Role of platelets in allergic airway inflammation.

Increasing evidence suggests an important role for platelets and their products (e.g., platelet factor 4, ß-thromboglobulin, RANTES, thromboxane, or serotonin) in the pathogenesis of allergic diseases. A variety of changes in platelet function have been observed in patients with asthma, such as alterations in platelet secretion, expression of surface molecules, aggregation, and adhesion. Moreover, platelets have been found to actively contribute to most of the characteristic features of asthma, including bronchial hyperresponsiveness, bronchoconstriction, airway inflammation, and airway remodeling. This review brings together the current available data from both experimental and clinical studies that have investigated the role of platelets in allergic airway inflammation and asthma. It is anticipated that a better understanding of the role of platelets in the pathogenesis of asthma might lead to novel promising therapeutic approaches in the treatment of allergic airway diseases.

Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury.

Exposure of isolated perfused rabbit lungs (IPL) to ischemia-reperfusion causes a transient increase in pulmonary arterial (PA) pressure at the onset of reperfusion. Because thromboxane A2 (TxA2) is a potent vasoconstrictor, we hypothesized that it may contribute to the ischemia-reperfusion-induced pressor response. To evaluate this hypothesis, we exposed IPL perfused with a cell-free solution to 40 min of warm ischemia followed by reperfusion and measured perfusate immunoreactive thromboxane B2 (iTxB2) and 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha). We observed that ischemia-reperfusion IPL compared with controls had an increase in PA pressure (40.2 +/- 4.8 vs. 9.3 +/- 0.3 mmHg, P < 0.05), lung edema (29.3 +/- 6.3 vs. -0.2 +/- 0.2 g, P < 0.05), iTxB2 perfusate levels (155 +/- 22 vs. < 50 pg/ml, P < 0.05), and i6-keto-PGF1 alpha (436 +/- 33 vs. 61 +/- 16 pg/ml, P < 0.05). In ischemia-reperfusion IPL, infusion of SQ 29548 (10(-6) M), a specific TxA2/prostaglandin H2 receptor antagonist, attenuated the PA pressor response and the degree of edema. We conclude that pulmonary hypertension associated with ischemia-reperfusion results in part from pulmonary release of TxA2. Furthermore, TxA2 directly through membrane effects or indirectly through hydrostatic mechanisms increases the severity of ischemia-reperfusion-induced lung edema.

Prostaglandins and cyclic nucleotides as effectors in non-lymphocyte mediated surveillance processes ( short review).

This paper reviews the evidence pointing to a role of prostaglandins and cyclic AMP in the regulation of surveillance processes against transformed cells carried out by activated monocytes macrophages and natural killer (NK) cells. Specific topics of discussion include: (a) the regulation of monocyte/macrophage system and NK cells by prostaglandins and cyclic AMP; and (b) the possible immunomodulatory role of thromboxanes generated by activated monocytes and macrophages. Also the role of cyclic AMP dependent and independent protein kinases as well as their link with oncogenes is briefly reviewed.

Urinary prostaglandins and thromboxane in patients with chronic glomerulonephritis.

To evaluate the potential contribution of prostaglandins (PGs) and thromboxane (TX) to the development of chronic glomerulonephritis, we measured the urinary excretion of PGE, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 by radioimmunoassay in 36 patients with chronic glomerulonephritis. In patients with nephrotic syndrome, urinary excretion of PGE and TXB2 was highly increased, whereas that of PGF2 alpha and 6-keto-PGF1 alpha remained normal. In patients with non-nephrotic chronic glomerulonephritis, urinary excretion of TXB2 was significantly increased, whereas that of PGE and 6-keto-PGF1 alpha remained normal and that of PGF2 alpha was significantly decreased. In patients with chronic renal failure, the urinary excretion of all PGS and TX was markedly decreased presumably due to a decrease in the number of cells which can metabolize arachidonic acid. These results suggest that TXA2 plays an important role as an exaggerating factor in the development of chronic glomerulonephritis, particularly that accompanying nephrotic syndrome, and that renal synthesis of PGE is compensatorily increased to maintain renal function in nephrotic syndrome.

