Restoration of gap junctions in the regenerative process of ethanol-induced gastric mucosal injury

Gap junctions mediate intercellular communication and play an important role in cell proliferation and differentiation. The present study examined the expression of the gap junction protein connexin 32 in rat gastric mucosa during the regenerative process of ethanol-induced gastric mucosal injury. Absolute ethanol (0.5 mL/100 g bodyweight) was administered to rats via gastric intubation. Following the treatment, rats were killed periodically, and gastric tissues were processed for indirect immunofluorescence microscopy using an anti-connexin 32 antibody. Haematoxylin and eosin (H&E), periodic acid Schiff (PAS) and Bromodeoxyuridine (BrdU) staining were also performed in serial sections. Gastric injuries were limited in the mucosal layer. The injury was most severe 1 h after treatment, and was completely resolved by the 4th day after treatment. The number of immunoreactive spots for gap junctions was markedly decreased 1 h after the ethanol treatment. Reappearance of these immunostaining gap junctions occurred with repair of the injury. The reappearance of connexin 32 after injury was delayed in comparison with both the histologic resolution of the injury and the normalization of PAS-stained mucus. In contrast, the time course of reappearance of gap junctions closely paralleled the appearance of BrdU-labelled cells. These results indicate that morphologic repair is different to the recovery of cell maturity and cell proliferation in the regenerative gastric mucosa.     

Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats

We have recently reported that steady-state gastric mucosal blood flow (GMBF) is decreased in streptozotocin (STZ) diabetic rats, and that their GMBF response to burn-stress is impaired, probably via a nitric oxide (NO)-mediated mechanism. Accordingly, this study was designed to investigate the relation of aldose reductase (AR) and NO synthase to the regulation of GMBF during chronic hyperglycemia. STZ rats were treated with or without chronic oral administration of an AR inhibitor, epalrestat (EPA) and/or an NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). GMBF was measured by laser-Doppler velocimetry (LDV). In the STZ rats, GMBF after a 24-h fasting period was decreased significantly 4 weeks after the onset of diabetes and this was accompanied by an increase in the gastric ulcer index (UI) (a measure of the length of gastric erosions and ulcers). Chronic oral administration of EPA to the STZ rats dose-dependently inhibited the increased UI and the decreased GMBF after the fasting stress, whereas chronic oral administration of L-NAME further increased the UI and further decreased the GMBF. EPA administered in combination with L-NAME to the STZ rats reduced the effects of L-NAME, but the effects did not reach significance. These results suggest that EPA protects the gastric mucosa of diabetic rats, by preventing the decrease in GMBF that is, at least in part, caused by NO-related mechanisms. (Received Mar. 3, 1998; accepted Aug. 28, 1998)     

Heterogeneous distribution of microcirculatory disturbance in the gastric mucosa during gastric hypercontraction in rats

Gastric mucosal lesions induced by gastric hypermotility are characteristically observed along the gastric mucosal folds. To determine the role of microcirculatory disturbance in this particular condition, we measured the gastric mucosal haemodynamics after vagal stimulation and also examined histologically the transparent specimens of the transverse section of the contracted stomach in rats. Gastric mucosal haemodynamics measured with a reflectance spectrophotometer showed the repetition of ischaemia-reperfusion during gastric hypermotility. The rapidly frozen and transparent specimen of the corpus showed that gastric mucosa was stretched at the crest and compressed at the base of the mucosal folds. Characteristic distribution of red blood cells was observed; it was dense at the crest of the mucosal folds and sparse at the base. These results suggest that gastric hypermotility may induce the distinctive heterogeneous microcirculatory disturbance in the folds and may contribute to the characteristic localization of mucosal lesions.     

