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1.
Inhaled heparin has been shown to inhibit allergic bronchoconstriction in sheep that develop only acute responses to antigen (acute responders) but was ineffective in sheep that develop both acute and late airway responses (LAR) (dual responders). Because the antiallergic activity of heparin is molecular-weight dependent, we hypothesized that heparin-derived oligosaccharides (<2, 500) with potential anti-inflammatory activity may attenuate the LAR in the dual-responder sheep. Specific lung resistance was measured in 24 dual-responder sheep before and serially for 8 h after challenge with Ascaris suum antigen for demonstration of early airway response (EAR) and LAR, without and after treatment with inhaled medium-, low-, and ultralow-molecular-weight (ULMW) heparins and "non-anticoagulant" fractions (NAF) of heparin. Airway responsiveness was estimated before and 24 h postantigen as the cumulative provocating dose of carbachol that increased specific lung resistance by 400%. Only ULMW heparins caused a dose-dependent inhibition of antigen-induced EAR and LAR and postantigen airway hyperresponsiveness (AHR), whereas low- and medium-molecular-weight heparins were ineffective. The effects of ULMW heparin and ULMW NAF-heparin were comparable and inhibited the LAR and AHR even when administered "after" the antigen challenge. The ULMW NAF-heparin failed to inhibit the bronchoconstrictor response to histamine, carbachol, and leukotriene D(4), excluding a direct effect on airway smooth muscle. In six sheep, segmental antigen challenge caused a marked increase in bronchoalveolar lavage histamine, which was not prevented by inhaled ULMW NAF-heparin. The results of this study in the dual-responder sheep demonstrate that 1) the antiallergic activity of inhaled "fractionated" heparins is molecular-weight dependent, 2) only ULMW heparins inhibit the antigen-induced EAR and LAR and postantigen AHR, and 3) the antiallergic activity is mediated by nonanticoagulant fractions and resides in the ULMW chains of <2,500. 相似文献
2.
Campo Carlos; Molinari Jussara F.; Ungo Jaime; Ahmed Tahir 《Journal of applied physiology》1999,86(2):549-557
We have hypothesized that antiallergic activity of inhaledheparin is molecular weight dependent and mediated by"nonanticoagulant fractions" (NAF-heparin). Therefore, we studiedcomparative effects of high-, medium-, and ultralow-molecular-weight(HMW, MMW, and ULMW, respectively) NAF-heparins on acutebronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR)in allergic sheep. Specific lung resistance was measured in 23 allergicsheep, before and immediately after challenge withAscaris suum antigen, without andafter pretreatment with inhaled NAF-heparins. Airwayresponsiveness was estimated before and 2 h postantigen as thecumulative provocating dose of carbachol in breath units, whichincreased specific lung resistance by 400%. NAF-heparins attenuatedABR and AHR in a molecular-weight-dependent fashion. HMW NAF-heparin(n = 8) was the least effective agent: it attenuated ABR [inhibitory dose causing 50% protection(ID50) = 4 mg/kg] but hadno effect on AHR. MMW NAF-heparin (n = 8) showed intermediate efficacy (ABRID50 = 0.8 mg/kg, AHRID50 = 1.4 mg/kg), whereas ULMWNAF-heparin (n = 7) was the mosteffective agent (ABR ID50 = 0.4 mg/kg, AHR ID50 = 0.2 mg/kg). ULMWNAF-heparin was 3.5 times more potent in attenuating antigen-inducedAHR when administered "after" antigen challenge and failed toinhibit the bronchoconstrictor response to carbachol and histamine. In15 additional sheep, segmental antigen challenge caused a marked increase in histamine in bronchoalveolar lavage fluid that was notprevented by any of the inhaled NAF-heparins. These data indicate thatantiallergic activity of inhaled heparin is independent of itsanticoagulant action and resides in the <2,500 ULMW chains. Theantiallergic activity of NAF-heparins is mediated by an unknown biological action and may have therapeutic potential. 相似文献
3.
