Publications

Cultured glomerular mesangial cells (MC) respond to low concentrations of bacterial endotoxin (ET) by secreting prostaglandins and interleukin-1. To evaluate further the nature of ET-induced mesangial cell activation, the authors evaluated the effects of this agent on MC morphology and cytoskeletal organization. Bacterial ET, in concentrations as low as I ng/ml, induced reversible membrane ruffling, cellular rounding, and extension of many filopodia and lamellopodia. Augmented fluid-phase pinocytosis occurred in parallel, as determined by transmission electron microscopy and tritiated sucrose uptake. These cellular morphologic and functional changes were associated with an extensive, but reversible, depolymerization of actin microfilaments. Actin gene expression was also modified by ET. At 4 to 6 hours after ET exposure, Northern blot analysis showed a twofold to fourfold increase in actin mRNA levels. In situ hybridizations of ET-stimulated cells at the light and electron microscopic levels demonstrated a markedly asymmetric distribution of actin mRNA, which was localized in the cellular periphery at filopodial and lamellopodial extensions, presumably sites of new actin protein synthesis. It is concluded that ET effects on MC are distinct from the nonspecific lytic or 'toxic' actions described for other cell types. Endotoxin induces a global activation of this cell type associated with major changes in membrane structure, cytoskeletal organization, and gene expression, which resemble in many respects the responses to peptide mitogens.

The regulation of gastrin secretion from antral G-cells is of major importance in the physiologic control of acid secretion. Gastrin secretion is highly dependent upon gastric intraluminal pH and is inhibited significantly by a pH of less than 3.0. Acute gastric alkalinization greater than pH 6.0 with antisecretory agents such as H2-receptor antagonists or H+/K+ ATPase inhibitors has little impact on fasting serum gastrin levels but promotes an enhanced sustained rise in meal-stimulated gastrin release. Courses of standard therapy with both H2-antagonists and H+/K+ inhibitors cause a significant rise in 24 h integrated plasma gastrin levels that is inversely correlated to the 24-h integrated gastric acidity. The rise in fasting or integrated plasma gastrin levels observed in patients treated with H2-antagonists is small and of unclear clinical significance. Therapy with antisecretory agents leads to earlier ulcer relapse than with other agents. A variety of factors have been proposed to explain the earlier ulcer relapse rate, including secondary hypergastrinemia with rebound acid hypersecretion after discontinuation of the drug. Secondary hypergastrinemia may also lead to tolerance to prolonged courses of H2-antagonists therapy with a decrease in acid inhibition. This may contribute to break-through ulcer recurrence during maintenance H2-antagonist therapy. However, the relative importance of hypergastrinemia and tolerance to H2-antagonists compared with other factors such as baseline gastric acid secretion, smoking status, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori status is difficult to assess.(ABSTRACT TRUNCATED AT 250 WORDS)

The optical density of suspensions of the digestive enzyme-containing zymogen granule, a roughly spherical 1 micron diameter membrane-enclosed subcellular structure isolated from the exocrine pancreas of mammals, is reduced greatly when they are suspended in physiological media. This reduction in optical density is accompanied by the release of the granule's protein contents. It has traditionally been assumed that this property is due to granule lysis; that is, dissolution of the particle and its consequent disappearance as a strongly scattering object. Thus, lysis would decrease optical density by decreasing the number density of suspended spheres (N) according to Beer's law. However, as a general matter, changes in the optical density of suspensions of spheres may be a function of changes in the refractive index (m) or radius (r) of the objects as well. In this study, we apply Mie theory of scattering by small particles, which, in conjunction with Beer's law, allows us to evaluate whether changes in the scattering properties of granule suspensions are due to changes in N, m or r. Scattering by granule suspensions was reduced in three ways-pH, calcium ion concentration, and detergent concentration. A simple reduction in particle number did not account for decreased scattering and protein release in any of these circumstances. Instead, the changes appear attributable to decreases in particle size and refractive index.