Impaired oxygenation of gastric mucosa in portal hypertension

Increased susceptibility to mucosal damage is a prominent feature of portal hypertensive gastropathy. Since the portal hypertensive gastric mucosa has extensive microvascular changes, we postulated that the increased sensitivity to mucosal damage could have an ischemic basis. We measured distribution of gastric serosal and mucosal oxygenation in a group of portal hypertensive and sham-operated rats, and then studied the effects of intragastric aspirin. In the basal state, gastric mucosa of portal hypertensive rats had significantly reduced oxygenation compared to controls (24±5 vs 45±7 mm Hg PO ₂,P < 0.02), while serosal oxygenation was similar between the two groups. Intragastric aspirin produced significantly greater mucosal damage to portal hypertensive rats and mucosal oxygenation was almost one third that of sham-operated controls. Systemic arterial pressures and oxygenation were similar between the two groups. We conclude that there is impairment of gastric mucosal oxygenation and increased mucosal damage by aspirin in portal hypertensive rats compared with sham-operated controls. These results support our hypothesis that the increased sensitivity of the portal hypertensive mucosa to damage is a consequence of impaired mucosal oxygenation.This study was supported by the Veterans Administration Research Service.This work was presented, in part, at the Plenary Session of the American Association for the Study of Liver Diseases, May 1988, New Orleans, Louisiana.     

Recovery of mucin content in surface layer of rat gastric mucosa after HCl-aspirin-induced mucosal damage

Quantitative changes in mucin (mucus glyco-protein) in different layers of rat gastric mucosa after mucosal damage induced by acidified acetylsalicylic acid (HCl-aspirin; 0.15N HCl, 20–200 mg acetylsalicylic acid/kg body weight) were studied. More than 50 mg/kg HCl-aspirin led to a significant increase in macroscopic gastric injury (expressed as ulcer index) at 3h, compared with control (no aspirin) and there was a significant recoverly at 7h. Three h after dosing with 50 mg/kg acidified aspirin, there was superficial mucosal damage and decreased mucin content in the surface mucosal layer. Mucin production recovered 7h after the administration of 50 mg/kg acidified aspirin. Doses of acidified aspirin higher than 100 mg/kg decreased mucin content in the surface and deep corpus mucosal layers and no recovery was seen 7h after the administration. Physiological damage after the administration of 50 mg/kg HCl-aspirin was limited mainly to surface epithelial mucus cells. An experimental model in which superficial erosion was induced in rat gastric mucosa was established with low-dose HCl-aspirin.     

Morphological and biochemical changes in gastric mucosa of aging rats

Although previous data from this laboratory have indicated that aging is associated with increased gastric mucosal proliferative activity, no direct assessment of proliferative potential of the tissue has been made during aging. In order to assess this, and to determine whether changes in mucosal proliferative potential would be reflected in growth of the tissue, we have examined the labeling index (LI), height and morphology of the gastric mucosa in young (4-month-old) and aged (24-month-old) Fischer-344 rats. In addition, tyrosine kinase (Tyr-k) activity and the levels of phosphotyrosine proteins were determined to evaluate their relationship to mucosal proliferative activity. Histologic evaluation revealed a marked atrophy of the mucosal glandular component with 32% reduction in height in aged rats when compared with young animals. In aged rats, there was also a decrease in gland density, resulting in a reduction in the number of epithelial cells of all types with evidence of decreased secretory activity. Despite the occurrence of mucosal atrophy in aged rats, LI in these animals was significantly increased by 28%. This was associated with a parallel rise in mucosal Tyr-k activity, and a two-to threefold increase in the relative concentrations of seven phosphotyrosine membrane proteins with M_r of 120, 105, 90, 60, 55, 48 and 32 kDa. We conclude that (1) although aging is associated with increased gastric mucosal proliferative activity, this does not result in mucosal growth and that (2) Tyr-k and tyrosine phosphorylation of certain proteins play a role in the regulation of gastric mucosal cell proliferation during aging.     

Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats

Background and Aim:  Based on our previous studies that Artemisia asiatica extracts exert either antioxidative or cytoprotective actions against non-steroidal anti-inflammatory drugs or Helicobacter pylori -induced gastric mucosal injury, or imposes qualified ulcer healing in an acetic acid-induced gastric ulcer model, we investigated the protective effects of Artemisia asiatica extracts against ethanol-induced gastric mucosal injury.
Methods:  Sprague–Dawley rats received 4 g/kg body weight (BW) of absolute ethanol intragastrically, which produced visible hemorrhagic gastric lesions 60 min later.
Results:  In this animal setting, the pretreatment of Artemisia extracts (30 or 100 mg/kg BW), 1 h before ethanol administration, significantly attenuated the source of gastric injury, which was assessed with gross and microscopic analysis ( P  < 0.01). Protection from alcohol-induced damage with Artemisia pretreatment was associated with significantly decreased lipid peroxidation, protecting gastric mucosa from glutathione depletion, as well as the inhibition of the cytochrome 2E1 ethanol-metabolizing enzyme. It attenuated the expressions of ethanol-induced pro-inflammatory cytokines, including interleukin (IL)-1β and interferon-γ, a weak activation of IL-10, the inhibition of the alcohol-induced overexpression of intercellular adhesion molecule-1, and the considerable induction of heat shock protein-72 expression in gastric mucosal homogenates .
Conclusion:  The data suggest that the ethanol extracts of Artemisia asiatica exerted significant protection from alcohol-induced gastric mucosal injury through bioregulation, which is essential for cytoprotection and anti-inflammation.     

Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat

The relation of blood flow stasis to the development of unequivocal histologic necrosis (loss of parietal cells from the column of contiguous cells) in ethanol-induced gastric mucosal injury was studied in anesthetized rats. The most rapid vascular change that occurred when the gastric mucosa was exposed to 100% ethanol was a severe segmental constriction of the large submucosal venules. At 22 sec, the average venular diameter was 52.2±6.0% of the original one. This was followed by complete superficial mucosal blood flow stasis at 49±4 sec and appearance of histologic evidence of necrosis in one of seven rats at 2.5 min, four of six rats at 10 min, and seven of seven rats at 60 min. We conclude that in ethanol-induced gastric mucosal injury, submucosal venular constriction occurs first, followed by cessation of mucosal blood flow to be followed later on with histologic evidence of necrosis.     

Modulatory action of adenosine on gastric function and ethanol-induced mucosal damage in rats

This study examines the gastric effects of adenosine and its antagonist, theophylline, on secretory function, mucosal blood flow, and on ethanol-induced glandular mucosal damage in rats that were fasted for 24 hr before experimentation. The animals were anesthetized with sodium pentobarbitone (50 mg/kg intraperitoneal) and their tracheae cannulated. An ex vivo stomach chamber then was prepared. The luminal bathing solution was collected every 15 min and the concentrations of H⁺ and Na⁺ were determined by a pH autotitrator and an ionmeter, respectively. The glandular mucosal blood flow was measured by a laser Doppler flowmeter and the severity of lesions was determined by measuring the hemorrhagic areas. Adenosine administration (2.5 or 7.5 mg/kg, subcutaneous) markedly lowered the H⁺ and Na⁺ output but increased the secretory volume and mucosal blood flow in a dose-dependent manner. The same doses of the nucleoside also prevented ethanol-induced mucosal damage. These effects were prevented by pretreatment with theophylline (30 or 60 mg/kg, subcutaneous). Ethanol given alone significantly depressed the H⁺ and Na⁺ secretion. Both effects were not modified by adenosine treatment. However, the depressive action of ethanol on mucosal blood flow was prevented by adenosine. These findings indicate that adenosine modulates the physiological function of the stomach. It also directly activates the defensive mechanism of the stomach, which is partially mediated by the improvement of the gastric mucosal blood flow and an increase in the nonacid component of gastric secretion.     

Divergent effects of irritants on the gastric mucosa in rats during various stages after bile duct ligation

Background and Aim: Controversy exists as to whether rats after bile duct ligation (BDL) are more susceptible to gastric mucosal damage (GMD) induced by irritants. In the present study we characterize GMD after intragastric instillation of either ethanol or hydrochloric acid (HCL), 3 and 21 days after the surgical procedure. Methods: Bile duct ligation and sham operated (SO) rats were studied. Results: Three days after surgery, BDL rats exhibited a reduction in gastric mucosal nitric oxide synthase (NOS) activity but an increase in ethanol‐induced GMD. Twenty‐one days after surgery gastric mucosal prostaglandin (PG) E₂ generation in BDL rats was increased while NOS activity in both groups was similar. Ethanol‐induced GMD in SO rats was higher. Pretreatment with NG‐nitro‐L‐arginine methyl ester, prior to ethanol administration was associated with an increase in gastric mucosal PGE₂ generation: (147% in SO and 104% in BDL rats) and in GMD (176% in SO and 303% in BDL rats). HCL induced GMD was of similar magnitude in both groups in both time periods. Conclusions: The gastric resistance to damage by irritants in rats with BDL is not a static phenomenon. This may result from sequential changes that occur in the gastric mucosal defense mechanisms during the evolution of liver disease.     