Inhibition of amyloidosis using low-molecular-weight heparins 总被引:2,自引:0,他引:2
BACKGROUND: Amyloid diseases are characterized by the tissue deposition of extracellular proteinaceous material, which results in organ dysfunction and death. Colocalization of heparan sulfate (HS) proteoglycans to amyloid deposits suggests that they may be an early event in amyloid formation and play an important role in fibril formation. Structural analysis has demonstrated that HS interacts with amyloidogenic proteins resulting in structural changes that allow for an increase in beta-sheet content, possibly enhancing fibrillogenesis. Recent studies have shown that small-molecule anionic sulfonates or sulfates can arrest inflammation-associated (AA) amyloid induction. MATERIALS AND METHODS: In the present study, we examine the effect of low-molecular-weight heparins (LMWHs) on the development of amyloid in the mouse model of AA amyloid. In addition, in vitro fibril formation assays were performed to determine the effect of LMWHs on fibrillogenesis. RESULTS: Injection of mice with clinically relevant doses of LMWHs (enoxaparin and dalteparin) demonstrated a reduction in AA amyloid deposition. These compounds were capable of arresting the progression of AA amyloid and eventually resulting in regression of the amyloid deposits. In vitro analysis indicated that LMWHs prevented AA and Abeta peptide fibril formation by impeding the structural changes necessary for fibril formation. CONCLUSIONS: Our findings suggest that the LMWHs may provide beneficial effects against the development of amyloidoses, including Alzheimer's disease. 相似文献
4.
Background
Previous studies showed that heparin''s anti-allergic activity is molecular weight dependent and resides in oligosaccharide fractions of <2500 daltons.Objective
To investigate the structural sequence of heparin''s anti-allergic domain, we used nitrous acid depolymerization of porcine heparin to prepare an oligosaccharide, and then fractionated it into disaccharide, tetrasaccharide, hexasaccharide, and octasaccharide fractions. The anti-allergic activity of each oligosaccharide fraction was tested in allergic sheep.Methods
Allergic sheep without (acute responder) and with late airway responses (LAR; dual responder) were challenged with Ascaris suum antigen with and without inhaled oligosaccharide pretreatment and the effects on specific lung resistance and airway hyperresponsiveness (AHR) to carbachol determined. Additional inflammatory cell recruitment studies were performed in immunized ovalbumin-challenged BALB/C mice with and without treatment.Results
The inhaled tetrasaccharide fraction was the minimal effective chain length to show anti-allergic activity. This fraction showed activity in both groups of sheep; it was also effective in inhibiting LAR and AHR, when administered after the antigen challenge. Tetrasaccharide failed to modify the bronchoconstrictor responses to airway smooth muscle agonists (histamine, carbachol and LTD4), and had no effect on antigen-induced histamine release in bronchoalveolar lavage fluid in sheep. In mice, inhaled tetrasaccharide also attenuated the ovalbumin-induced peribronchial inflammatory response and eosinophil influx in the bronchoalveolar lavage fluid. Chemical analysis identified the active structure to be a pentasulfated tetrasaccharide ([IdoU2S (1→4)GlcNS6S (1→4) IdoU2S (1→4) AMan-6S]) which lacked anti-coagulant activity.Conclusions
These results demonstrate that heparin tetrasaccharide possesses potent anti-allergic and anti-inflammatory properties, and that the domains responsible for anti-allergic and anti-coagulant activity are distinctly different. 相似文献5.
