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PubMed2004

Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection.

Ischemia and reperfusion injury (IRI) represents the major problem in clinical liver transplantation. We have shown that transcription of signal transducer and activator of transcription 4 (Stat4) plays a key role in the mechanism of hepatic IRI, whereas local induction of interleukin 13 (IL-13) is cytoprotective. The disruption of innate Toll-like receptor 4 (TLR4) signaling prevents mouse livers from undergoing fulminant IRI. This study analyzes in vivo interplay between innate (TLR4) and adaptive (Stat6) immunity in Ad-IL-13 (recombinant adenovirus encoding IL-13) cytoprotection in hepatic IRI. Using a partial 90-min lobar warm ischemia model, groups of wild-type and Stat6-deficient knockout mice were assessed for the severity of hepatocellular damage at 6 hr postreperfusion. Unlike in wild-type mice, treatment of Stat6 knockout recipients with Ad-IL-13 failed to improve hepatic function/histology. The expression of mRNAs encoding tumor necrosis factor alpha/IL-1 beta and IL-2/interferon gamma remained depressed in the wild-type plus Ad-IL-13 group, but not in the Stat6 knockout plus Ad-IL-13 group. Ad-IL-13 increased antioxidant heme oxygenase 1 (HO-1) expression and prevented TLR4 activation in livers of Stat6-competent (wild-type) mice. In contrast, low HO-1 expression and enhanced TLR4 expression were recorded in Stat6 knockout recipients despite Ad-IL-13 therapy. Thus (1) Stat6 is required for Ad-IL-13 to prevent IRI, and (2) depression of TLR4 activation is Stat6 dependent. In conclusion, the Stat6 pathway operates as a key negative regulator in the hepatic inflammatory ischemia-reperfusion response. This study outlines requirements for Ad-IL-13 use to maximize the organ donor pool through the use of liver transplants despite prolonged ischemia.

Animals↗
PubMed2002

Novel phenanthridinone inhibitors of poly (adenosine 5'-diphosphate-ribose) synthetase: potent cytoprotective and antishock agents.

OBJECTIVE: To synthesize novel inhibitors of the nuclear enzyme poly(adenosine 5'-diphosphate [ADP]-ribose) synthetase (PARS), also known as poly(ADP-ribose) polymerase (PARP), and to test them in in vitro models of oxidant-induced cytotoxicity and in endotoxin and splanchnic occlusion-reperfusion-induced shock. DESIGN: Randomized, prospective laboratory study. SETTING: Research laboratory. SUBJECTS: Murine macrophages, thymocytes, and endothelial cells; Balb/c mice and Wistar rats. INTERVENTIONS: Macrophages and endothelial cells were treated with peroxynitrite and bleomycin to induce PARS activation, and thymocytes were treated with peroxynitrite to induce cell necrosis. Novel PARS inhibitors were synthesized and used to reduce PARS activation and to reverse cytotoxicity. Balb/c mice were subjected to splanchnic occlusion and reperfusion and were pretreated with various doses (1-10 mg/kg intraperitoneally) of PJ34, a selected, potent, water-soluble PARS inhibitor. The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. Wistar rats were subjected to Escherichia coli bacterial lipopolysaccharide (40 mg/kg intraperitoneally). PJ34 was also used at 10 mg/kg intraperitoneally, 1 hr before lipopolysaccharide or at 25 mg/kg intraperitoneally 1 hr after lipopolysaccharide treatment. Serum concentrations of indicators or multiple organ injury, concentrations of various proinflammatory mediators, and tissue concentrations of myeloperoxidase and malondialdehyde were measured. In addition, survival rates and vascular contractile and relaxant responses were recorded. MEASUREMENTS AND MAIN RESULTS: Appropriate modifications of the phenanthridinone core structure yielded significant increases in the potency of the compounds, both as PARS inhibitors and as cytoprotective agents. The compound N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (designated as PJ34) was one of the potent PARS inhibitors of the series, and it dose-dependently protected against thymocyte necrosis, with a half-maximal restoration of cell viability of 35 nM and complete protection at 200 nM. PARS activation also was visualized by immunohistochemistry and was dose-dependently suppressed by PJ34. The effect of PJ34 was dose-dependently reversed by excess nicotinamide adenine dinucleotide (oxidized). The PARS inhibitors dose-dependently suppressed proinflammatory cytokine and chemokine production and restored viability in immunostimulated macrophages. PJ34 was selected for the subsequent in vivo studies. PJ34 significantly protected against splanchnic reperfusion-induced intestinal hyperpermeability in the mouse. PJ34 reduced peak plasma concentrations of tumor necrosis factor-alpha, interleukin-1beta, and nitrite/nitrate in the plasma of lipopolysaccharide-treated rats. PJ34 ameliorated the lipopolysaccharide-induced increases in indexes of liver and kidney failure and concentrations of myeloperoxidase and malondialdehyde in the lung and gut. Lipopolysaccharide elicited vascular dysfunction, which was normalized by PJ34. Lipopolysaccharide-induced mortality was reduced by PJ34 (both pre- and posttreatment). CONCLUSIONS: The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.