Monoamine oxidase B inhibition reduces gastric mucosal blood flow,basal acid secretion,and cold water restraint-induced gastric mucosal injury in rats

Inhibition of monoamine oxidase B (MAO B) by selective inhibitors pargyline and l-deprenyl increases dopamine (DA) and norepinephrine (NE) concentrations in nucleus accumbens (NACB) and is associated with reduction in cold water restraint-induced gastric mucosal injury, inhibition of basal gastric acid output, and regional gastric mucosal blood flow. Similar effects were not observed with administration of MAO A inhibitors. These observations suggest that activation of central dopamine and norepinephrine receptors, particularly in NACB, are involved in the control of gastric mucosal function.Supported by PHS grant DK 38198 (G.K.).     

Effects of gastric distension and prostaglandin on acid ethanol-induced mucosal lesions in the rat

The effects of gastric distension on the morphology of acidified ethanol (AE) -induced mucosal lesions and on the protective action of 16,16-dm PGE₂ were investigated in rats. AE (50% ethanol in 150 mM HCl) was given by gavage in the intact stomach or through a fistula prepared in the forestomach in the pylorus-ligated stomach. AE produced elongated bands of hemorrhagic necrosis within 1 hr in the former, while in the pylorus-ligated stomach the shape of lesions varied depending upon the volume of irritant. One milliliter produced bandlike lesions, whereas 2 ml or more induced widespread lesions; such volumes were observed to remove the mucosal folds. 16,16-dm PGE₂ (0.3–10 g/kg, subcutaneous) dose dependently reduced bandlike lesions in the intact stomach, but had no or little effect on non-band-like lesions in the pylorus-ligated stomach. This agent (10 g/kg) had a slight effect on the reduction of PD caused by 10-min exposure of the stomach to AE (2 ml) in the intact stomach, while such effects were not apparent in the pylorus-ligated stomach. Oral gentian violet (2 ml, 0.3% w/v) produced bandlike staining of the mucosa in intact rats, but the effect was blocked by pyloric ligation. 16,16-dm PGE₂ also significantly prevented the localized staining pattern seen in intact rats. These results suggest that (1) the bandlike pattern of AE-induced injury is dependent on the presence of mucosal folds (distending the stomach abolishes mucosal folds and widespread injury results); (2) 16,16-dm PGE₂ prevented the fold-related, bandlike lesions and bandlike staining of the mucosa, but failed to abolish the generalized lesions; and (3) PG cytoprotection appears associated with the formation of bandlike lesions which are dependent on the presence of mucosal folds.     

Effects of ammonia solution on the gastric mucosa in cirrhotic rats and therapeutic effects of geranylgeranylacetone

BACKGROUND: We designed an animal model in order to clarify whether Helicobacter pylori infection causes the gastric mucosal lesion frequently seen in cirrhotic patients. METHODS: Ammonia (NH3) solution was given to rats with carbon tetrachloride-induced cirrhosis. The gastric mucosal hexosamine (Hx) content and histopathological findings in the cirrhotic rats were analysed and compared with those of the intact liver rats. Moreover, the usefulness of geranylgeranylacetone (GGA) was investigated in both rat groups. Both rat groups were subdivided according to the treatment as follows: a control group, an NH3 (0.02% solution) group, and an NH3 + GGA (400 mg/kg per day) group; and fed for 4 weeks. RESULTS: The gastric mucosal Hx content of the control group of the cirrhotic rats (16.7 +/- 5.2 microg/mg) was significantly lower than that of the control group of the intact liver rats (26.6 +/- 4.5 microg/mg, P < 0.05). In the cirrhotic rats, the Hx content of both the NH3 (31.9 +/- 13.1 microg/mg) and the NH3 + GGA group (31.9 +/- 9.8 microg/mg) was significantly higher than the Hx content of the control group (P < 0.05). Microscopically, in the cirrhotic rats, while scattered mucosal erosions were recognized in three of five rats of the NH3 group, there were no erosions in any rats of the NH3 + GGA group. CONCLUSIONS: These data suggest that the gastric mucosal defence mechanism is defective in liver cirrhosis and that NH3 enhances this defensive mechanism by acting as mild irritant; however, in some cirrhotics this results in gastric erosion due to excessive irritation. Geranylgeranylacetone protects the gastric mucosa against NH3 irritation in cirrhotics without enhancing the Hx content. Thus, H. pylori infection may be a possible cause of the gastric mucosal lesion in patients with liver cirrhosis. The mechanism of the therapeutic effect of GGA is not due to an enhancement of the gastric mucosal Hx content.     

