Polymorphonuclear leukocyte elastase activity is increased by bacterial lipopolysaccharide: a response inhibited by glucocorticoids

Human neutrophil elastase is thought to play an important role in connective tissue destruction in diseases such as emphysema and arthritis. In this article, it is demonstrated that the elastase activity of mature human peripheral blood neutrophils can be rapidly increased in vitro by treatment of the cells with lipopolysaccharide from E. coli and that this increase is inhibited by corticosteroid pretreatment of the cells and by inhibitors of protein synthesis. Alterations in intracellular enzyme content of the mature polymorph in response to bacterial products or other stimuli may be important for amplification of the inflammatory response.     

Selective induction of cardiovascular responses to des-Arg9-bradykinin by bacterial endotoxin

Bacterial lipopolysaccharide (LPS) induces in 5 h a hypotensive response mediated by the B1-receptor for kinins in the rabbit, an effect which is not observed in untreated animals. The present study is intended to evaluate the capacity of other acute toxic treatments to induce such a response and to analyze the mechanism of induction. Intravenous injections of inulin (20 mg), Naja venom (50 micrograms), compound 48/80 (1 mg), and etiocholanolone (6 mg) failed to induce hypotensive response to des-Arg9-bradykinin (the selective agonist of the B1-receptor) in 5 h. LPS from Salmonella (100 micrograms) and E. coli (10 micrograms) were highly effective, whereas trypsin (2 mg) gave doubtful responses. White blood cell counts revealed a profound and rapid neutropenic effect of the 2 LPS and a less marked one for trypsin. It is concluded that (1) LPS is a selective inducer of a new cardiovascular response to kinins mediated by the B1-receptor, and (2) that the mechanism of induction may include an intimate interaction between neutrophil leukocytes and blood vessel walls.     

Characterization of the in vitro interaction between thymocytes and a medullary thymic epithelial cell line

T-cell differentiation is known to be mediated by lympho-stromal interactions. However, the precise role of cellular complexes formed during this process is far from clear. We have previously established a thymic medullary epithelial cell-line, E-5, and have shown the adherence of thymocytes by a receptor-mediated-mechanism. We report here that the thymocytes able of complex-formation with E-5 cells appear at day 16 of gestation. Moreover, while the proportion of such thymocytes is constant throughout post-natal life, their absolute number decreases with thymic involution. We have also investigated the influence of the genetic background of thymocytes on adherence and found that polymorphic regions of H-2 genes were not involved in contact recognition. Therefore, this type of lympho-stromal interactions is unlikely to participate in the education to self MHC-restriction. However, thymocytes from B6/lpr mice, which spontaneously develop systemic lupus erythematosus (SLE) and have impaired T-cell differentiation, were shown incapable of adhering to E-5 cells. These results are interpreted as showing that interaction between thymocytes and medullary epithelial cells reflect a discrete stage of T-cell differentiation.     

The contractile effect of bombesin, gastrin releasing peptide and various fragments in the rat stomach strip

The contractile activity of bombesin (BB) and related peptides including the gastrin releasing peptide (GRP) was evaluated in the rat stomach strip. BB and GRP were found to elicit concentration-dependent contractile effects in concentrations varying between 5.0 X 10(-10) and 5.0 X 10(-7) M. EC50 values of BB and GRP were 6.5 X 10(-9) and 10(-8) M, respectively. The contractile effect of BB (1.5 X 10(-8) M) was not modified by a mixture of antagonists containing atropine (1.7 X 10(-6) M), mepyramine (1.2 X 10(-6) M), methysergide (1.4 X 10(-6) M), phentolamine (1.8 X 10(-6) M), propranolol (1.9 X 10(-6) M) and indomethacin (7.0 X 10(-6) M), nor by the nerve paralyzing drug tetrodotoxin (1.6 X 10(-6) M). These results suggest the existence of BB receptors in the rat stomach strip. The results also suggest that the contractile effects of BB in this tissue result from a direct effect on the smooth muscle cell. The data derived from our structure-activity study indicate that deletion of the N-terminal sequence pGlu1-Gln2-Arg3-Leu4-Gly5- from the BB molecule causes practically no loss of affinity and intrinsic activity. Further shortening of BB gives rise to a gradual reduction of both parameters. Residual contractile activity could still be observed with the tetra- and pentapeptide BB-(11-14) and BB-(10-14) at 10(-5) M.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological modeling of drug and metabolite: disposition of oxazepam and oxazepam glucuronides in the recirculating perfused mouse liver preparation

