Healing Of Chronic Ulcers Research Articles

Therapeutic effect of rebamipide on ammonia-induced gastric mucosal hemorrhagic lesion in rats.

Rebamipide, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinone-4-yl]-propionic acid, a novel antipeptic ulcer agent, has been reported to prevent various acute experimental gastric mucosal lesions and to accelerate the healing of chronic ulcers. Therapeutic effect of rebamipide was investigated with regard to the inhibitory effect on xanthine oxidase activity and type conversion of the enzyme which play a profound role in oxygen radicals generation system. Intraperitoneal administration of rebamipide at 60 mg/kg body weight reduced the xanthine oxidase activity, lipid peroxide content in ammonia induced hemorrhagic lesion. These results suggest that the therapeutic effect of rebamipide on gastric mucosal lesion may be in part due to the inhibitory activity of xanthine oxidase and type conversion rate of the enzyme.

Expression of natural peptide antibiotics in human skin

Skin infections make a substantial contribution to the total burden of infectious disease worldwide. In addition to their role as primary pathogens many organisms aggravate inflammatory skin conditions such as atopic eczema or contribute to the delayed healing of chronic ulcers and infected surgical wounds. Natural antibiotics are evolutionarily conserved peptides with broad antimicrobial activity which contribute to the innate resistance of insects, plants, and mammals to invading pathogens. 1 Kagan BL Ganz T Lehrer RI Defensins: a family of antimicrobial and cytotoxic peptides. Toxicology. 1994; 87: 131-149 Crossref PubMed Scopus (176) Google Scholar Antimicrobial peptides of the defensin family with broad activity against gram-negative bacteria, fungi, mycobacteria, and enveloped viruses have been isolated from neutrophil granules, macrophages, and some specialised epithelial cells of the small intestine. 1 Kagan BL Ganz T Lehrer RI Defensins: a family of antimicrobial and cytotoxic peptides. Toxicology. 1994; 87: 131-149 Crossref PubMed Scopus (176) Google Scholar With a combination of PCR and in-situ hybridisation we have identified and localised expression of a member of the defensin family to keratinocytes in normal human skin.

Cell cycle progression during gastric ulcer healing by ebrotidine and sucralfate

1. 1. The effect of antiulcer agents, ebrotidine and sucralfate, on the expression of gastric mucosal proliferating cell nuclear antigen (PCNA) and cyclin-dependent kinase (p34Cdk2) during chronic ulcer healing was examined. 2. 2. Rats with experimentally induced gastric ulcers were treated twice daily for 14 days with either ebrotidine at 100 mg/kg, sucralfate at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for quantitization of gastric mucosal PCNA and Cdk2 expression. 3. 3. The assays revealed that the ulcer healing was accompanied by a marked elevation in mucosal expression of PCNA and Cdk2. The maximum increase in PCNA (4.7-fold) occurred by the second day of healing, and the expression of Cdk2 reached a maximum increase (2.3-fold) by the fourth day. 4. 4. Accelerated ulcer healing with ebrotidine (7 days) and sucralfate (8 days) treatments was reflected in a significant enhancement of PCNA and Cdk2 expression. By the second day of treatment, ebrotidine evoked a 15-fold increase in PCNA expression, and sucralfate produced an 11.8-fold enhancement. The mucosal expression of Cdk2 attained a maximum of 4.3-fold increase over that of the controls by the sixth day of healing with ebrotidine, and a fivefold increase in Cdk2 expression occurred by the fourth day of ulcer treatment with sucralfate. 5. 5. The findings implicate cell cycle regulatory proteins in the processes leading to mucosal repair and suggest that the two drugs exert a similar effect on the expression of proteins that control cell cycle progression.

