Biomedical subjects
Publications and source records attributed to R H Morris.
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Phosphatidylcholine (PC) is the major phospholipid of pulmonary surfactant and it is hypothesized that PC and its subspecies modulate the functions of alveolar macrophages. The most abundant of these subspecies is dipalmitoylphosphatidylcholine (DPPC). This study was undertaken to determine the effect of PC on monocyte function using a human monocytic cell line, MonoMac-6 (MM6). This study showed that preincubation of MM6 cells with DPPC at 125 microg/ml for 2 h inhibited the oxidative response to either zymosan or phorbol-12-myristate-13-acetate (PMA) by 30% (P < 0.001). This inhibition with DPPC was independent of LPS priming. When DPPC was replaced with 1-palmitoyl-2-arachidonoyl phosphatidylcholine (PAPC) there was no inhibition and in contrast a significant increase in oxidant production was observed. We also demonstrated that total PC (tPC; a heterogeneous species of PC from egg) and DPPC but not PAPC significantly inhibited the release of TNF-alpha from MM6 cells (P < 0.05). DPPC did not inhibit phosphorylation of the mitogen activated protein kinases (MAPKs) p44/p42 or p38 in stimulated cells. Measurements of membrane fluidity with spin label EPR spectroscopy indicate that DPPC incorporation significantly alters the membrane fluidity of MM6 cells. These results suggest that DPPC, the major component of pulmonary surfactant, may play a role in modulating leucocyte inflammatory responses in the lung. This may in part be related to membrane effects but does not include alterations in p44/p42 or p38 MAPK signalling.
OBJECTIVES: First, we sought to study the effects of short- and long-term vitamin C therapy on oxidative stress and endothelial dysfunction in chronic heart failure (CHF), and second, we sought to investigate the role of neutrophils as a cause of oxidative stress in CHF. BACKGROUND: Oxidative stress may contribute to endothelial dysfunction in CHF. Vitamin C ameliorates endothelial dysfunction in CHF, presumably by reducing oxidative stress, but this is unproven. METHODS: We studied 55 patients with CHF (ischemic and nonischemic etiologies) and 15 control subjects. Flow-mediated dilation (FMD) in the brachial artery was measured by ultrasound wall-tracking, neutrophil superoxide anion (O2-) generation by lucigenin-enhanced chemiluminescence and oxidative stress by measurement of free radicals (FRs) in venous blood using electron paramagnetic resonance (EPR) spectroscopy and plasma thiobarbituric acid reactive substances (TBARS). Measurements were performed at baseline in all subjects. The effects of short-term (intravenous) and long-term (oral) vitamin C therapy versus placebo were tested in patients with nonischemic CHF. RESULTS: At baseline, FRs were higher in patients with CHF than in control subjects (p < 0.01), TBARS were greater (p < 0.005), neutrophil O2- -generating capacity was enhanced (p < 0.005) and FMD was lower (p < 0.0001). Compared with placebo, short-term vitamin C therapy reduced FR levels (p < 0.05), tended to reduce TBARS and increased FMD (p < 0.05), but did not affect neutrophil O2- -generating capacity. Long-term vitamin C therapy reduced FR levels (p < 0.05), reduced TBARS (p < 0.05) and improved FMD (p < 0.05), but also reduced neutrophil O2- -generating capacity (p < 0.05). Endothelial dysfunction was not related to oxidative stress, and improvements in FMD with vitamin C therapy did not relate to reductions in oxidative stress. CONCLUSIONS: Oxidative stress is increased in ischemic and nonischemic CHF, and neutrophils may be an important cause. Vitamin C reduces oxidative stress, increases FMD and, when given long term, decreases neutrophil O2- generation, but the lack of a correlation between changes in endothelial function and oxidative stress with vitamin C implies possible additional non-antioxidant benefits of vitamin C.