Oxidant stress modulates murine allergic airway responses 总被引:4,自引:0,他引:4
Talati M Meyrick B Peebles RS Davies SS Dworski R Mernaugh R Mitchell D Boothby M Roberts LJ Sheller JR 《Free radical biology & medicine》2006,40(7):1210-1219
The allergic inflammation occurring in asthma is believed to be accompanied by the production of free radicals. To investigate the role of free radicals and the cells affected we turned to a murine model of allergic inflammation produced by sensitization to ovalbumin with subsequent aerosol challenge. We examined oxidant stress by measuring and localizing the sensitive and specific marker of lipid peroxidation, the F2-isoprostanes. F2-isoprostanes in whole lung increased from 0.30 +/- 0.08 ng/lung at baseline to a peak of 0.061 +/- 0.09 ng/lung on the ninth day of daily aerosol allergen challenge. Increased immunoreactivity to 15-F2t-IsoP (8-iso-PGF2alpha) or to isoketal protein adducts was found in epithelial cells 24 h after the first aerosol challenge and at 5 days in macrophages. Collagen surrounding airways and blood vessels, and airway and vascular smooth muscle, also exhibited increased immunoreactivity after ovalbumin challenge. Dietary vitamin E restriction in conjunction with allergic inflammation led to increased whole lung F2-isoprostanes while supplemental vitamin E suppressed their formation. Similar changes in immunoreactivity to F2-isoprostanes were seen. Airway responsiveness to methacholine was also increased by vitamin E depletion and decreased slightly by supplementation with the antioxidant. Our findings indicate that allergic airway inflammation in mice is associated with an increase in oxidant stress, which is most striking in airway epithelial cells and macrophages. Oxidant stress plays a role in the production of airway responsiveness. 相似文献
6.
De Sanctis George T.; Wolyniec Walter W.; Green Francis H.Y.; Qin Shixin; Jiao Aiping; Finn Patricia W.; Noonan Thomas; Joetham Anthony A.; Gelfand Erwin; Doerschuk Claire M.; Drazen Jeffrey M. 《Journal of applied physiology》1997,83(3):681-687
De Sanctis, George T., Walter W. Wolyniec, Francis H. Y. Green, Shixin Qin, Aiping Jiao, Patricia W. Finn, Thomas Noonan, Anthony A. Joetham, Erwin Gelfand, Claire M. Doerschuk, and Jeffrey M. Drazen. Reduction of allergic airway responses inP-selectin-deficient mice. J. Appl.Physiol. 83(3): 681-687, 1997.P-selectin is an adhesion receptor that has been shown to be important in therecruitment of eosinophils and lymphocytes in a variety of inflammatoryconditions. Because cellular recruitment is thought to be a criticalevent in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airwayresponsiveness and cellular trafficking noted in wild-type (+/+) mice.Both (+/+) and P-selectin-deficient (/) micesensitized and challenged with ovalbumin (OVA/OVA) exhibited thesame capacity to produce increased titers of total and OVA-specificimmunoglobulin E. Airway responsiveness to methacholine wassignificantly greater in the (+/+) (OVA/OVA) animals than it was in therespective (/) (OVA/OVA) group or control groups(P = 0.0016). Bronchoalveolarlavage fluid from (/) (OVA/OVA) mice contained significantlyfewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA)mice (P < 0.05). These resultssuggest that the predominant role of P-selectin in OVA-inducedairway hyperresponsiveness is to promote the airway inflammatoryresponse to allergen inhalation. 相似文献
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DiMaria G. U.; Wang C. G.; Bates J. H.; Guttmann R.; Martin J. G. 《Journal of applied physiology》1987,62(3):1317-1323
We measured the changes in upper and lower airway resistance after inhalation of aerosols of methacholine (MCh) in doubling concentrations (16, 32, 64, and 128 mg/ml) in 11 anesthetized nonintubated spontaneously breathing rats. Upper airway resistance (Ru) increased from a control value of 0.48 +/- 0.04 cmH2O X ml-1 X s (mean +/- SE) to 0.85 +/- 0.15 after 128 mg/ml MCh, whereas lower airway resistance (Rlo) increased from 0.11 +/- 0.03 to 0.21 +/- 0.04. However, there was no correlation between the magnitudes of the changes in Ru and Rlo. In a further seven anesthetized spontaneously breathing rats aerosols of MCh were delivered into the lower airways via a tracheostomy and resulted in increases in Rlo from a control value of 0.20 +/- 0.03 to 0.66 +/- 0.12 after 128 mg/ml MCh. Ru also increased to approximately double its control value. We conclude that inhaled MCh causes narrowing of both Ru and Rlo in the anesthetized rat, the changes in Ru and Rlo are not correlated, and changes in Ru can occur when MCh deposition occurs only in the lower airways. 相似文献
10.
