Background: Human seminal plasma (HSP)-induced hypersensitivity is one of the serious complications with sexual intercourse. The clinical manifestations of HSP-induced hypersensitivity may be related to the release of vasoactive mediators from mast cell induced by HSP. It has recently been reported that HSP modulates immune systems and induces mast cell degranulation and histamine release from rat peritoneal mast cells (RPMC). Ketotifen and disodium cromoglycate (DSCG), anti-asthmatic and anti-allergic drugs, have a role of mast cell stabilization and inhibit mast cell-induced leukocyte rolling and adhesion. But the inhibitory agents of HSP-induced mast cell activation are unknown. This study was performed to investigate the effects of DSCG and ketotifen on the HSP-induced mast cell activation. Methods: For this, influences of DSCG and ketotifen on the human seminal plasma-induced degranulation, histamine release and morphological changes of RPMC were observed. Results: The mast cell degranulation and histamine release of RPMC by HSP were induced in a dose-dependent fashion. The HSP-induced cytomorphological changes such as swelling, intracellular vacoules, and interrupted cell boundary were significantly inhibited by pretreatment with DSCG or ketotifen. DSCG and Ketotifen inhibited the HSP-induced degranulation and histamine release from RPMC. Conclusion: From the above results, it is suggested that DSCG and ketotifen have a inhibitory effect of the HSP-induced mast cell activation. DSCG and ketotifen may be used for treatment of HSP-induced hypersensitivity.
Kim, Hyun Ji;Park, Mi Kyung;Kim, Soo Youl;Lee, Chang Hoon
Biomolecules & Therapeutics
/
v.22
no.6
/
pp.540-546
/
2014
The high mortality rates associated with cancer reflect the metastatic spread of tumor cells from the site of their origin. Metastasis, in fact, is the cause of 90% of cancer deaths. Therefore, considerable effort is being made to inhibit metastasis. In the present study, we screened ketotifen for anti-migratory and anti-invasive activities against MDA-MB-231 breast cancer and HT-1080 fibrosarcoma cancer cells. Cancer cell migration and invasion were measured using multi-well chambers. Additionally, western blots were used to examine the effects of ketotifen on the expressions of CDC42, Rho, Rac, and matrix metalloproteinase 9 (MMP-9). The results showed that ketotifen dose-dependently suppressed the migration and invasion of MDA-MB-231 and HT-1080 cells. Ketotifen also suppressed the expressions of CDC42, Rac, and Rho, which, significantly, are involved in MDA-MB-231 and HT-1080 cancer cell migration. Moreover, ketotifen suppressed the expression and activity of MMP-9, which is involved in degradation of the extracellular matrix leading to invasion. The overall data suggested that ketotifen suppresses the migration and invasion of MDA-MB-231 and HT-1080 cancer cells via inhibition of CDC42, Rac, Rho, and MMP-9 expression.
Purpose : The intestinal mucosal defect has been known as one of the pathogenicmechanisms of IgA nephropathy. Oral antigens usually induce the activation of Th2 cells and mast cells. These cells secrete cytokines IL-4, IL-5 and TGF-$\beta$, which increase IgA production. Although ketotifen (benzocycloheptathiophene) is an H1 antagonist and a mast cell membrane stabilizer, it could protect the gastrointestinal membrane through inhibiting the production of IL-4, IL-5, PGE2, and LTB4, and decreasing the activity of nitric oxide synthease. Therefore, we have investigated if ketotifen may protect the development of IgA nephropathy with an oral antigen. Methods : ICR mice were used as an animal model orally with Poliovax only [ketotifen (-)], the other group was given oral ketotifen [ketotifen (+)] in addition to Poliovax. Results : Mesangial IgA deposition developed in 11 out of the 18 mice in the ketotifen (-) group, while in three out of the nine mice in ketotifen (+) group. The mesangial change developed in 16 out of the 18 mice in the ketotifen (-) group, while in five out of the nine mice in the ketotifen (+) group. Serum IL-4 and IL-5 levels were not significantly lower in the latter group than in the former. Conclusion : According to the statistical results from the above, ketotifen therapy would be beneficial to reducing mesangial changes in IgA nephropathy.