Animals↗
PubMed2003

L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent.

PURPOSE OF REVIEW: In recent years, evidence has mounted in favor of the antiinflammatory, immunomodulatory and cytoprotective effects of the simplest amino acid L-glycine. This article will focus on the recent findings about the responsible mechanisms of protection and review the beneficial effects of glycine in different disease states. RECENT FINDINGS: Glycine protects against shock caused by hemorrhage, endotoxin and sepsis, prevents ischemia/reperfusion and cold storage/reperfusion injury to a variety of tissues and organs including liver, kidney, heart, intestine and skeletal muscle, and diminishes liver and renal injury caused by hepatic and renal toxicants and drugs. Glycine also protects against peptidoglycan polysaccharide-induced arthritis and inhibits gastric secretion and protects the gastric mucosa against chemically and stress-induced ulcers. Glycine appears to exert several protective effects, including antiinflammatory, immunomodulatory and direct cytoprotective actions. Glycine acts on inflammatory cells such as macrophages to suppress activation of transcription factors and the formation of free radicals and inflammatory cytokines. In the plasma membrane, glycine appears to activate a chloride channel that stabilizes or hyperpolarizes the plasma membrane potential. As a consequence, agonist-induced opening of L-type voltage-dependent calcium channels and the resulting increases in intracellular calcium ions are suppressed, which may account for the immunomodulatory and antiinflammatory effects of glycine. Lastly, glycine blocks the opening of relatively non-specific pores in the plasma membrane that occurs as the penultimate event leading to necrotic cell death. SUMMARY: Multiple protective effects make glycine a promising treatment strategy for inflammatory diseases.

Adjuvants, Immunologic↗
PubMed2005

Radiation-induced craniofacial bone growth inhibition: efficacy of cytoprotection following a fractionated dose regimen.

BACKGROUND: Severe craniofacial growth disturbances are noted in 66 to 100 percent of children with head and neck cancers who received radiotherapy during their growing years. The authors have previously demonstrated the prevention of radiation-induced craniofacial bone growth inhibition following single-dose orthovoltage radiation to the orbitozygomatic complex in an infant rabbit model through the administration of the cytoprotective agent amifostine (WR-2721) before radiation treatment. The purpose of this study was to investigate the efficacy of cytoprotection using a fractionated dose regimen that better approximates the clinical application of radiation therapy. METHODS: Thirty 7-week-old male New Zealand rabbits were randomized into three groups (n = 10), each receiving six fractions of orthovoltage radiation to the right orbitozygomatic complex: group C, sham irradiation control; group F35, total dose of 35 Gy; and group F35A, total dose of 35 Gy with administration of amifostine 200 mg/kg intravenously 20 minutes before each fraction. Bone growth was evaluated up to skeletal maturity (age 21 weeks) with serial radiographs and computed tomography scans for cephalometric analysis, bone volume, and bone density measurements. RESULTS: Fractionated radiation resulted in significant (p < 0.05) bone growth inhibition compared with sham radiation in 16 of 21 cephalometric parameters measured and significantly (p < 0.05) reduced bone volume of the rabbit orbitozygomatic complex. Pretreatment with amifostine before each radiation fraction prevented growth deformities in four cephalometric parameters and significantly (p < 0.05) attenuated these effects in another seven parameters compared with radiated animals. Bone volumes were also significantly (p < 0.05) improved in F35A animals compared with F35 animals. CONCLUSIONS: This study establishes that fractionation of orthovoltage radiation does not prevent the development of growth disturbances of the rabbit craniofacial skeleton and also demonstrates that preirradiation administration of amifostine is highly effective in the prevention and attenuation of radiation-induced craniofacial bone growth inhibition.

