Elevated Histidine Decarboxylase Activity Research Articles

Histamine levels in embryonic chicken livers infected with very virulent infectious bursal disease virus

Histamine is an endogenous nitrogenous compound with extensive effects on immunologic cells and involved in many physiological functions. The current aim was to determine histamine levels in embryonic liver and its association with the pathogenicity of a very virulent infectious bursal disease virus (vvIBDV) isolate serially passaged in chicken embryos. A vvIBDV isolate and the passaged viruses were inoculated into SPF embryonated chicken eggs (0.2ml per egg) via the chorioallantoic membrane. Embryonic livers were collected at 24, 48, 72, 96, and 120h post-inoculation and histamine contents were quantified by fluorescence spectrophotometry analyses. Results showed that the histamine content in embryonic livers infected with the original vvIBDV isolate and the early passaged viruses significantly increased 48h post-inoculation, as compared with the adapted IBDV isolate (p<0.01) and controls (p<0.01), with the concentration peaking from 72h to 96h. Most of the infected chicken embryos died from 48h to 96h post-inoculation. Moreover, the histamine content in dead embryos was markedly increased compared with live embryos (p<0.05), peaking at 72h post-inoculation (p<0.01). There was an association between histamine content in embryonic livers and an elevation in histidine decarboxylase activity. Taken together, our results suggest that an excess of histamine correlates with inflammatory responses during vvIBDV infection. This study provides an incremental step in the understanding of the pathogenesis of vvIBDV.

Histamine production via mast cell-independent induction of histidine decarboxylase in response to lipopolysaccharide and interleukin-1

Histamine modulates immune responses. There are at least two ways histamine might be supplied: one is its release from cells that pool pre-formed histamine and the other is its de novo formation via induction of histidine decarboxylase (HDC). Lipopolysaccharide (LPS) and the proinflammatory cytokine interleukin (IL)-1 induce a marked elevation of HDC activity in various tissues or organs. To examine the contribution of mast cells to HDC induction in mice given LPS or IL-1, we examined the effects of LPS and IL-1 on HDC activity and/or histamine content in various organs (liver, lung, spleen or bone marrow) in mast cell-deficient mice (W/W v), their normal littermates (+/+) and BALB/c mice deficient in IL-1α, IL-1β and tumor necrosis factor (TNF)-α (IL-1αβ/TNFαKO mice). In non-stimulated mice, the histamine in the lung and spleen was contained largely within mast cells. The LPS-stimulated increase in HDC activity in a given organ was similar between +/+ and W/W v mice, and between IL-1αβ/TNFαKO BALB/c and control BALB/c mice, and led to increases in histamine. In W/W v and +/+ mice, IL-1α also elevated HDC activity. These results suggest that (i) in liver, lung and spleen, either the major cells supplying histamine via HDC induction in response to LPS and IL-1 are not mast cells, or mast cells are not a prerequisite for the induction of HDC; (ii) the cells in which HDC is induced by LPS and IL-1 are similar or identical in a given organ; and (iii) neither IL-1 nor TNF-α is a prerequisite for the induction of HDC by LPS.

Elevation of histidine decarboxylase activity in the stomach of mice by ulcerogenic drugs

Histamine is involved in the development of gastric lesions. To examine the contribution of the histamine-forming enzyme, histidine decarboxylase, to drug-induced gastric lesions, we compared the effects of aspirin, indomethacin and dexamethasone on histidine decarboxylase activity in mice. Administration of these drugs, orally or intraperitoneally, elevated histidine decarboxylase activity in the stomach but not in the liver, lung or spleen, dexamethasone being the most potent. In contrast, acetaminophen (a non-ulcerogenic drug) was inactive. These results and our previously reported findings (elevation of histidine decarboxylase activity by lipopolysaccharide, interleukin-1 and tumour necrosis factor, and by different types of stress) suggest that an elevation of histidine decarboxylase activity in the stomach may be a common feature of the responses to ulcerogenic stimuli. The possible participation of histidine decarboxylase in gastric lesions is discussed on the basis of the known actions of histamine, our findings and the effect of histamine H 2 receptor antagonists on histidine decarboxylase activity.