Eosinophils play an essential role in allergy reaction after parasite infection. To examine the immune reaction induced by eosinophils, we investigated the allergy reaction in BALB/c mice infected with Echinostoma hortense's metacercariae, as well as the effect of ketotifen, an anti-allergy drug, on eosinophil immune reaction in the villi of host intestine. The worm recovery rate was higher in ketotifen-treated mice than in untreated mice and the worms in ketotifen-treated mice survived longer than those in untreated mice. The antibody titer in the serum of ketotifen-treated mice was very low. Especially, Echinostoma hortense infection strongly increased serum IgE level and eosinophil infiltration into the villi of the mouse intestine. Ketotifen treatment suppressed eosinophil infiltration into the infected areas and inhibited IL-4 production. The reduced IL-4 production may be related with the reduction of IgE, IgG1 and IgG2 production. In conclusion, ketotifen inhibited eosinophil infiltration functioning in the allergy reaction induced by parasite infection and the expression of immunoglobulins and cytokines.
Ketotifen, a benzocycloheptathiophene, has an orally effective antiallergic as well as antihistaminic properties. In pervious studies, Ketotifen has shown encouraging results in patient with allergic rhinitis, either perennial or seasonal. 39 patients with allergic rhinitis had been treated with Ketotifen 1 mg twice daily for 8 weeks. And we obtained following results. 1) The efficacy rate in sneezing attack was 73.5%, in nasal discharge 71%, in nasal obstruction 58%. 2) Some improvements in at least one of three major symptoms were noted within 1 week in 30.7%, within 2 weeks in 55.8%, within 3 weeks in 66.7%, within 8 weeks in 87.2%. 3) Physical findings such as colour, swelling of turbinate, character of rhinorrhea were not improved significantly. 4) Side effect was observed only in one patient with abdominal pain and diarrhea, which was subsided after interruption of administration. These results suggested that Ketotifen was effective in treatment of allergic rhinitis.
In order to elucidate the role of platelet activating factor (PAF) in the acute lung injury induced by endotoxin (ETX), activities of phospholipase A2, lyso PAF acetyltransferase and oxidative stress by neutrophilic respiratory burst were probed in the present study. To induce acute lung injury, $100\;{\mu}g$ of E.coli ETX (type 0127; B8) was instilled directly into the tracheae of Sprague-Dawley rats. Five hours after the ETX instillation, induction of acute lung injury was confirmed by lung leak index and protein contents in the bronchoalveolar lavage (BAL) fluid. At the same time, lung phospholipase A2 (PLA2) activity and expression of group I and II secretory type PLA2 were examined. In these acutely injured rats, ketotifen fumarate, known as lyso PAF acetyltransferase inhibitor and mepacrine were administered to examine the role of PAF in the pathogenesis of the acute lung injury. To know the effect of the ETX in the synthesis of the PAF in the lungs, lyso PAF acetyltransferase activity and PAF content in the lungs were measured after treatments of ETX, ketotifen fumarate and mepacrine. In addition, the role of neutrophils causing the oxidative stress after ETX was examined by measuring lung myeloperoxidase (MPO) and enumerating neutrophils in the BAL fluid. To confirm the oxidative stress in the lungs, pulmonary contents of malondialdehyde (MDA) were measured. After instillation of the ETX in the lungs, lung leak index increased dramatically (p<0.001), whereas mepacrine and ketotifen decreased the lung leak index significantly (p<0.001). Lung PLA2 activity also increased (p<0.001) after ETX treatment compared with