Amifostine↗
PubMed2004

Adenoviral gene transfer of erythropoietin confers cytoprotection to isolated pancreatic islets.

BACKGROUND: The transfer of cytoprotective genes to isolated pancreatic islets may contribute to their enhanced survival in the transplant setting. Our laboratory established the expression of functional erythropoietin (EPO) receptors throughout pancreatic islets. Because EPO is a cytokine that promotes survival, we examined whether adenovirus-mediated gene transfer of EPO would result in cytoprotection of human pancreatic islets in culture and in the transplant setting. METHODS: Isolated human islets were transduced using an adenoviral vector coding for human EPO or green fluorescent protein. Comparison of cell death in culture was measured using annexin V-phycoerythrin and propidium iodide. Transplantation of transduced islets into diabetic nude mice was used to assess the effect of EPO on islet function and in vivo survival. RESULTS: Adenoviral delivery of EPO to pancreatic islets resulted in high-level EPO synthesis and secretion, which did not affect islet function in vitro or in vivo. Islets transduced with EPO were protected from apoptosis in culture and were at a functional advantage in vivo when compared with islets transduced with green fluorescent protein or untransduced islets. The high level of EPO had a negative effect on the blood chemistry of the animals that underwent transplantation. CONCLUSIONS: Overexpression of EPO protects islets from destruction and does not compromise islet function. Genetic engineering with EPO may be a viable approach for improving islet survival and engraftment in the transplant setting, but regulation of the gene's expression will be an important prerequisite to this strategy.

Adenoviridae↗
PubMed2005

Astroglial cytoprotection by erythropoietin pre-conditioning: implications for ischemic and degenerative CNS disorders.

Erythropoietin (Epo) is a glycoprotein secreted by the kidney in response to hypoxia that stimulates erythropoiesis through interaction with cell surface Epo receptors. Pre-treatment with Epo has been shown to protect neurons in models of ischemic injury. The mechanism responsible for this neuroprotection and the effects of Epo on astroglial and other non-neuronal cell populations remain unknown. In the present study, we determined whether Epo pre-treatment protects neonatal rat astrocytes from apoptotic cell death resulting from treatment with nitric oxide, staurosporine (STS) and arsenic trioxide and possible mechanisms mediating Epo-related cytoprotection. Epo (5-20 U/mL) significantly attenuated multiple hallmarks of apoptotic cell death in astroglia exposed to nitric oxide and STS but not arsenic trioxide. Epo (20 U/mL) induced mild oxidative stress as shown by increases in heme oxygenase (HO)-1 mRNA and protein expression that could be suppressed by antioxidant coadministration. Moreover, coincubation with tin-mesoporphyrin, a competitive inhibitor of HO activity, abrogated the cytoprotective effects of Epo (20 U/mL) in the face of STS treatment. Thus, induction of the ho-1 gene may contribute to the glioprotection accruing from high-dose Epo exposure. Epo may augment astroglial resistance to certain chemical stressors by oxidative stress-dependent and -independent mechanisms.

Animals↗
PubMed2005

Choline produces cytoprotective effects against ischemic myocardial injuries: evidence for the role of cardiac m3 subtype muscarinic acetylcholine receptors.

BACKGROUND/AIMS: Accumulating evidence indicates the presence of functional M3 subtype of acetylcholine muscarinic receptors (M(3)-mAChR), in addition to the well-recognized M(2)-mAChR, in the heart of various species including man. However, the pathophysiological role of the cardiac M(3)-mAChR remain undefined. This study was designed to explore the possible role of M(3)-mAChR in cytoprotection of myocardial infarction and several related signaling pathways as potential mechanisms. METHODS: Studies were performed in a rat model of myocardial infarction and in isolated myocytes. RESULTS: We found that choline relieved myocardial injuries during ischemia or under oxidative stress, which was achieved by correcting hemodynamic impairment, diminishing ventricular arrhythmias and protecting cardiomyocytes from apoptotic death. The beneficial effects of choline were reversed by the M(3)-selective antagonists but not by the M(2)-selective antagonist. Choline/M(3)-mAChR activated several survival signaling molecules (antiapoptotic proteins Bcl-2 and ERKs), increased endogenous antioxidant reserve (SOD), and reduced apoptotic mediators (proapoptotic proteins Fas and p38 MAPK) and intracellular Ca2+ overload. CONCLUSION: Choline improves cardiac function and reduces ischemic myocardial injuries via stimulating the cardiac M(3)-mAChRs which in turn result in alterations of multiple signaling pathways leading to cytoprotection. The findings suggest M(3)-mAChR as a new target for drug development for improving cardiac function and preventing cardiac injuries during ischemia/reperfusion.