The disposition of tracer doses of 3H-oxazepam was studied in the recirculating perfused mouse liver preparation. 3H-Oxazepam was biotransformed primarily to the diastereomeric 3H-oxazepam glucuronides, which either effluxed into the circulation or underwent biliary excretion. Three additional, unknown metabolites constituted a small fraction (5-10%) of the total radioactivity recovered in bile (7% of dose); no other metabolite was detected in perfusate. A physiologically based model, comprising the reservoir, liver blood and tissue, and bile, was fitted to reservoir concentrations of 3H-oxazepam and 3H-oxazepam glucuronides, and the cumulative amount excreted into bile. The model allowed for consideration of elimination pathways other than glucuronidation and the presence of a transport barrier for the oxazepam glucuronides across the hepatocyte membrane. The fitted results suggest a slight barrier existing for the transport of metabolites across the sinusoidal membrane, inasmuch as the transmembrane clearance was comparable to liver blood flow rate. Upon further comparison of estimates of formation, biliary, and transmembrane clearances for the oxazepam glucuronides, the rate-limiting step in the overall (biliary) clearance appears to be a poor capacity for biliary excretion. The influence of the cumulative volume loss that a recirculating perfused organ system incurs upon repeated sampling was discussed, and a compartmental method of correcting the observed concentrations of drug and generated metabolite was presented.     

Cost comparison of intraoperative autologous versus homologous transfusion

The cost of autologous transfusions using semiautomated instruments in 52 orthopedic cases, 75 coronary artery bypass graft (CABG) cases, and 218 aortic aneurysm cases was compared to the cost of equal amounts of homologous blood. While none of the orthopedic cases reached cost equivalence (median cost deficit per case, +97), 31 percent of the CABG cases (median cost deficit per case, +61) and 56 percent of the thoracic aortic aneurysm cases (mean cost surplus per case, +30) did so. In most cases, the major orthopedic and CABG procedures do not reach cost equivalence and might be served better by other means of autologous blood recovery. The more expensive semicontinuous flow devices are more cost-effective for higher-yield cases, such as major aortic aneurysm procedures.     

Somatostatin: Interaction with the sympathetic nervous system in guinea pigs

We have investigated the cardiovascular effects of somatostatin (SS) in anesthetized guinea pigs. SS was found to produce a dose-dependent vasodepressor effect and bradycardia. The size of the vasodepressor response to SS was dependent on the pre-injection level of blood pressure. The higher the blood pressure was, the larger was the response to SS. Atropine (1 mg kg^?1) did not alter the effects of SS thus suggesting that SS neither activates cholinergic nerves nor interacts with muscarinic receptors. SS (5 μg kg^?1 min^?1) markedly inhibited the pressor effects of dimethylphenylpiperazinium (DMPP), a relatively specific ganglionic stimulant, and of isoproterenol, a beta receptor agonist, without interfering with their positive chronotropic effects. The pressor effects and tachycardia evoked by bolus injections of noradrenaline and of tyramine were usually enhanced during SS infusions. Guanethidine, a drug known to paralyse adrenergic neurons, modified similarly to SS, the cardiovascular effects of noradrenaline and of DMPP. The results suggest that the vasodepressor effect of SS results from a selective depression of the sympathetic outflow to the blood vessels via a presynaptic inhibitory effect on adrenergic neurons. The slowing of heart rate caused by SS is most likely the result of a direct depressant effect on the sinoatrial node.     

Ovarian metastases: computed tomographic appearances

Computed tomographic scans of 34 patients with ovarian metastases were reviewed to assess the radiographic appearances and to correlate these with the primary neoplasms. Primary neoplasms were located in the colon (20 patients), breast (six), stomach (five), small bowel (one), bladder (one), and Wilms tumor of the kidney (one). The radiographic appearance of the metastatic lesions could be described as predominantly cystic (14 lesions), mixed (12 lesions), or solid (seven lesions). There was one false-negative examination which showed no ovarian enlargement, although neoplastic deposits were found on the ovary at laparotomy. The cystic and mixed lesions tended to be larger in overall diameter than the solid. The metastases from gastric carcinoma appeared solid in four of five cases. The metastases from the other neoplasms had variable appearances simulating primary ovarian carcinoma.