Gastric Mucosal Cell Cycle Regulation with Ulcer Healing by Sulglycotide

Background: The progression of the events associated with gastric mucosal repair is controlled in an orderly manner by a plethora of the extracellular cues exerting their effect on the cell cycle regulatory proteins, cyclins, and cyclin-dependent kinases, the expression of which varies through the cycle stages. The purpose of this study was to evaluate the expression of cyclin-dependent kinase (Cdk2) and proliferating cell nuclear antigen (PCNA) during chronic ulcer healing with sulglycotide. Methods: Rats with experimentally induced gastric ulcers were treated twice daily for 14 days either with sulglycotide at 200 mg/kg or vehicle, and at different stages of the treatment their stomachs were used for macroscopic damage assessment and quantitation of gastric mucosal Cdk2 and PCNA expression. Results: The assays showed that the ulcer healing was accompanied by an increase in mucosal expression of Cdk2 and PCNA. The maximum increase in Cdk2 (2.3-fold) occurred by the 4th day of healing, whereas the expression of PCNA reached a maximum increase (4.7-fold) on the 2nd day of healing. An accelerated ulcer healing (10 days) with sulglycotide treatment was reflected in a marked enhancement in Cdk2 and PCNA. In comparison with the controls, sulglycotide caused a 2.2-fold enhancement in PCNA expression by the 2nd day of treatment and a 2.5-fold enhancement by the 6th day, whereas the Cdk2 expression attained a maximum 2.1-fold increase by the 6th day of treatment and remained substantially increased for up to 10 days. Conclusions: The findings show a complex interplay between the extracellular cues and cell cycle regulatory proteins, an orderly progression that drives the mucosal repair process. We also show that the gastroprotective agent sulglycotide is capable of affecting the expression of the cell cycle regulatory proteins that control cell cycle progression through Gl and into S phase.

Synchronized induction in bFGF and Cdk2 during gastric ulcer healing.

The processes of gastric mucosal repair are regulated by growth factors triggering the signals for cell cycle progression. We examined the expression of gastric mucosal basic fibroblast factor (bFGF) and cyclin dependent kinase (p34Cdk2) at different stages of chronic ulcer healing. The results of assays revealed that ulcer healing was accompanied by an increase in mucosal expression of bFGF and Cdk2. A significant induction in bFGF and Cdk2 occurred by the 2nd day of ulcer healing, reached the respective maximums of 2.3- and 2.2-fold increase by the 4th day of healing, and remained still elevated (20%) on the 14th day when the ulcer was essentially healed. The results demonstrate a synchronized induction in bFGF and cell cycle regulatory kinase, Cdk2, with ulcer healing.

Enhancement in gastric mucosal EGF and PDGF receptor expression with ulcer healing by sulglycotide

1. 1. The effect of an antiulcer agent, sulglycotide, on mucosal expression of EGF and PDGF receptors with chronic ulcer healing was investigated. 2. 2. Rats with experimentally-induced gastric ulcers were treated twice daily for 14 consecutive days, either with sulglycotide at 200 mg/kg or vehicle, and at different stages of treatment used for quantitation of gastric mucosal EGF and PDGF receptors. 3. 3. The ulcer healing was accompanied by an increase in mucosal expression of both types of receptors. A 1.8-fold increase in EGF and 3.1-fold increase in PDGF receptors occurred by the 4th day following the development of ulcer and reached a maximum of 2.4-3.9-fold increase by the 10–14th day. 4. 4. Treatment with sulglycotide caused accelerated ulcer healing accompanied by a significant enhancement in the receptors expression. A 2.3- and 3.6-fold increase in EGF and PDGF receptor expression occurred by the 4th day of sulglycotide treatment, reaching a 5.5- and 5.6-fold respective increase by the 10th day when the ulcer essentially healed. 5. 5. The results attest to the ability of sulglycotide to stimulate the gastric mucosal proliferative activities associated with ulcer healing.

Enhancement in gastric mucosal laminin receptor expression with ulcer healing by sucralfate: [formula omitted], J. Piotrowski, S. Sano and A. Slomiany. Res. Ctr., UMDNJ, Newark, NJ 07103

The expression of gastric mucosal laminin receptor during chronic ulcer healing in the presence of sucralfate treatment was investigated. Rats with induced gastric ulcers were treated twice daily for 20 consecutive days either with sucralfate at 100mg/kg or vehicle, and at different stages of treatment used for gastric mucosal laminin receptor quantitation. The assays revealed that accelerated ulcer healing (8 days) in the presence of sucralfate was accompanied by a significant enhancement in the laminin receptor expression. A 2.8-fold increase in the receptor expression over that of controls occurred by the 3rd day of sucralfate treatment, reached a maximum of 3.1-fold increase by the 7th day and remained elevated even after 20 days of treatment. The results attest to the ability of sucralfate to stimulate and promote the events associated with gastric mucosal integrity restoration.