Francisco Robert 《Journal of hematology & oncology》2010,3(1):1-12
Prostate cancer remains a significant public health problem, with limited therapeutic options in the setting of castrate-resistant metastatic disease. Angiogenesis inhibition is a relatively novel antineoplastic approach, which targets the reliance of tumor growth on the formation of new blood vessels. This strategy has been used successfully in other solid tumor types, with the FDA approval of anti-angiogenic agents in breast, lung, colon, brain, and kidney cancer. The application of anti-angiogenic therapy to prostate cancer is reviewed in this article, with attention to efficacy and toxicity results from several classes of anti-angiogenic agents. Ultimately, the fate of anti-angiogenic agents in prostate cancer rests on the eagerly anticipated results of several key phase III studies. 相似文献
11.
E. S. Ostanina V. P. Varlamov G. I. Yakovlev 《Applied Biochemistry and Microbiology》2008,44(1):32-37
Inhibition of enzymatic activity of lipase (EC 3.1.1.3) from the fungus Candida rugosa and wheat (Triticum aestivum L.) germ by low-molecular-weight chitosan with an average molecular weight of 5.7 kDa in reactions of p-nitrophenyl palmitate cleavage was studied. Preincubation of lipases with chitosan, prior to addition of the substrate to solution, showed that equilibrium during the lipase-inhibitor complex formation was reached within 30 min. The inhibition constants for C. rugosa lipase and wheat germ lipase were 1.4 and 0.9 mM, respectively. The contribution of electrostatic interactions to the complex formation between chitosan and lipases is insignificant. 相似文献
12.
Inhibition of Th2-mediated allergic airway inflammatory disease by CD137 costimulation 总被引:3,自引:0,他引:3
Sun Y Blink SE Liu W Lee Y Chen B Solway J Weinstock J Chen L Fu YX 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(2):814-821
The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8(+) T cells and stimulate IFN-gamma production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-gamma and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion. 相似文献
13.
Inhibition of enzymatic activity of lipase (EC 3.1.1.3) from the fungus Candida rugosa and wheat (Triticum aestivum L.) germ by low-molecular-weight chitosan with an average molecular weight of 5.7 kDa in reactions of p-nitrophenyl palmitate cleavage was studied. Preincubation of lipases with chitosan, prior to addition of the substrate to solution, showed that equilibrium during the lipase-inhibitor complex formation was reached within 30 min. The inhibition constants for C. rugosa lipase and wheat germ lipase were 1.4 and 0.9 mM, respectively. The contribution of electrostatic interactions to the complex formation between chitosan and lipases is insignificant. 相似文献
14.
E. S. Ostanina V. P. Varlamov G. I. Yakovlev 《Applied Biochemistry and Microbiology》2007,43(6):655-660
Inhibition of enzymatic activity of lipase (EC 3.1.1.3) from the fungus Candida rugosa and wheat (Triticum aestivum L.) germ by low-molecular-weight chitosan with an average molecular weight of 5.7 kDa in reactions of p-nitrophenyl palmitate cleavage was studied. Preincubation of lipases with chitosan, prior to addition of the substrate to solution, showed that equilibrium during the lipase-inhibitor complex formation was reached within 30 min. The inhibition constants for C. rugosa lipase and wheat germ lipase were 1.4 and 0.9 mM, respectively. The contribution of electrostatic interactions to the complex formation between chitosan and lipases is insignificant. 相似文献
15.
Hikari Koga Nobuaki Miyahara Yasuko Fuchimoto Genyo Ikeda Koichi Waseda Katsuichiro Ono Yasushi Tanimoto Mikio Kataoka Erwin W Gelfand Mitsune Tanimoto Arihiko Kanehiro 《Respiratory research》2013,14(1):8
Background
Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice.Methods
BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge.Results
Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice.Conclusion
These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge. 相似文献16.
