced oxidative tissue damage. It is thus evident that
the increase of NO concentration is related to the lesion of pancreas and other organs.
In addition, the activity of SOD as an antioxidant was significantly decreased and
that of MDA as a lipid peroxidase was significantly increased, which further indicated
that free radical production and oxidation were intensified by arginine and reversed
by lysine administration.

Since cytokines are found to induce oxidative stress by the generation of oxygen free
radicals, iNOS expression, NO and superoxide production. Cytokine resulted in a large
increase in iNOS protein levels. This increment was inhibited by administration of
L-Lysine. As a consequence the amounts of NO was significant decreased. L-Lysine availability
was inversely proportional to superoxide production perhaps as a result in suppression
of pancreatitis.

The positive actions of L-lysine on antioxidant status is likely to reflect, in large
part, enhancement of GSH and/peroxidase systems as the main line of antioxidant defense.
GSH,may regenerate it from GSSG via a GSSG reductase catalyzed reaction. The net action
of L-Lysine is to remove free radicals and protect against oxidative damage of these
radicals.

Lysine treatment significantly decreased the histopathological scores and protected
against elevation of serum amylase, ALT, AST activities, and IL-6 level. Pancreatic
injury and hydrolytic enzyme release activate pro-inflammatory cells, resulting in
the production of inflammatory mediators as cytokines, which cause a systemic multiple
organ injury 24], 25].