Abstract Activated platelets expressing P-selectin in their surfaces are known to adhere to monocytes and neutrophils. We examined the possibility that the leukocytes are functionally modified by their adhesion to activated platelets. We used human peripheral blood monocytes and neutrophils and measured superoxide anion generation by these cells cultured with platelets. The levels of superoxide anion production were found to be markedly elevated when thrombin-activated platelets were used. The extent of this enhancement was much smaller when leukocytes were cultured with resting platelets than activated platelets. The increase depended on incubation time and platelet concentration. The membranes prepared from activated platelets also induced superoxide anion production, but the culture supernatant of activated platelets did not. The enhanced superoxide anion production was inhibited by anti-P-selectin antibody, anti-sialyl-Lewis X antibody, or a soluble recombinant P-selectin fusion protein. These results indicate that the adhesion of activated platelets to the leukocytes through P-selectin was a crucial step for the activation of leukocyte function, and support the idea that activated platelets are actively involved in inflammation processes.
The effect of tranilast, an inhibitor for IgE-mediated mediator release from mast cells, on plasma extravasation induced by the intradermal injection of substance P in rats was examined. Tranilast (100 mg/kg, intraperitoneally) decreased plasma extravasation induced by substance P (10−-7-− 10−-5 M). Tranilast decreased plasma extravasation induced by the amino-terminal peptide substance P1–9 (10−-6-−10−-4 m), which is active for rat mast cells, but not by the carboxy-terminal peptide substance P6–11 (10−-6-−10−-4 M), which is inactive for the mast cells. Therefore, tranilast prevents substance P-induced plasma extravasation most likely by inhibiting mast cell degranulation.
Bronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide. A survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged ≥ 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated. Asthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by > 80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting β2 agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA. These results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA.
To determine the mechanism by which substance P (SP) activates human neutrophils, we examined the potency of SP for inducing chemotaxis, lysozyme release, and increase in cytosolic free Ca2+ concentration ( [Ca2+] i) in human blood neutrohils. We also examined the effects of EGTA and of a formyl-Met-Leu-Phe (FMLP) antagonist on the responses. SP (10-6 to 10-4 M) induced chemotaxis, lysozyme release, and the increase in [Ca2+] i of the neutrophils dose-dependently. Preincubation with EGTA (10 mM) decreased the SP-induced increase in [Ca2+] i by 90%, whereas EGTA decreased the FMLP-induced increase in [Ca2+] i only by 37%, suggesting that the activations of human neutrophils by SP are dependent on the influx of extracellular Ca2+. An FMLP antagonist, boc-Phe-Leu-Phe-Leu-Phe, inhibited the FMLP-induced chemotaxis and increase in [Ca2+] i, but it did not inhibit the SP-induced respones.We suggest that SP induces the activations of human neutrophils by the different mechanism from that of FMLP.