Elevation of histidine decarboxylase activity in skeletal muscles and stomach in mice by stress and exercise.

The effects of different types of stress (water bathing, cold, restraint, and prolonged walking) on histidine decarboxylase (HDC) activity in masseter, quadriceps femoris, and pectoralis superficial muscles, and in the stomach were examined in mice. All of these stresses elevated gastric HDC activity. Although water bathing, in which muscle activity was slight, was sufficiently stressful to produce gastric hemorrhage and to increase gastric HDC activity, it produced no detectable elevation of HDC activity in any of the muscles examined. The other stresses all elevated HDC activity in all three muscles. We devised two methods of restraint, one accompanied by mastication and the other not. The former elevated HDC activity in the masseter muscle, but the latter did not. These results suggest that 1) HDC activity in the stomach is an index of responses to stress, 2) the elevation of HDC activity in skeletal muscles during stress is induced partly or wholly by muscle activity and/or muscle tension, and 3) stress itself does not always induce an elevation of HDC activity in skeletal muscles.

Induction of the activity of the histamine-forming enzyme, histidine decarboxylase, in mice by IL-18 and by IL-18 plus IL-12

IL-18 shares functional properties with IL-12, which induces an elevation of histidine decarboxylase (HDC) activity in mouse tissues. Therefore, we examined the effects of IL-18 and IL-18+IL-12 on HDC activity. IL-18, IL-12 or IL-18+IL-12 was intraperitoneally injected into BALB/c and C3H/HeN mice and their HDC activities were measured. IL-18, at effective antitumour doses, induced HDC activity in lung, liver, spleen and bone. The IL-18-induced HDC elevation was more rapid than that induced by IL-12. As with IL-12, repeated injections of IL-18 produced more HDC activity than a single injection. Repeated injections of IL-18+IL-12 induced serious illness and produced marked HDC activity. However, an inhibitor of HDC did not prevent the illness. IL-18 may be involved in the stimulation of histamine synthesis during the course of immune responses, though an elevation of HDC activity is not itself the direct cause of the serious illness induced by IL-18+IL-12.

Elevation of histidine decarboxylase activity in the mandible of mice by Prevotella intermedia lipopolysaccharide and its augmentation by an aminobisphosphonate

Lipopolysaccharide (LPS) produced by Gram-negative bacteria is an important cause of inflammation. Aminobisphosphonates are potent inhibitors of bone resorption but have inflammatory side-effects. Here, the effects of LPS from Prevotella intermedia (a prevalent Gram-negative bacterium both in periodontitis and endodontal infections) and alendronate (an aminobisphosphonate) on the activity of the histamine-forming enzyme, histidine decarboxylase (HDC), were examined in mouse mandible. Intravenous injection of P. intermedia LPS increased HDC activity in the mandible, maximal activity being induced within 3–6 h of the injection. The elevation of HDC activity was dependent on the dose of LPS, 10 μg/kg (0.25 μg/mouse) producing a significant elevation in enzyme activity. Intraperitoneal injection of alendronate (40 μmol/kg) also produced an increase in HDC activity. Moreover, the elevation of HDC activity induced by P. intermedia LPS was markedly augmented in mice given alendronate 3 days before the LPS injection. These results (i) suggest that P. intermedia LPS may stimulate the synthesis of histamine in the mandible and that the newly formed histamine may make at least some contribution to the development of inflammation (apical periodontitis and/or osteomyelitis); (ii) should encourage the clinical testing of antihistaminergic agents against inflammation; and (iii) confirm that care needs to be taken when administering aminobisphosphonates to patients.

Induction by interleukin-1, tumor necrosis factor and lipopolysaccharides of histidine decarboxylase in the stomach and prolonged accumulation of gastric acid.

