Publications

The gastric duodenal mucosa normally is protected from the damaging effects of gastric acid and pepsin by ill-defined mechanisms. Ulcers may arise when there is an imbalance between the aggressive and defensive factors that renders the mucosa susceptible to damage. A variety of factors have been identified that may favor the development of peptic ulcers, but no single pathophysiologic defect applies in all ulcer patients. In duodenal ulcers, gastric acid hypersecretion is observed in as many as one third of patients; however, most patients with duodenal ulcers secrete normal amounts of gastric acid. Decreased mucosal bicarbonate secretion may be important in at least some duodenal ulcer patients. Use of NSAIDs may cause either gastric or duodenal ulcers, probably through the inhibition of mucosal prostaglandin synthesis and disruption of mucosal defenses. Finally, a recently identified bacterium, H. pylori, causes a chronic gastritis that is found in the overwhelming majority of patients with duodenal ulcers and non-NSAID-associated gastric ulcers. This bacterium may play a pivotal role in ulcer pathogenesis and, especially, in ulcer recurrences. A number of drugs of proved efficacy are available for the treatment of acute duodenal and gastric ulcers. The H2 receptor antagonists administered once daily remain the mainstay of ulcer therapy because of their efficacy, ease of use, and excellent safety profile. More thorough and long-lasting acid inhibition is afforded by the H+/K(+)-ATPase inhibitor omeprazole. This agent also promotes more rapid ulcer healing, but in most patients, this minor advantage may not justify the higher cost. It is not known whether more rapid healing will translate into lower ulcer complication rates. Until further data are available, this drug may be preferable in patients with large or complicated ulcers. In patients with refractory ulcers, omeprazole is clearly superior to other available agents. Agents that promote mucosal defense mechanisms are becoming increasingly popular in the treatment of duodenal ulcers but have undergone less testing than in gastric ulcers. Sucralfate 1 g four times daily is equivalent to H2 antagonists in the treatment of duodenal ulcers and, probably, gastric ulcers. Its requirement for multiple daily doses makes it somewhat less attractive at present to most patients. Low- to medium-dose Al-containing antacids are inexpensive and efficacious in duodenal ulcer therapy. They should remain as therapeutic options for the compliant patient in whom cost considerations are important. Colloidal bismuth subcitrate 120 mg four times a day is comparable to other agents in the acute treatment of duodenal ulcers and likely gastric ulcers.(ABSTRACT TRUNCATED AT 400 WORDS)

Localized absence of epithelial Langerhans cells (LC) has been shown to affect systemic immune responses, allow microbial colonization and play a possible role in carcinogenesis. Because use of smokeless tobacco is associated with abnormal oral mucosal changes and development of carcinoma, we examined lesion and control specimens from 17 current users of smokeless tobacco to determine whether lesions showed changes in LC number or antigen expression. We identified LC by immunohistochemistry with antibodies to the antigens T6, HLA-DR, HLA-DQ, and HLA-DP. Lesion specimens contained fewer LC (means of 6 LC/mm and 10 LC/mm2) than did the corresponding control specimens (means of 14 LC/mm and 30 LC/mm2), and in each pair of lesion and autologous control specimens the reduction in LC was on average 58% (range, 3% to 95%). There were no apparent differences between lesion and control specimens in the number of LC expressing each of the four marker antigens. Reductions in LC occurred in all types of smokeless tobacco-associated lesions, regardless of increased epithelial thickness or changes in keratinization. Our data indicate that smokeless tobacco reduces the number of Langerhans cells at its site of contact with the oral mucosa.

The mesangial cell MMPs and their inhibitor may represent proteins through which biological modifiers such as cytokines and growth factors can control and influence the organization of the glomerulus. At the present we can only speculate on their exact function in glomerular disease. They could conceivably play a role in glomerular conditions where mesangial hypercellularity and cytoplasmic interposition between the endothelium and the basement membrane are frequent occurrences, and in which cytokine-enhanced synthesis of matrix-degrading enzymes could result in severe structural damage. A number of glomerular diseases such as diabetic nephropathy are characterized by the accumulation of glomerular matrix proteins. This could be explained by the inappropriate expression of intrinsic mesangial cell MMPs or TIMP. Further investigation of these proteins in experimental models of glomerular disease or in situ hybridization studies using the available probes promises to be a rewarding area of research during the next few years. For these studies the availability of rTIMP and recent developments in the design of synthetic inhibitors of MMPs may allow more searching investigations into the role of MMP in the pathophysiology of glomerular disease.

Cultured rat glomerular epithelial cells (GEC) were examined for their ability to release extracellular matrix-degrading proteinases with [3H]gelatin as substrate. GEC-conditioned media, under serum-free conditions, contained modest amounts of gelatinase activity (1 to 10 U/mg of protein); the activity was maximal at neutral pH, was inhibited by zinc chelators, was not inhibited by tissue inhibitor of metalloproteinase-2, and could not be further activated by trypsin or organomercurials. Gelatin substrate sodium dodecyl sulfate-polyacrylamide gels of GEC-conditioned medium revealed several zones of lysis, with molecular sizes of 150 kd (major band), and 220, 86 to 93, and 52 to 54 kd (minor bands). Northern blot analysis demonstrated that the GEC metalloproteinase(s) were distinct from the 68- to 72-kd type IV collagenase/gelatinase present in mesangial cells or the 92-kd type IV collagenase present in neutrophils. The GEC gelatinolytic activity also degraded insoluble type IV collagen in glomerular basement membrane in a dose-dependent manner. The major metalloproteinase activity responsible for the type IV collagen degradation has a molecular size of 150 kd with a type IV collagen substrate gel. Thus, GEC produce several neutral metalloproteinases, which, by virtue of their substrate specificity, may play an important role in glomerular basement membrane remodeling and in glomerular diseases characterized by alterations in basement membrane permeability.