Nitric Oxide in Gastroprotective and Ulcer Healing Effects of Sucralfate

Sucralfate is known to protect gastric mucosa against the damaging action of strong irritants and to accelerate healing of chronic ulcers, but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and healing effects can be obtained with exogenous donors of nitric oxide (NO) and prostaglandins (PG). The area of gastric lesions was measured by planimetry. Gastric blood flow was determined using laser Doppler flowmetry. The role of NO in the prevention of ethanol-induced gastric damage and in the healing of gastric ulcerations by sucralfate and nocloprost, a stable PGE2 analog, was therefore assessed. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate. The doses of L-NNA attenuating significantly the protective effects of sucralfate were 25-50 mg/kg. The effects of L-NNA were reversed by the addition of L-arginine but not D-arginine. For comparison, the gastroprotective (but not hyperemic) effects of nocloprost were not affected by the pretreatment with L-NNA and/or arginine. Daily treatment with L-NNA (50 mg/kg per day) prolonged the healing of chronic gastric ulcers and significantly reduced the acceleration of healing by sucralfate. We conclude that (i) the gastroprotective and hyperemic effects of sucralfate involve, at least in part, the NO-arginine pathway, (ii) the ulcer healing effects of sucralfate may also involve NO, probably through the hyperemia around the ulcer, and (iii) NO is not essential for the mucosal protection of PGE2 analog, but may account for the gastric vasodilatory effect of this PG.

Wound Healing: An endpoint for complex peripheral angioplasty.

The standard endpoint for lower limb revascularization is long-term patency; however, in high-risk patients with end-stage ischemia, healing of chronic ulcerations has been proposed as an acceptable endpoint. To evaluate if today's minimally invasive interventions, in combination with comprehensive wound healing procedures, can resolve nonhealing wounds, we performed a retrospective review of chronic ulceration patients treated at the San Francisco Wound Care Center. Eight-five patients with 96 limbs at risk due to nonhealing ulcers were treated with a variety of endovascular procedures: 7 patients (group I) received Palmaz stents for unilateral iliac occlusions; 42 limbs (group II) in 39 patients were treated with balloon angioplasty for superficial femoral and popliteal lesions; and 47 extremities in 39 patients (group III) underwent rotational atherectomy for tibioperoneal lesions. Comprehensive wound management techniques, including the application of growth factors, were used. All group I wounds healed, although 6 of 7 patients required additional procedures to address outflow lesions. In groups II and III, primary patencies were similar (64% and 70%, respectively), and nine treated sites reoccluded in each group. Restenotic lesions were retreated in both groups (three in group II and four in group III) secondary patencies were 71% and 78%, respectively. There were more amputations in group III patients (five) compared to group II (one). In both groups after 5 months, 90% of wounds had healed in group II and 72% in group III. The use of endovascular procedures appears to play an important role in the healing of chronic lower extremity ulcerations in high-risk patients with end-stage ischemia.

Wound Healing: An Endpoint for Complex Peripheral Angioplasty

Purpose: The standard endpoint for lower limb revascularization is long-term patency; however, in high-risk patients with end-stage ischemia, healing of chronic ulcerations has been proposed as an acceptable endpoint. To evaluate if today's minimally invasive interventions, in combination with comprehensive wound healing procedures, can resolve nonhealing wounds, we performed a retrospective review of chronic ulceration patients treated at the San Francisco Wound Care Center. Methods: Eight-five patients with 96 limbs at risk due to nonhealing ulcers were treated with a variety of endovacular procedures: 7 patients (group 1) received PalmazR stents for unilateral iliac occlusions; 42 limbs (group II) in 39 patients were treated with balloon angioplasty for superficial femoral and popliteal lesions; and 47 extremities in 39 patients (group III) underwent rotational atherectomy for tibioperoneal lesions. Comprehensive wound management techniques, including the application of growth factors, were used. Results: All group I wounds healed, although 6 of 7 patients required additional procedures to address outflow lesions. In groups II and III, primary patencies were similar (64% and 70%, respectively), and nine treated sites reoccluded in each group. Restenotic lesions were retreated in both groups (three in group II and four in group III); secondary patencies were 71% and 78%, respectively. There were more amputations in group III patients (five) compared to group II (one). In both groups after 5 months, 90% of wounds had healed in group II and 72% in group III. Conclusion: The use of endovascular procedures appears to play an important role in the healing of chronic lower extremity ulcerations in high-risk patients with end-stage ischemia.