1. Injection of interleukin-1 (IL-1) into pylorus-ligated rats has been shown strongly to inhibit gastric secretion. However, in the present study, we found that an intraperitoneal injection of IL-1 into intact (non-pylorus-ligated) fasted mice rapidly (within 30 min) induced an accumulation of gastric acid ('early response'). When the dose of IL-1 was larger, the accumulation lasted for a longer period. 2. Injection of IL-1 also caused a later elevation of the activity of histidine decarboxylase (HDC), the histamine-forming enzyme, in the stomach ('later response'). 3. Cimetidine, an antagonist of histamine H2-receptors, suppressed the accumulation of gastric acid in both the early and later periods. An irreversible inhibitor of HDC, alpha-fluoromethylhistidine, partially inhibited the accumulation in the later period. 4. IL-1, when injected 1 h after feeding in mice fasted overnight, markedly retarded gastric emptying. 5. Tumour necrosis factor (TNF) and lipopolysaccharide (LPS) or endotoxin from E. coli both had IL-1-like effects on the stomach, and their effects are presumably mediated by IL-1. 6. These results support the idea that an inhibition of gastric emptying and an elevation of HDC activity in the stomach may explain the findings that a long-lasting accumulation of gastric acid is induced by IL-1 despite its potent inhibition of gastric acid secretion. 7. On the basis of these results, and in the light of the known actions of histamine, the possible roles of IL-1 in gastric inflammation and ulceration are discussed.

Induction of histidine decarboxylase in skeletal muscle in mice by electrical stimulation, prolonged walking and interleukin-1.

1. In normal non-exercised skeletal muscles in mice, the activity of histidine decarboxylase (HDC), the enzyme which forms histamine, was very low. 2. HDC activity in the quadriceps femoris muscle was markedly elevated following contractions evoked by even a few minutes of direct electrical stimulation, peaking at 8-12 h following contraction lasting 10 min, and gradually decreasing during the 24 h following contraction. The elevation in HDC activity depended on the duration and strength of stimulation. 3. Direct electrical stimulation induced a quantitatively similar elevation of HDC activity in the muscles of mast-cell-deficient mice (W/Wv mice). 4. Prolonged walking at a speed of 6 m min-1 for up to 6 h with a 30 min rest period at 3 h also elevated muscle HDC activity, the magnitude of the elevation being related to the duration of the walking. Repeated exercise (training) for several days diminished the elevation of muscle HDC activity induced by walking. In contrast, starvation augmented the elevation of muscle HDC activity induced by walking. 5. Intraperitoneal injection of interleukin-1beta (IL-1beta) also elevated muscle HDC activity in a dose-dependent manner, as little as 1 microg kg-1 of IL-1 producing a significant elevation of muscle HDC activity. 6. IL-1beta was immunohistochemically detected in normal non-exercised quadriceps femoris muscle. We could not detect a significant increase in IL-1beta after exercise in the muscle or in serum: it may be below the level of detection. 7. On the basis of these results, together with those reported previously and the known actions of histamine, we propose that an elevation of HDC activity and generation of histamine occur in skeletal muscle following muscle contraction possibly as a result of induction by IL-1beta and that the histamine may be involved in fatigue in skeletal muscle as part of a defence mechanism preventing damage to the muscle.

Mobilization of gastric histamine during repeated administration of a proton potassium adenosine triphosphatase inhibitor in intact and antrectomized rats

Intact and antrectomized female rats were treated with the potent proton pump inhibitor, E3810 (daily 40 mg/kg weight, s.c.) for 4 weeks. Plasma gastrin concentration and urinary excretion of N-terminal big gastrin increased until day 14 and persisted at a high level in intact rats treated with E3810, but did not increase in antrectomized rats. Urinary excretion of histamine increased progressively and reached 7 times the control value following 4 weeks of treatment with E3810 in intact rats, but not in antrectomized rats. At the termination of the treatment, the endocrine cell density in the oxyntic mucosa of intact rats had increased by 85% with increased histamine content and elevated histidine decarboxylase activity, while antrectomized rats showed a low histamine level and low histidine decarboxylase activity. Administration of gastrin-17 I (10 μg/kg weight, sc) itself caused a significant increase in urinary excretion of histamine, which was inhibited by the specific gastrin receptor antagonist, L-365,260. These results suggests that the massive urinary excretion of histamine caused by the treatment with E3810 reflects gastrin-induced mobilization of gastric histamine and that neither E3810 itself nor E3810-induced luminal pH elevation has direct effects on mobilization of oxyntic mucosal histamine.