胃癌和癌前病变中树突状细胞的免疫组化研究

目的 通过研究胃粘膜中S100+,HLA-DR+,CD4+和CD8+产物的表达情况,以了解DC细胞在胃粘膜免疫中的作用．方法 胃癌(143例)、慢性萎缩性胃炎(41例)、不典型增生(15例)、肠上皮化生(27例)和正常对照组(10例)共236例,都经内镜和病理诊断明确．采用HE染色、SP免疫酶标抗体组化染色法与图象分析技术相结合,观察胃粘膜中S-100+,HLA-DR+,GD4+CD8+细胞数量、平均面积和平均吸光度的变化。结果 胃癌患者胃粘膜中S100+(0．6±0．2)μm2,HLA-DR+(0．9±0．2)细胞数量明显多于正常胃粘膜(P     

Effects of alcohol on lectin binding affinity in rat gastric mucosa

Fluoresceinated lectins were employed to qualitatively evaluate cell surface carbohydrates, with and without ethanol exposure, in rat stomach mucosae. Rats received 1 ml of saline, or 50% or 100% ethanol orally. After 30 min, tissue samples of the glandular stomach were retrieved, cryosectioned, and incubated with one of a panel of lectins. Another set of sections was preincubated with neuraminidase to remove sialic acid residues. Qualitative evaluation of lectin binding showed that although several different sites stained, concanavalin A was the only lectin to stain the extracellular matrix, and soybean agglutinin the only lectin to stain chief cells. Neuraminidase preincubation enhanced lectin binding to both stained and previously unstained sites. Ethanol, both 50% and 100%, produced changes in both neuraminidase-treated and untreated tissues, increasing the specific binding of concanavalin A, Ulex europaeusagglutinin I, and wheat germ agglutinin, while decreasing Helix pomatiaagglutinin and soybean agglutinin. These results suggest that ethanol can, through unknown mechanisms, alter carbohydrate binding affinity.Supported by NIAAA grant AA 06887 and NIH grant DK 25838.     

Appearance of specific mucins recognized by monoclonal antibodies in rat gastric mucosa healing from HCl-induced gastric mucosal damage

Background Mucus is an important factor in the physiological defense mechanism of the gastrointestinal tract. We have reported that two distinct antigenicities reacting with anti-mucin monoclonal antibodies (mAbs), HCM31 and RGM26, emerged in epithelial cells regenerating from acetic acid-induced gastric damage in the rat. Here, we examined whether the expression of specific mucins occurred during the healing stage of acute gastric mucosal lesions, and what was the principal alteration of the mucus in the regenerating process of gastric epithelia from slight mucosal lesions.Methods Eight-week-old male Wistar rats were used. The animals were administered 0.6N hydrochloric acid, or 0.5% carboxymethyl cellulose sodium salt into their stomachs. Twenty-four, 48, and 72h after the HCl administration, their stomachs were removed. Immunohistochemical observation was performed after staining with the mAbs, RGM21, RGM26, HIK1083, or HCM31.Results Twenty-four hours after the administration of HCl, mucous cells stained with RGM26 emerged in the deeper area of the surface epithelial cells in the damaged corpus mucosa. After 48h, HCM31-positive cells were noted in the epithelial cells where the mucosal damage reached more deeply.Conclusions The appearance of specific mucin species was observed in the regenerating epithelia of the rat during the healing process from acute gastric mucosal damage.     