Animals↗
PubMed2006

Targets of cytoprotection in acute ischemic stroke: present and future.

Although the management of stroke has improved remarkably over the last decade due mainly to the advent of thrombolysis, most neuroprotective agents, although successful in animal studies, have failed in humans. Our increasing knowledge concerning the ischemic cascade is leading to a considerable development of pharmacological tools suggesting that each step of this cascade might be a target for cytoprotection. Glutamate has long been recognized to play key roles in the pathophysiology of ischemia. However, although some trials are still ongoing, the results from several completed trials with drugs interfering with the glutamatergic pathway have been disappointing. Regarding the inhibition of glutamate release as a possible target for cytoprotection, it might be afforded either by decreasing glutamate efflux or by increasing glutamate uptake. In this context, it has been shown that glutamate transport is the primary and only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels. This transport is executed by the five high-affinity, sodium-dependent plasma membrane glutamate transporters. Among them, the transporter EAAT2 is responsible for up to 90% of all glutamate transport. We will discuss the effect of different neuroprotective tools (membrane stabilizers or endogenous neuroprotection) affecting glutamate efflux and/or expression of EAAT2. We will also describe the finding of a novel polymorphism in the EAAT2 promoter region which could be responsible for differences in both gene function and regulation under pathological conditions such as cerebral ischemia, and which might well account for the failure of glutamate antagonists in the clinical practice. These results may possess important therapeutic implications in the management of patients at risk of ischemic events, since it has been demonstrated that those patients with progressing stroke have higher plasma concentrations of glutamate which remain elevated up to 24 h when compared to the levels in patients without neurological deterioration.

Animals↗
PubMed2004

Vascular endothelial growth factor and its receptor, Flk-1/KDR, are cytoprotective in the extravascular compartment of the ovarian follicle.

Vascular endothelial growth factor (VEGF) is a potent mitogen and cytoprotective factor for vascular endothelial cells. Although VEGF is ubiquitously expressed, its role in nonvascular tissues is poorly understood. VEGF interacts with various cell surface receptors to mediate its cellular effects. It previously has been thought that the VEGF receptor Flk-1/KDR, its main signaling receptor, was expressed exclusively by endothelial cells. However, in the present study using bovine and rodent models, we demonstrate that VEGF and Flk-1/KDR are coexpressed in ovarian granulosa cells. VEGF and Flk-1/KDR mRNA and protein were both detectable in follicle tissue sections and in vitro cultured granulosa cells. Expression of both ligand and receptor increased in healthy follicles throughout follicular development. VEGF treatment of serum-starved and cytokine-exposed granulosa cells resulted in enhanced survival, and this cytoprotection was ameliorated when Flk-1/KDR signaling was inhibited. Reduced expression of Flk-1/KDR was also associated with the onset and progression of follicle atresia, suggesting involvement in follicular health in vivo. The results of this study demonstrate for the first time expression of Flk-1/KDR in ovarian granulosa cells and identify a novel extravascular role for VEGF and its receptor in ovarian function.

Animals↗
PubMed2005

Cytoprotective mechanism of baicalin against endothelial cell damage by peroxynitrite.