The Effect of Omeprazole-Induced Hypergastrinemia on the Oxyntic Mucosa of Mastomys

Mastomys is a rodent with a high incidence of spontaneous carcinoids in the acid-producing part of the stomach. The present study was conducted to examine whether hypergastrinemia could promote tumor formation in this species. Mastomys, 4 months of age, were treated for 5 months with omeprazole subcutaneously, 100 mumol/kg body weight daily, and compared with mastomys given the vehicle only. The plasma gastrin concentration and the number of antral gastrin cells were increased in the omeprazole-treated group. The hypergastrinemia was associated with elevated histidine decarboxylase activity and histamine content in the oxyntic mucosa and with a trophic effect on the oxyntic mucosa and the enterochromaffin-like cells. However, no carcinoid tumors were observed, possibly because the strain of mastomys studied does not produce carcinoids spontaneously.

Histamine synthesis and catabolism in various tissues in diabetic rats

In view of the observations that (1) plasma histamine concentrations are significantly higher in diabetic patients and diabetic rats than those in controls, and (2) tissue concentrations of histamine are elevated in rats with experimental diabetes, we have investigated histamine synthesis, as reflected by histidine decarboxylase (HDC) activity, and histamine catabolism, as reflected by histaminase activity, in various tissues of the diabetic rat. Rats with streptozotocin-induced diabetes mellitus (DM) showed an increase in histamine synthesis in various tissues; this was most marked in the aorta and to a lesser, but significant, extent in the kidneys, lungs, and heart, but not in the brain, stomach, or skin. Tissue content of histamine was significantly increased in all tissues except the stomach and skin. We conclude that tissue histamine synthesis is significantly increased in diabetic animals and that this increase is most marked in the aorta. The elevation in HDC activity in these tissues probably accounts for the increase in tissue and plasma concentrations of histamine in diabetic animals, since there is no change in histamine catabolism. This increase in histamine synthesis and release may contribute to the pathogenesis of endothelial damage in diabetic microangiopathy and macroangiopathy.

Effects of Bilateral Nephrectomy on Endocrine Cells of Rat Stomach

It has previously been shown that in the rat nephrectomy is followed by hypergastrinemia, elevated histidine decarboxylase activity, and lowered histamine content in the gastric mucosa; paradoxically this is accompanied by low gastric acid secretion and lack of response to pentagastrin. The present report deals with the morphological changes in the histamine-containing cells, gastrin (G) cells, and the parietal cells after nephrectomy. The number of gastric enterochromaffin, enterochromaffin-like and G cells was assessed by fluorescence histochemistry. In addition, the concentration of 5-HT in the pyloric mucosa and of histamine in the oxyntic mucosa was determined. Under the fluorescence microscope the enterochromaffin-like cells appeared reduced in number (p < 0.001) corresponding with significant lowering of gastric mucosal histamine content (p < 0.01) after nephrectomy. The number of enterochromaffin cells and gastrin cells was not affected, neither was the 5-HT content. The histamine-containing enter...

Effect of cimetidine on gastric mucosal histamine and histidine decarboxylase activity in rats.

In conscious rats and in anaesthetized gastric fistula rats, the effects of low and high doses of the histamine H2-receptor antagonist cimetidine was studied on gastric mucosal histamine concentration and histidine decarboxylase activity with or without concomitant administration of pentagastrin. In conscious animals a singleinjection of pentagastrin reduced gastric mucosal histamine concentration and elevated histidine decarboxylase activity. This effect was not antagonized by low doses of cimetidine. High doses of cimetidine, like pentagastrin, reduced the histamine concentration and elevated the histidine decarboxylase activity. In anaesthetized rats low doses of cimetidine and reduced gastric acid secretion. The effects of cimetidine on gastric mucosal histamine and histidine decarboxylase were less pronounced than in conscious animals. The histidine decarboxylase stimulating activity of high doses of cimetidine was not abolished by gastric perfusion with acid suggesting that endogenously released gastrin is not involved. A feedback relationship between the blockade of the target organ and increased histamine biosynthesis is discussed.