control, which was reversed by mepacrine and ketotifen (p<0.001). In the examination of expression of group I and II secretory PLA2, mRNA synthesis of the group II PLA2 was enhanced by ETX treatment, whereas ketotifen and WEB 2086, the PAF receptor antagonist, decreased the expression. The activity of the lysoPAF acetyltransferase increased (p<0.001) after treatment of ETX, which implies the increased synthesis of PAF by the remodelling of lysoPAF in the lungs. Consequently, the contents of the PAF in the lungs were increased by ETX compared with control (p<0.001), while mepacrine (p<0.001) and ketotifen (p<0.01) decreased the synthesis of the PAF in the lungs of ETX treated rats. The infiltration of the neutrophils was confirmed by measuring and enumerating lung MPO and the neutrophils in the BAL fluid respectively. Compared with control, ETX increased lung MPO and number of neutrophils in BAL significantly (p<0.001) whereas mepacrine and ketotifen decrerased number of neutrophils (p<0.001) and MPO (p<0.05, p<0.001, respectively). The lung MDA contents were also increased (p<0.001) by ETX treatment, but treatment with mepacrine (p<0.001) and ketotifen (p<0.01) decreased the lung MDA contents. Collectively, we conclude that ETX increases PLA2 activity, and that the subsequently increased production of PAF was ensued by the remodelling of the lyso PAF resulting in tissue injury by means of oxidative stress in the lungs.
Anti-allergic action of each water extracts of some crude drugs was investigated in mice and rats. The activity of hyaluronidase which was used in the screening test of anti-allergic action was inhibited significantly by Amomi Semen, Asiasari Radix, Cimicifugae Rhizoma, Cinnamomi Ramulus, Glycyrrhizae Radix and Scutellariae Radix. The 48-hour homologous passive cutaneous anaphylaxis(48-hr PCA) in mouse ear was inhibited significantly by intraperitoneal(i.p.) injection of Amomi Semen, Cimicifugae Rhizoma, and ketotifen, a comparative drug of an anti-allergic action. The increase of vascular permeability induced by histamine or serotonin was inhibited significantly by i.p. injection of Amomi Semen, Cimicifugae Rhizoma, Cinnamomi Ramulus and ketotifen. In rat dorsal skin, the increase of vascular permeability which was induced by histamine, serotonin or compound 48/80 was inhibited significantly by i.p. injection of Amomi Semen, Asiasari Radix, Cimicifugae Rhizoma, Scutellariae Radix and ketotifen. Armeniacae Semen and Liriopis Tuber which had not inhibited hyaluronidase activity did not inhibit 48-hr PCA and the increase of histamine, serotonin or compound 48/80-induced vascular permeability in mice and rats. These results suggest that each water extract of Amomi Semen and Cimicifugae Rhizoma has anti-allergic action.
Objectives : In this study, we investigated the effect of Saposhnikoviae Radix on allergic responses in ovalbumin(OVA)-induced Allergic rhinitis(AR) mice. Methods : BALB/c mice were orally administrated with Saposhnikoviae Radix water extract (SRW, 50 mg/kg) or anti-histamine drug, Ketotifen (10 mg/kg) as a reference drug, followed by sensitization and challenge of OVA. Mice were measured clinical symptoms and the serum levels of histamine, IgE, IL-4, and IFN-${\gamma}$, and observed histopathological changes of nasal mucosa H&E staining. Results : SRW significantly decreased rubs and the serum levels of histamine, IgE, and IL-4, and then increased the serum levels of IFN-${\gamma}$ in OVA-induced AR mice, and inhibited histopathological changes of nasal mucosa with inflammation and the eosinophils infilteration. Conclusions : These data suggest that SRW has anti-allergic effect through the inhibitory property of Saposhnikoviae Radix against allergic responses in allergic rhinitis.