This study was performed to investigate the value of interleukin 4 as a marker of activity in mild atopic disease. We compared IL-4 levels to eosinophil cationic protein (ECP), a suggested inflammatory marker in allergic disease, in patients with hayfever. Patients with hayfever were assessed during January and then in late June at the height of the grass pollen season, and their levels of serum ECP and IL-4 compared. Serum ECP was determined by radio-immunoassay and serum IL-4 by a high-sensitivity enzyme-linked immunosorbent assay. ECP was found to increase significantly in patients with hayfever during the grass pollen season (P<0.01). Conversely, serum levels of IL-4 were found to decrease significantly over the same period when compared with winter values. ECP and IL-4 were not seen to correlate significantly with each other. The fall in serum IL-4 seen during the grass pollen season in the hayfever patients may reflect allergen driven upregulation of membrane IL-4 receptor expression or sequestration of cytokine producing cells to inflammatory sites. These findings suggest that serum IL-4 is a poor indicator of inflammatory status in allergic disease.
The regulation of pro- and anti-mediator release from cells within the alveolar space would represent a desirable mechanism serving to protect this delicate gas-exchanging region of the lung. This study investigates the effect of alveolar surfactant lipids on the regulation of tumour necrosis factor alpha (TNF-alpha), a potent inflammatory cytokine, and prostaglandin E(2)(PGE(2)), a lipid mediator with anti-inflammatory properties. The results of this investigation reveal a marked effect on the release of these two important mediators from a monocytic cell line, MonoMac 6 (MM6), by phosphatidylcholine (PC), phosphatidylethanolamine (PE), cholesterol (Chol) and sphingomyelin (SM). PC, PE and Chol demonstrated marked downregulation of TNF-alpha production at lipid concentrations of 125 and 250 microg/ml. Interestingly, SM significantly up regulated the release of TNF-alpha at these concentrations. However, the release of PGE(2)in MM6 cells incubated with the same lipids was significantly increased with PC and Chol, and significantly decreased in cells pre-treated with SM. This indicates a role for these lipids in alveolar immunoregulation.
Interleukin 4 (IL-4) was measured in the serum of normals and mild atopic patients using a high sensitivity ELISA system involving an amplification stage. The method was found to have a limit of detection of 0.02 pg/ml after a square root transformation of the concentration data and to show good reproducibility with coefficients of variation between 11 and 14%. Recoveries of standard IL-4 from serum was greater than 90%. Markedly elevated levels of IL-4 were seen in the atopic groups compared with the normals. No association was found between total white cell counts, lymphocyte or eosinophil counts and serum IL-4 levels. This study demonstrates that serum IL-4 levels can distinguish between atopic subjects and normals, even in mild or symptomless disease. This may prove valuable in the management of atopic disorders.
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One hundred and fourteen Corynebacterium diphtheriae, toxigenic, gravis type, pharyngeal carriers were identified during a diphtheria epidemic in Elgin, Texas. All carriers were treated with erythromycin estolate, 1 g/day in divided doses for 6 days. Serial pharyngeal cultures were obtained in order to monitor the bacteriological response. Seventy-two carriers had positive cultures immediately prior to the start of therapy, and only these individuals were considered in the analysis of the effects of erythromycin. Forty-eight hours after institution of therapy, 96% of the carriers had become culture negative; all were negative by the 4th day of therapy, and all remained culture negative while taking the drug. Two days after cessation of therapy, all but one (99%) were culture negative. However, upon reculture 2 weeks later, 15 (21%) had relapsed to the carrier state. There were no significant differences in the serum diphtheria antitoxin levels, immunization status, age, sex, or socioeconomic status of those who relapsed and those who remained culture negative. This study demonstrates that erythromycin is effective in converting carriers to culture-negative status, but when given for only 6 days it is associated with large numbers of relapses. Because previous studies have not included follow-up cultures 2 weeks after therapy, it is suggested that all C. diphtheriae carriers be treated with either erythromycin or penicillin and that all be recultured at a minimum of 2 weeks after completion of therapy to assure eradication of the diphtheria organisms.
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