Seminars on Ulcer Healing

The main object ive of the meet ing is to coordinate an d synthes!ze new data pert inent to ulcer healing and relapse in the gastrointestinal tract, i . e , mechan i sm of healing and factors stimulating and delaying ulcer healing. In addition, special overv iew lectures on topics of general interest will be given b y wel l -known scientists and clinicians. At the end, the major topics will be summar ized in the form of " t a k e h o m e m e s s a g e s " b y prominent exper ts in the field. The concept of acute gas t roprotect ion (cytoprotect ion) of the 1980s is giving w a y to the emerging issues related to chronic ulcer healing, relapse and growth factors. The unique features of this sympos ium are (1) the synthesi s of advances in basic sciences related to ulcer healing and clinical data available both on ulcer healing and relapse, as wel l as (2) the emphasis on the ulcer healing proper t ies of antiucler drugs. In addition (3) the re levance and implications of quality of ulcer healing will be reviewed both in animal models and with clinical data. Thus, mostly new data on repair o f erosions, ulcer healing and~or relapse, rather than the results on prevention o f acute mucosal lesions will be presented and discussed.

Mechanisms of gastroduodenal protection by sucralfate

Over the past 5–10 years, a number of studies have shown that topical sucralfate enhances a number of gastric and duodenal mechanisms, e.g., the “mucus-bicarbonate barrier,” mucosal hydrophobicity, mucosal blood flow, cell viability, and local production of prostaglandins, as well as endogenous mediators of tissue injury and repair. It seems likely that the complex actions of sucralfate are in part related to direct interaction between the drug or its components (aluminum, sucrose, and sulfate) and gastric mucosal tissues, and in part related to effects of the drug on the various mucosal mediators of tissue injury and repair. Local actions may play a role in accelerating healing of ulcer-damaged mucosa, but this does not explain the protective actions of sucralfate on normal mucosa. Thus sucralfate appears to enhance the protective function of the “mucus-bicarbonate” barrier by actions on both components. This may depend in part on an interaction with the unstirred layer overlying gastric epithelium. Sucralfate has also been shown to increase the hydrophobicity of mucus gel. There is little doubt that sucralfate increases local production and release of protective prostaglandins (PGs), but the precise role played by these agents in mediating mucosal protection and in chronic ulcer healing remains uncertain. Currently, the mechanism of action of sucralfate on vascular integrity remains unknown and the role of PGs in this protective function is unclear. There is little evidence that epidermal growth factor plays any role in mediating mucosal protection by sucralfate, but it may be important in its ulcer-healing action. Sucralfate has been shown to be truly “cytoprotective” in that it protects isolated epithelial cells from damage by noxious agents. In animals treated with sucralfate, the surface epithelial cells were disrupted, but necrotic lesions in the deep proliferative zone were virtually absent. It seems likely that investigations of the actions of sucralfate and its components will move ever closer to defining the target cells, the intracellular events, and the mediators that bring about its protective and ulcer-healing activity.

The Mode of Action of Sucralfate: The 1×1×1 Mechanism of Action

Of the multiple actions of sucralfate, not all are equally relevant. In fact, certain actions of the drug contribute to healing of acute ulcers or to ulcer prevention, whereas other actions are more important in accelerating the healing of gastric and duodenal ulcers. The action of sucralfate can now be defined by the '1 x 1 x 1' mechanism of action--that is, one action of sucralfate is important for acute prevention, one is relevant to both acute and chronic protection, and one is important for chronic ulcer healing. Maintenance of mucosal vascular integrity and of blood flow, which ensures rapid epithelial restitution to repair superficial defects, are the most important acute actions of sucralfate. On the other hand, increased bicarbonate and mucus secretion seem to be relevant in both acute and chronic protection of the gastroduodenal mucosa. Finally, the enhanced binding by sucralfate of fibroblast growth factor and epidermal growth factor stimulates angiogenesis, granulation tissue, and epithelization for ulcer healing. This 1 x 1 x 1 theory of the mechanism of action of sucralfate concentrates on the relevant effects of this drug (which has more than a dozen actions) and may help to elucidate the molecular mechanism of action.