To evaluate the mechanism responsible for the cytoprotective effects of baicalin, an antioxidant flavonoid isolated from Scutellaria baicalensis, we investigated its effects against peroxynitrite (ONOO-)-induced endothelial cell (EC) damage. Baicalin showed efficient antioxidative actions by its ability to scavenge ONOO and inhibit ONOO(-)-mediated nitrotyrosine formation in vitro. Using an EC (YPEN-1) culture system, baicalin exhibited cytoprotective effects against cell death by ONOO- that was induced exogenously with tert-butyl hydroperoxide (t-BHP) in the YPEN-1 model. Baicalin was also found to reduce the intracellular precursors of ONOO-, NO* and O2(-) in the t-BHP-treated ECs. Evidence from Western blotting further revealed down-regulated expressions of iNOS and COX2, endogenous sources of NO* and O2(-) by baicalin treatment. In addition, pre-incubation of baicalin with EC suppressed t-BHP-induced nuclear factor kappa-B binding activity as determined by the transfection assay and Western blot analysis, further indicating baicalin's inhibition of iNOS and COX-2 expression. Based on the present data, we propose that baicalin scavenges ONOO- and protects cells against injury. Based on these data, it was concluded that baicalin is potentially a useful antioxidant against ONOO- and NO* and an inhibitor of iNOS and COX-2.

Cell Line↗
PubMed2005

Heat shock protein-70 mediates the cytoprotective effect of carbon monoxide: involvement of p38 beta MAPK and heat shock factor-1.

Carbon monoxide (CO), a product of heme oxygenase activity, exerts antiapoptotic and anti-inflammatory effects in vitro and in vivo. The anti-inflammatory effects of CO involve the inhibition of TNF-alpha expression and the enhancement of IL-10 production, resulting in reduced mortality after endotoxin challenge. In this study we demonstrate for the first time that the protective effects of CO involve the increased expression of the 70-kDa inducible heat shock protein (Hsp70) in murine lung endothelial cells and fibroblasts. The p38beta MAPK mediated the effects of CO on cytoprotection and Hsp70 regulation. Suppression of Hsp70 expression and/or genetic deletion of heat shock factor-1, the principle transcriptional regulator of Hsp70, attenuated the cytoprotective and immunomodulatory effects of CO in mouse lung cells and in vivo. These data provide a novel mechanism for the protective effects of CO and underscore a potential application of this gaseous molecule in anti-inflammatory therapies.

Active Transport, Cell Nucleus↗
PubMed1999

The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine.

Administered before cytotoxic chemotherapy or radiation, the aminothiol, amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumor response. The basis for the selectivity of action resides in the anabolism of amifostine at the normal tissue site by membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol, WR-1065, is followed by rapid uptake into normal tissues. In contrast, uptake into tumor tissue is slow to negligible. Pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. Preclinical studies show significant protection of marrow progenitor cells. Synergistic effects in marrow recovery are noted with the sequential use of amifostine and granulocyte colony-stimulating factor. Protection of kidneys and neural tissues from cisplatin toxicity has been shown, as well as protection of the heart, intestinal crypt cells, and pulmonary tissues from chemotherapy and radiation, and vasculoconnective and musculoconnective tissue in an irradiated field. Comparative in vitro and in vivo studies using murine and human tumor xenografts show no protection of antitumor effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as the basis for the clinical development program for this new broad-spectrum cytoprotective agent.

Amifostine↗
PubMed2000

[Role of membrane lipids in myocardial cytoprotection].

The cardiomyocyte capacity to regulate ATP production to face any change in energy demand is a major determinant of cardiac function. This process is based on a balanced fatty acid (FA) metabolism, because FA is the main fuel of the heart, although the most expensive one in oxygen. The pathway is, however, weakly controlled by the cardiac myocyte which can well regulate FA mitochondrial entry but not cell FA uptake. For this reason, several pathological situations often result from either harmful accumulation of FA and derivatives or excess FA-oxidation. Control of the FA/glucose balance by decreased energy production from FA would thus offer an alternative strategy in the treatment of ischaemia, providing the cardiomyocytes weak ability in handling the non-metabolised FA is controlled. The initiation and the regulation of cardiac contraction both result from membrane activity; the other major role of lipids in the heart is their contribution to membrane homeostasis through phospholipid synthesis pathways and phospholipases. The anti-anginal activity of Trimetazidine, reported as a cytoprotective effect without a haemo-dynamic component; is associated with reduced use of FA for energy. However, accumulation of FA and derivatives has never been observed. Trimetazidine is reported to increase significantly the synthesis of phospholipids without influencing the other lipid classes, thus increasing the incorporation of FA in membrane structures. This cytoprotection appears to be based on the redirection of the use of FA to phospholipid synthesis, which would decrease their availability for energy production. This class of compounds, with the same properties as Trimetazidine, offers a metabolic approach to the treatment of ischaemia.