Long W. M.; Yerger L. D.; Martinez H.; Codias E.; Sprung C. L.; Abraham W. M.; Wanner A. 《Journal of applied physiology》1988,65(1):272-282
Ascaris suum antigen effects on mean airflow resistance (RL) and bronchial arterial blood flow (Qbr) were studied in allergic anesthetized sheep with documented airway responses. Qbr was measured with electromagnetic flow probes, and supplemental O2 prevented antigen-induced hypoxemia. Aerosol challenge with this specific antigen increased RL and Qbr significantly. Cromolyn sodium aerosol pretreatment prevented antigen-induced increases in RL but not in Qbr. Intravenous cromolyn, however, prevented increases in Qbr and RL, suggesting a role for mast cell degranulation in both bronchomotor and bronchovascular responses to antigen. Antigen-induced increases in Qbr were not solely attributable to histamine release. Indomethacin pretreatment attenuated the antigen-induced increase in Qbr, thus suggesting that vasodilator cyclooxygenase products contribute to the vascular response. Antigen challenge significantly decreased Qbr after indomethacin and metiamide pretreatment, which suggests that vasoconstrictor substances released after antigen exposure also modulate Qbr; however, released vasodilators overshadow vasoconstrictor effects. Thus antigen challenge affects Qbr by locally releasing histamine and vasodilator prostaglandins as well as vasoconstrictor substances. These effects were independent of antigen-induced changes in systemic and pulmonary hemodynamics. 相似文献
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Roy S Lai H Zouaoui R Duffner J Zhou H P Jayaraman L Zhao G Ganguly T Kishimoto TK Venkataraman G 《Glycobiology》2011,21(9):1194-1205
A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1α), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates. 相似文献
19.
Allergic sheep with antigen-induced early and late responses were used to determine whether airway hyperresponsiveness (AHR) to carbachol is present during the late response and whether blocking the late response with the leukotriene D4 (LTD4) antagonist MK-571 also blocks this AHR. To do this, we first showed that MK-571 blocked the antigen-induced late response, and then, in a separate study, we determined the effect of MK-571 treatment on airway responsiveness 6 h after antigen challenge (at the start of the late response). MK-571 (5 mg, by metered dose inhaler) given 30 min before and 4 h after Ascaris suum challenge had no effect on the acute response to antigen but blocked (P less than 0.05) the late response compared with placebo (n = 7). In the second study (n = 6), the antigen-induced acute increases in mean specific lung resistance (sRL) were also similar in the placebo (249%) and drug trials (247%). By 6 h postchallenge, however, mean sRL in the placebo trial began to increase (54%, P less than 0.05), whereas in the drug trial mean sRL was baseline. Nevertheless, AHR was apparent in both trials as indicated by a mean twofold leftward shift in the dose-response curves to inhaled carbachol (P less than 0.05 vs. prechallenge). Bronchoalveolar lavage at 6 h showed that MK-571 did not prevent the inflammatory cell influx into the lung. These observations suggest that although LTD4 may be a mediator of the late response in sheep, it is not a primary mediator affecting cholinergic AHR during this period. 相似文献
20.
Cutting edge: Deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses 总被引:3,自引:0,他引:3
Wang B Huang X Wolters PJ Sun J Kitamoto S Yang M Riese R Leng L Chapman HA Finn PW David JR Bucala R Shi GP 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(9):5779-5784
Increased levels of macrophage migration inhibitory factor (MIF) in serum, sputum, and bronchioalveolar lavage fluid (BALF) from asthmatic patients and time/dose-dependent expression of MIF in eosinophils in response to phorbol myristate acetate suggest the participation of MIF in airway inflammation. In this study, we examined inflammation in OVA-sensitized mouse lungs in wild-type and MIF-deficient mice (MIF(-/-)). We report increased MIF in the lung and BALF of sensitized wild-type mice. MIF(-/-) mice demonstrated significant reductions in serum IgE and alveolar inflammatory cell recruitment. Reduced Th1/Th2 cytokines and chemokines also were detected in serum or BALF from MIF(-/-) mice. Importantly, alveolar macrophages and mast cells, but not dendritic cells or splenocytes, from MIF(-/-) mice demonstrated impaired CD4+ T cell activation, and the reconstitution of wild-type mast cells in MIF(-/-) mice restored the phenotype of OVA-induced airway inflammation, revealing a novel and essential role of mast cell-derived MIF in experimentally induced airway allergic diseases. 相似文献