Backgraound : There have been many reports on the pathogenesis of sepsis-induced acute respiratory distress syndrome(ARDS) but, the precise mechanism has not been elucidated. This study examined the protective effect of an inhibition of platelet activating factor(PAF) remodeling and the adhesion molecule on the oxidative stress of the lungs in rats with an endotoxin induced acute lung injury(ALI). Methods : ALI was induced in Sprague-Dawley rats by instilling an E-coli endotoxin into the trachea. Ketotifen and fucoidan were used respectively to inhibit PAF remodeling and adhesion molecule. The lung leak index, lung myeloperoxidase(MPO) activity, bronchoalveolar lavage(BAL) fluid neutrophil count and lyso PAF acetyltransferase activity(AT), were measured and an ultrastructural study and cytochemical electron microscopy were performed. Results : The lung leak index, lung MPO activity, BAL fluid neutrophil count and lyso PAF AT activity was higher in the endotoxin-treated rats. In addition, severe destruction of the pulmonary architecture and increased hydrogen peroxide production were identified. These changes were reversed by ketotifen. However, fucoidan did not appear to have any protective effects. Conclusion : The inhibition of PAF remodeling appeared to be effective in decreasing the endotoxin-induced ALI. In addition, this effect might be derived from the inhibition of neutrophilic oxidative stress. However, the inhibition of the adhesion molecules by fucoidan appeared to be ineffective in decreasing the endotoxin-induced ALI.
Background : Since the exact pathogenesis of sepsis-induced ARDS has not been elucidated, the mechanisms of enhanced neutrophilic respiratory burst were probed in endotoxin primed neutrophils associated with the roles of phospholipase A2(PLA2), platelet activating factor(PAF) and apoptosis. Methods : In isolated fresh human neutrophils, effects of the inhibition of PLA2 and PAF on the apoptosis were examined by the method of Annexin-FITC/dual PIflow cytometry. The roles of PLA2 and PAF on the neutrophilic respiratory burst were also examined by measuring oxidant generation in cytochrome-c reduction assay. Activities of the PLA2 and lysoPAF acetyltransferase (lysoPAF AT) of the neutrophils were determined to understand the effect of endotoxin on these enzymatic activities which may be related to the neutrophilic respiratory burst and apoptosis. In addition, the role roles of PLA2 and PAF in neutrophilic adhesion to bovine endothelial cells were examined in vitro by neutrophil adhesion assay. To investigate the effect of oxidants on pulmonary surfactant, cytochemical ultrastructural microscopy was performed. To inhibit PLA2 and PAF, non-specific PLA2 inhibitor mepacrine (100 nM) and WEB 2086 (100 nM) or ketotifen fumarate (10 ${\mu}g$/ml) were used respectively in all in vitro experimental sets. WEB 2086 is PAF receptor antagonist, and ketotifen fumarate is a lyso PAF AT inhibitor. Results: The mapacrine treatment, provided and the endotoxin (ETX) treatment, resulted in increased apoptosis of neutrophils (p<0.001) while treatments of WEB 2086 and ketotifen did not. The inhibition of PLA2 and PAF decreased (p<0.001) production of oxidants from PMA-stimulated neutrophils. While endotoxin increased the PLA2 activity of neutrophils (p<0.01), mepacrine supressed (p<0.001) the activity, provided after treatment of ETX. The lyso PAF actyltransferase activity (lyso PAF AT) increased (p<0.01) after treatment of ETX. In contrast, mepacrine, WEB 2086 and ketotifen showed a tendency of decreasing the activity after treatment of ETX. The treatment of ETX incresed (p<0.001) neutrophil adhesion to endothelial cells, which was reversed by inhibition of PLA2 and PAF (p<0.01). The binding of oxidants to pu1monary surfactant was identified histologically. Conclusions : The enhanced neutrophilic respiratory burst by ETX plays a pivotal role in the pathogenesis of ARDS in terms of oxidayive oxidative stress. Increased production of oxidants from neutrophils is mediated by the activations of PLA2 and lyso PAF AT.
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