Increase in the urinary excretion of histamine after SRBC immunization of rats

Summary The twenty-four hour urinary excretion of histamine was determined daily in five rats for nine days after sheep red blood cell (SRBC) immunization. Our prior and current studies in rats have shown an increase in splenic and gastric histamine formation by elevated histidine decarboxylase activity after SRBC immunization. The twenty-four urinary excretion of histamine was elevated throughout the period of study with the peak elevation at six days post immunization. These findings after a humoral immune stimulus, as well as prior observations on cellular immunity, suggest the potential value of this noninvasive technic of monitoring urinary histamine in daily estimations of the total body level of histamine formation and release in laboratory and clinical situations in which this type of information may be of value. The increase in the production and release of histamine in immune challenge situations may be an important factor in the increased incidence of gastrointestinal bleeding in patients with renal transplantation, extensive burns with sepsis, and septic shock.

Histidine decarboxylase inhibitors and second-set allograft survival

A 33-fold increase in histidine decarboxylase (HDC) activity of allografted rat skin has been found during rejection. 1 Full-thickness grafts were carried out from inbred Lewis to inbred PA rats and the peak elevation in HDC activity occurred ten days after grafting. No such change occurred in autografted skin. An increase in HDC activity also has been encountered in rat spleen, but not in intestinal-tract Peyer's patches lymphoid tissue, after skin allografting across this same histocompatibility barrier according to T.C. Moore and R.W. Schayer (unpublished data). These observations, and the finding of an increase in 24-hour urinary histamine excretion in the rat during skin allograft rejection, 2 suggest an involvement of intracellular histamine formation from increased HDC activity in the biologic mechanism of allograft rejection. Kahlson 3 has found 24-hour urinary histamine excretion to be a useful means of monitoring intracellular histamine formation from increased HDC activity. Histamine is formed

Histidine decarboxylase inhibitors and second-set allograft survival.

A 33-fold increase in histidine decarboxylase (HDC) activity of allografted rat skin has been found during rejection. 1 Full-thickness grafts were carried out from inbred Lewis to inbred PA rats and the peak elevation in HDC activity occurred ten days after grafting. No such change occurred in autografted skin. An increase in HDC activity also has been encountered in rat spleen, but not in intestinal-tract Peyer's patches lymphoid tissue, after skin allografting across this same histocompatibility barrier according to T.C. Moore and R.W. Schayer (unpublished data). These observations, and the finding of an increase in 24-hour urinary histamine excretion in the rat during skin allograft rejection, 2 suggest an involvement of intracellular histamine formation from increased HDC activity in the biologic mechanism of allograft rejection. Kahlson 3 has found 24-hour urinary histamine excretion to be a useful means of monitoring intracellular histamine formation from increased HDC activity. Histamine is formed

Effect of Vagotomy on the Quantitative Histological Distribution of Histamine and Histidine Decarboxylase in the Rat Stomach

Determinations were made of the quantitative histological distribution of histamine and histidine decarboxylase in the body of the glandular stomach of fed and 14-hr fasted rats subjected to pyloroplasty and to pyloroplasty with vagotomy for comparison with untreated rats. Pyloroplasty on fasted rats had no significant effect on the concentration of histamine which was localized predominantly in the chief cell zone. However, the superimposed vagotomy was associated with some increase in the concentration. With the fed rats, the concentration was essentially unchanged from normal in either group of operated animals and it also was about the same as that in the normal fasted group. Histidine decarboxylase activity, which was also localized predominantly in the chief cell zone, underwent an increase in concentration following pyloroplasty of the fasted rats; no additional effect was observed with added vagotomy. The higher concentration of the enzyme activity in the fed rats was markedly further elevated in both groups of operated animals but these groups did not differ significantly from one another. An explanation of the elevation of histidine decarboxylase activity following pyloroplasty requires further investigation, but the lack of effect of the superimposed vagotomy on the enzyme activity would appear to rule out direct vagal control as the sole factor in determining the enzyme function at this site.