Contribution of capsaicin-sensitive afferent nerves to rapid recovery from ethanol-induced gastric epithelial damage in rats

BACKGROUND AND AIM: It is well known that capsaicin-sensitive nerve signaling acts as a protective factor against various ulcerogens. However, the contribution of topical capsaicin-sensitive nerves within the stomach to rapid restitution has not been fully investigated. The present study was therefore conducted focusing on recovery from gastric mucosal damage induced by ethanol in vivo. METHODS: Male Sprague-Dawley rats were fasted and anesthetized. 51Cr-EDTA was administered intravenously and gastric mucosal integrity was continuously monitored by measuring the blood to lumen 51Cr-EDTA clearance. Capsaicin or vehicle was irrigated before, together with or after the perfusion of 20% ethanol, followed by perfusion with saline. In another experiment, ruthenium red, a capsaicin-sensitive cation antagonist, was given before the ethanol-capsaicin perfusion. Furthermore, this study was verified using lafutidine, a histamine H2-receptor antagonist, which has a gastric mucosal protective action through the capsaicin-sensitive afferent nerves. RESULTS: When capsaicin was administered before ethanol treatment, mucosal damage was significantly reduced and recovery was significantly rapid compared to the control. When capsaicin (160 micro M) and ethanol were administered simultaneously, the mucosal damage was exacerbated but recovery was nevertheless more rapid than the control group. With a lower dose of capsaicin (80 micro M), mucosal damage was not exacerbated and recovery was enhanced. When capsaicin or lafutidine was administered after the induction of ethanol injury no change was detected regarding the damage. However, recovery was significantly accelerated. Ruthenium red reversed the action of post-treatment with capsaicin on restitution. CONCLUSIONS: These results indicate that luminal administration of capsaicin exerts protection against and accelerates restitution from gastric damage in the very early phase after ethanol injury. This action is probably due to activation of topical capsaicin-sensitive afferent nerves in the rat.     

Recovery from gastric mucus depletion in the intact guinea pig mucosa

Background: In developed countries one‐third of the population is infected with the gastric pathogen Helicobacter pylori. In the early stages of H. pylori‐induced gastritis, typical symptoms include gastric erosions and mucus depletions. Artificial mucus depletion was generated, demonstrating both consequent irritation and recovery processes in the mucosa. Methods: The mucus depletion was examined by removing a small cylinder of mucus from the surface of the explanted guinea pig corpus mucosa, leaving the epithelial surface intact. pH microelectrodes were inserted into the mucosa in vitro, measuring the epicellular mucus pH, the pH _i of the underlying epithelial cells and the pH inside the gastric glands during mucus regeneration. Using infrared microscopy, the same process of mucus layer renewal was followed in anaesthetized animals. Results: The depletion exposed the tissue surface to low luminal pH levels. At a luminal pH of 2.5, a decrease was observed in the crypt outlet pH and surface cell pH _i , while deeper cells were less affected. However, a subsequent neutralization in the deep gland lumen was found. During the repair process, a quarter of the mucus layer was regenerated within the first 5?min. This newly secreted mucus formed a structure similar to that before depletion. Within 45 min, pH _i and tissue‐near pH values had fully recovered. Conclusion: Following mucus depletion, there is a decrease in surface cell pH _i and crypt outlet pH values. The repair process is then characterized by extensive mucus secretion and local cessation of acid secretion.     

Induction of a 72-kDa heat-shock protein in cultured rat gastric mucosal cells and rat gastric mucosa by zinc L-carnosine

An antiulcer drug, zinc l-carnosine (polaprezinc), provides gastric mucosal protection against various irritants. In this study, we evaluated the effects of zinc l-carnosine on expression of 72-kDa heat shock protein (HSP72, stress inducible HSP70), which is known as an endogenous cytoprotectant in a wide variety of cells, including rat gastric mucosa in vitro and in vivo. Expression of HSP72 after exposure to zinc l-carnosine, zinc sulfate, or l-carnosine (1–300 M) in rat gastric mucosal cells (RGM1) and intragastric administration of zinc l-carnosine, zinc sulfate (30 or 100 mg/kg) and l-carnosine (76 mg/kg) was investigated by western blotting and densitometric analysis. Exposure to zinc l-carnosine and zinc sulfate increased the expression of HSP72 significantly in RGM1 cells. Intragastric administration of zinc l-carnosine and zinc sulfate showed significant increment in HSP72 in rat gastric mucosa also in vivo. The ability to induce HSP72 is significantly higher in zinc l-carnosine compared with zinc sulfate based on molecular concentration in vivo. However, l-carnosine did not increase the expression of HSP72 in vitro and in vivo. Zinc derivatives, especially zinc l-carnosine, could be a strong HSP72 (chaperon) inducer, which has been known to enhance mucosal protective ability.