Heparin Inhibits the Immediate Response to Antigen in the Skin and Lungs of Allergic Subjects

Bowler, Simon; Smith, Sheree; Lavercombe, Peter S

doi:10.1164/ajrccm/147.1.160

Cited by 126 publications

(74 citation statements)

References 16 publications

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“…Despite evaluating a group of patients potentially at risk of pulmonary bleeding, inhaled heparin was safe and well tolerated, with no bleeding complications. Furthermore, consistent with the short half-life of heparin and data demonstrating little systemic absorption from the tracheobronchial tree, there was no evidence of any cumulative effect of heparin upon systemic coagulation markers, extending previous findings [12,24,30,31].…”

Section: Discussionsupporting

confidence: 86%

Inhaled heparin in cystic fibrosis

Serisier

Shute²,

Hockey³

et al. 2006

Eur Respir J

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Cystic fibrosis (CF) is characterised by inspissated airway secretions and chronic endobronchial infection associated with exuberant neutrophilic inflammation. Unfractionated heparin may be mucolytic and has demonstrated a number of anti-inflammatory properties; however, further safety data are needed in these subjects who are at risk of airway bleeding. The current study aimed to assess the medium-term safety and tolerability of moderately high-dose inhaled heparin in CF adults and to explore possible in vivo mucolytic and anti-inflammatory outcomes.A randomised, double-blind, placebo-controlled crossover study of twice daily inhalation of 50,000 IU of heparin for 2 weeks was undertaken in CF adults, with a 1-week washout period. Eighteen subjects were randomised and 14 (mean¡SD age 23¡7.8 yrs and percentage-predicted forced expiratory volume in one second 52.1¡15.56%) completed the study protocol.Heparin neither affected blood coagulation parameters nor resulted in any increase in adverse events. Heparin inhalation had no significant effect upon forced expiratory volume in one second, symptoms of sputum clearance or sputum inflammatory markers.The current pilot study demonstrated no evidence of improved sputum clearance with 50,000 IU of inhaled heparin given twice daily to adult cystic fibrosis subjects. However, inhaled heparin was safe and the future evaluation of larger doses over a longer period may be warranted.

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Section: Discussionsupporting

confidence: 86%

Inhaled heparin in cystic fibrosis

Serisier

Shute²,

Hockey³

et al. 2006

Eur Respir J

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“…Similar to the arginase inhibitor ABH [45], pretreatment with inhaled heparin also reduced allergen-induced bronchial obstructive reactions in allergic sheep and guinea pigs [64,66,67]. Furthermore, both exercise-and allergen-induced asthmatic reactions in asthmatic patients were reduced by inhaled heparin as well [68][69][70]. However, inhalation of the heparinderivative IVX-0142 did not significantly affect allergeninduced early and late asthmatic responses, AHR and exhaled NO in patients with mild asthma, which may have been due to underdosing of the drug [71].…”

Section: +mentioning

confidence: 94%

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Maarsingh¹,

Bossenga²,

Bos³

et al. 2009

Eur Respir J

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ABSTRACT:Peroxynitrite has been shown to be crucially involved in airway hyperresponsiveness (AHR) after the late asthmatic reaction (LAR). Peroxynitrite production may result from simultaneous synthesis of nitric oxide (NO) and superoxide by inducible NOsynthase (iNOS) at low L-arginine concentrations. L-Arginine availability to iNOS is regulated by its cellular uptake, which can be inhibited by eosinophil-derived polycations and by arginase, which competes with iNOS for the common substrate.Using a guinea pig model of allergic asthma, we investigated whether aberrant L-arginine homeostasis could underlie peroxynitrite-mediated AHR after the LAR.After the LAR, arginase activity in the airways and eosinophil peroxidase release from bronchoalveolar lavage cells were increased. These changes were associated with a 2.0-fold AHR to methacholine as measured in isolated perfused tracheal preparations. AHR was reduced by exogenous L-arginine administration. Moreover, both the arginase inhibitor N v -hydroxy-nor-Larginine (nor-NOHA) and the polycation antagonist heparin normalised airway responsiveness. These effects were reversed by the nitric oxide synthase inhibitor N v -nitro-L-arginine methyl ester (L-NAME), indicating that both agents reduced AHR by restoring bronchodilating NO production.In conclusion, in allergen-challenged guinea pigs, the AHR after the LAR is caused by arginaseand polycation-induced attenuation of L-arginine availability to iNOS, which may switch the enzyme to simultaneous production of superoxide and NO, and, consequently, peroxynitrite.

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“…For example, it has been shown to suppress neutrophil function and chemotaxis in vitro (Matzner et al, 1984;Bazzoni et al, 1993), reduce neutrophil migration into the inflamed rat paw (McGovern, 1957) and inhibit increases in vascular permeability in rabbit skin (Lecomte & Hugues, 1954;Carr, 1979). Heparin also appears to diminish the bronchoconstrictor response of sheep to allergic and nonallergic stimuli (Ahmed et al, 1992) and the immediate response to antigen in the skin and lungs of allergic human subjects (Bowler et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Suppression by intradermal administration of heparin of eosinophil accumulation but not oedema formation in inflammatory reactions in guinea‐pig skin

Teixeira

Hellewell

1993

British J Pharmacology

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1 Heparin is widely used in the treatment of thrombotic disorders and as an aid in surgery. Antiinflammatory effects of heparin have also been described. In this study, we have investigated the effects of locally-injected heparin on the oedema formation and eosinophil accumulation induced by various inflammatory stimuli in guinea-pig skin.2 Heparin dose-dependently suppressed the accumulation of "'In-labelled eosinosphils induced by i.d. injection of zymosan-activated plasma (ZAP). The "'In-eosinophil accumulation induced by other inflammatory stimuli (compound 48/80, platelet activating factor, interleukin-8 and in a passive cutaneous anaphylaxis reaction) was also suppressed by locally-injected heparin. 3 Oedema formation in response to these same stimuli was not altered by the local injection of heparin. 4 Fucoidin, a negatively-charged sulphated algal polymer, had no effect on the "1'In-eosinophil accumulation or oedema formation induced by ZAP. Nevertheless, fucoidin significantly suppressed the oedema formation induced by i.d. injection of cationic protein-containing extracts of Schistosoma mansoni larvae. Heparin also inhibited oedema induced by the extracts, suggesting that both fucoidin and heparin were effectively neutralizing the cationic protein of the extracts to inhibit their oedemainducing activity.5 Thus, heparin significantly inhibited the accumulation of "'In-eosinophils, but not oedema formation, induced by various inflammatory stimuli. This, taken together with the lack of effect of fucoidin, suggests that heparin interferes with the process of eosinophil trafficking by a mechanism that does not depend on neutralisation of the charge of the stimulatory molecules.

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Heparin Inhibits the Immediate Response to Antigen in the Skin and Lungs of Allergic Subjects

Cited by 126 publications

References 16 publications

Inhaled heparin in cystic fibrosis

Inhaled heparin in cystic fibrosis

l-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction

Suppression by intradermal administration of heparin of eosinophil accumulation but not oedema formation in inflammatory reactions in guinea‐pig skin

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