Adenosine Triphosphate↗
PubMed2000

Left ventricular dysfunction and cytoprotection.

With the projections of increasing aging of the population, heart failure is expected to become a major health problem for most Western societies. Therefore, the study of the pathophysiological mechanisms involved in heart failure should be one of the main priorities of cardiovascular research. A substantial amount of knowledge has been gathered in the recent years on the mechanisms involved in the development of heart failure. One such mechanism is the development of myocyte's apoptosis. This apoptotic mechanism is responsible for a substantial decrease in the number of cardiac myocytes, and therefore for the worsening of heart failure. This apoptotic mechanism can be triggered by a number of mechanisms such as the adrenergic stimulation, the angiotensin II production, changes in calcium homeostasis, and changes in cellular metabolism. At least in theory, the development of therapies (such as beta blockers, ACE inhibitors, calcium channel blockers and trimetazidine) that can inhibit these mechanisms can have a cytoprotective role and therefore reduce the development of heart failure. Because of its main role in the production of energy for the cell, the mitochondrion is one of the mainframes of cell viability. If the mitochondrial function is decreased the myocyte will be in jeopardy. Therefore, drugs that can prevent mitochondrial dysfunction will obviously have a cytoprotective role in heart failure.

Cytoprotection↗
PubMed2002

[Role of the pS(2) in gastric mucosa adaptative cytoprotection from stress].

OBJECTIVE: To determine the expression of pS(2) (a member of trefoil peptides) in gastric mucosal of rats undergone WRS, and to probe the role of pS(2) in adaptive cytoprotection. METHODS: Wistar rats were exposed to single or repeated WRS for 4 h every other day for up to 6 days. Gastric mucosal blood flow (GMBF) was measured by LDF-3 Flowmeter. The degree of the gastric mucosal lesions (UI) was evaluated grossly and histologically. The expression of pS(2) was determined by RT-PCR and immunohistochemistry. RESULTS: (1) WRS applied once produced numerous gastric mucosal erosions. UI gradually declined and GMBF restored on 3 d, 5 d after stress. UI was reduced to 20.8% and GMBF increased up to 94.5% of normal value. The expression of pS(2) was increased during the healing of stress-induced ulceration. The same results were observed by immunohistochemistry (0.50 +/- 0.13 vs 0.70 +/- 0.11, P < 0.01). (2) With repeated WRS, the adaptative cytoprotection against stress was developed. UI after four consecutive WRS was 22% of UI after one WRS. GMBF after four consecutive was 94.2% of normal value. Cell proliferation in the neck regions of gastric glands was activated. The expression of pS(2) was increased by using RT-PCR (0.37 +/- 0.02 vs 0.77 +/- 0.01, P < 0.01) and immunohistochemistry (0.55 +/- 0.04 vs 2.46 +/- 0.08, P < 0.01). CONCLUSION: Increased expression of pS(2) could play an important role in adaptation of gastric mucose developed after repeated WRS.

Adaptation, Physiological↗
PubMed2002

[Autocrine expression of hepatocyte growth factor and its cytoprotective effect on hepatocyte poisoning].