Radioimmunoassay of prostaglandins and thromboxanes.

1. Decide on what organ or other biological material to study and select the proper compound for this study from the knowledge of precursor acid metabolism. Develop the RIA for this compound or a stable derivative thereof. 2. Whichever sample type is assayed (extracted or unextracted), the possibility of the presence of nonspecific interfering factors must be constantly kept in mind. Make dilution tests and assay for parallelism; however, do not accept parallelism as an absolute criterion of absence of nonspecific influence. 3. Use two or more completely different separation techniques for comparison when validating the RIA. 4. When evaluating the RIA, do not limit the investigation to the traditional reliability criteria: sensitivity, specificity, precision, and accuracy. The RIA may seem reliable at this stage and still give completely unrealistic values when applied to biological material. The method must be evaluated by other studies as well. 5. In the experimental design, aim at following the changes in prostaglandin levels in a series of samples instead of measuring absolute levels in single samples. 6. Make comparative studies employing different quantitative methods.

Eicosanoids and platelet-activating factor in allergic respiratory diseases.

The nature of the lipid mediators released at an inflammatory site in the airways is dependent not only on the individual cells and inflammatory stimuli present but also on a complex interaction between neighboring cells and their lipid products. These lipid mediators share overlapping activities, and current research is directed toward determining the critical molecules involved in the pathogenesis of particular inflammatory states. How may the release of these lipid mediators play a role in the pathogenesis of asthma? Allergic persons after inhalation of specific allergen have a dual bronchospastic response. The early asthmatic response occurring shortly after allergen challenge is most likely secondary to the action of bronchoconstrictor molecules (e.g., LTC4, PGD2, PAF) released by human lung mast cells as a consequence of IgE-mediated degranulation. An inflammatory process than occurs in the airways that is characterized by an influx of eosinophils and neutrophils into the airway epithelium and bronchial fluids. This inflammatory response corresponds to the late asthmatic phase occurring several hours after allergen challenge. Release of sulfidopeptide leukotrienes, PAF, and cyclooxygenase products by cells infiltrating the airways may be involved in the bronchial smooth muscle constriction, mucosal edema, and mucus hypersecretion observed during these late asthmatic responses. In the future, the therapeutic use of specific antagonists of the biosynthetic enzymes of the 5-lipoxygenase pathway and receptor antagonists of the eicosanoids and PAF holds great promise for the modulation of airway inflammation.

Eicosanoids and renal allograft rejection.

The role of eicosanoids as mediators of inflammation in the course of renal allograft rejection is reviewed. Elucidation of their particular roles has come from the use of specific inhibitors, and one looks forward to their application in human transplant management. As illustrated by the experience with the use of fish oils, additional benefit over that of standard immunosuppression is anticipated but quantitating that benefit in individuals may not be easy.

Leukotrienes, thromboxane, and platelet activating factor in organ transplantation.

The antirejection eicosanoids--PGE2, (PGD2), and PGI2--have an attenuating effect on T-cell proliferation by inhibition of IL-1, IL-2, and class II antigen expression on macrophages, and the prorejection eicosanoids--TXA2, LTB4, LTC4, and LTD4--enhance T-cell proliferation. LTB4 stimulates IL-1 and IL-2 formation and expression of IL-2 receptor. The mechanism of enhancement of T-cell proliferation by TXA2 has not been demonstrated. LTC4 and LTD4 promote gamma-interferon release and can replace IL-2 as a stimulator of gamma-interferon. PAF at high concentrations inhibits lymphocyte proliferation. The eicosanoids interfere with the same mechanisms as CsA and corticosteroids on T-cell clonal expansion. In experimental organ transplantation, corticosteroids can be replaced by compounds preventing the formation or expression of the prorejection eicosanoids or analogs of antirejection eicosanoids as well as by PAF antagonists. In addition, these drugs exert synergistic effect with CsA and azathioprine.