PROMOTED HEALING OF LEPROUS ULCERS BY TRANSCUTANEOUS NERVE STIMULATION

Low-frequency (2 Hz) transcutaneous electrical nerve stimulation (TNS) may produce widespread and prolonged increases in skin temperature in patients with peripheral vascular insufficiency due to improved microcirculation. The method has previously been used successfully to potentiate healing of chronic ulcers of various etiology. The present report describes a similar study, using TNS treatment in attempts to accelerate healing of chronic leprous ulcers that had resisted treatment for several months or years. All other treatment, local and systemic chemotherapy, and daily regime remained as far as possible unaltered. The study was limited to ulceration in the soft tissue of the foot or lower leg. Eleven TNS sessions, each of 30 min duration, were applied per week. In 19 patients (6 out- and 13 in-patients), in whom the TNS treatment was not interrupted, all ulcers healed completely within a mean of 5.2 weeks (range 3-12 weeks). The mean size of the ulcers was 5.2 cu.cm (range 0.2-48.3 cu.cm), and they had persisted for a mean of 15.8 months (range 2-60 months). The 'healing index', i.e. the mean reduction of the ulcer cavity per week, was 1.0 cu.cm/week. The study demonstrates a clear therapeutic effect for low-frequency TNS in patients with leprous ulcers. The mechanisms involved in the accelerated healing are assumed to be increased microcirculation due to sympatho-inhibition and release of endogenous corticosteroids.

Treatment of chronic venous ulcers with sheets of cultured allogenic keratinocytes

Cultured keratinocytes were used as allografts to treat 51 patients with chronic venous ulceration or rheumatoid ulcers unresponsive to all previous conventional treatments including split skin grafts. Although early epithelialization could be seen in the centre of some ulcers, a major effect appeared to be healing from the previously indolent edge. This treatment appears to provide some clinical benefit in healing of chronic ulceration.

Prostaglandin content in the rat gastric mucosa during healing of chronic ulcers induced by acetic acid.

Non-steroidal anti-inflammatory compounds delayed the regeneration of chronic gastric ulcers induced by acetic acid in the rat. The delayed regeneration was connected with a decreased PGE2 content in the proliferating tissue. Glucocorticoid influenced neither the regeneration of mucosal damages nor the gastric PGE2 content. The carboanhydrase inhibitor, acetazolamide, also did not alter the restoration of gastric mucosa after being damaged. From the clinical point of view, the safe use of NOSAC will be emphasized in patients with ulcer anamnese. The findings with prednisolone did not confirm a similar safe use of this drug in patients.

III. Cancer of the Stomach: Some Pathological Considerations

The problem of ulcer-cancer remains an exceedingly difficult one, since the pathological criteria on which this diagnosis must be based are still not fully established. The presence of malignancy can usually be determined with complete certainty and, indeed, in most cases without difficulty. In the stomach, as in the rest of the digestive tract, the various coats are well defined, even in the margins of chronic peptic ulcers, and the degree of invasion by epithelial malignancy can be accurately assessed. The chief if not the only source of error is the mistaking of deep epithelial heterotopia, not uncommon in the margins of healing chronic ulcers, for malignancy, and this is probably the reason for the very high incidence figures for ulcer-cancer given by some observers in the past. Deep heterotopia may penetrate, but it never in my experience transgresses, the muscular coat, contrasting in this respect with that other non-neoplastic but highly invasive lesion, endometriosis. Deep gastric heterotopia also remains more or less confined to the margin of the healing ulcer and does not spread centrifugally, like cancer, in the lymphatics of the submucosa. The chief histological difficulty is in determining whether there is sufficient evidence to say that a simple chronic ulcer has certainly preceded the onset of epithelial malignancy.