OBJECTIVES: To construct pEGFP-hepatic growth factor (HGF) expression vector, detect its transient expression in transfected human hepatocytes, and to investigate the influence of autocrine HGF expression on the proliferative potential and cytoprotective effects in human hepatocyte. METHODS: Human HGF cDNA was ligated to pEGFP vector. The recombinant plasmid was transfected into human hepatocyte line QZG with liposome. The expression of HGF protein was observed by fluorescence microscopy and immunohistochemistry. Hepatic cells were collected 24, 48, and 72 hours after transfection to detect the number of [(3)H]-TdR uptake in DNA. DNA synthesis was observed by using PCNA stain immunohistochemistry. Acute liver cell damage was induced by carbon tetrachloride. The supernatant of culture 10 days after transfection of pEGFP-HGF was collected to put in the normal culture of hepatic cells. Another sample of supernatant was added with anti-HGF antibody to block the HGF activity as control. Cytoprotective effect was observed by examining the survival rate of hepatocytes and leakage of intracellular alanine transaminase (ALT) and potassium ions. RESULTS: HGF identification of pEGFP-HGF by enzyme digestion showed that HGF fragment had been cloned into BamH I and Sal I sites of pEGFP-N3. Expression of GFP in transfected hepatocytes was observed with fluorescence microscopy. The [(3)H]-TdR uptake became 7 times as much as in the control group 96 hours after transfection. After HGF transfection, survival rate of hepatocytes poisoned by CCl4 significantly increased (83% vs 61%, P < 0.05), and leakage of intracellular alanine transaminase and potassium ions decreased (35.16 U x L-1 vs 65.31 U x L-1, P < 0.01; and 5.59 mmol/L vs 6.02 mmol/L, P < 0.01 respectively). Culture of transfected hepatic cells promoted the proliferation of other non-transfected cells. This effect was blocked by anti-HGF antibody. CONCLUSION: Transfected HGF is expressed in hepatic cells and has the activity of promoting cell division and protecting hepatic cells against poisoning.

Carbon Tetrachloride↗
PubMedDate not supplied

Cytoprotection by melatonin and growth hormone in early rat myocardial infarction as revealed by Feulgen DNA staining.

OBJECTIVE: To examine the cytoprotective effect of melatonin or recombinant human growth hormone (hGH) on the early phase of a running myocardial infarction in rats by using the Feulgen staining. METHODS: Rats were subjected to surgical ligature of the left coronary artery or its sham-operation and were studied 1.5 3 h later. Melatonin was administered in the drinking water (100 microg/ml water) for 7 days before surgery. Recombinant hGH (2 IU/kg) was given ip at the time of surgery. Feulgen-stained histological cardiac sections were examined by light microscopy and image analysis. RESULTS: Infarcted rats receiving vehicle exhibited large, diffuse cardiac lesions with a marked positivity for Feulgen reaction. About 18 20% of the total area recorded became injured 1.5 or 3 h after infarction, respectively. Infarcted rats treated with melatonin or hGH, or the combination of both, and killed 3 h after surgery, showed cardiac sections with scattered lesions and only a few isolated injured muscle fibers. A similar effectiveness of melatonin and hGH, alone or in combination, to decrease injured area by 86 87% and the number of cardiac lesions by 75 80% was observed. CONCLUSION: A significant cytoprotective effect of melatonin or hGH is demonstrable in an early phase of myocardial infarction in rats.

Animals↗
PubMed2003

Effects of sulfhydryl compounds on pancreatic cytoprotection in acute necrotic pancreatitis.

OBJECTIVE: To observe sulfhydryl compound variation in the injury of pancreatic cells and the effects of external sulfhydryl compounds on cytoprotection. METHODS: Male Wistar mice were divided randomly into three groups: groups A and B served as animal models (retrograde duct infusion with 5% sodium taurocholate), in group A, 45 animals were treated with normal saline therapy, in group B, 45 animals were treated with Tiopronin therapy; and group C, 15 animals, were designated as normal control. Animals were killed at 2, 4, 6, 12 and 24 h, and pancreatic tissue was analyzed for total sulfhydryl (TSH), nonprotein sulfhydryl (NPSH) and malondialdehyde (MDA). Histopathology, serum amylase (Sam) and C reactive protein (CRP) were assessed as well. RESULTS: Levels of Sam and CRP increased in both group A and group B, with corresponding pathological changes of acute nerotic pancreatitis (ANP). Levels of TSH, NPSH and protein sulfhydryl (PSH) in group A decreased markedly during pancreatitis (P < 0.01), but MDA increased significantly (P < 0.01). The depletion of NPSH in group B was markedly ameliorated at 4 h or 6 h, when Tiopronin was prophylactically administered (P < 0.05), after which the level of MDA showed very little increase when compared to group A (P < 0.01). Histopathological damage was attenuated to a certain extent, in regards to serum amylase and CRP. CONCLUSIONS: All sulfhydryl compounds decreased significantly during ANP; external sulfhydryl compound could protect the pancreatic cells most likely as a type of scavengers of oxygen free radicals, which are critically involved in the pathophysiology of ANP. Sulfhydryl plays an important role in the action of pancreatic cytoprotection.

Acute Disease↗