Effect of Inhaled Heparin on Methacholine-Induced Bronchial Hyperreactivity

Ceyhan, Berrin; Celikel, Turgay

doi:10.1378/chest.107.4.1009

Cited by 33 publications

(24 citation statements)

References 21 publications

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“…Previous studies have indicated that treatment with inhaled heparin before allergen challenge significantly reduced allergen-induced pulmonary eosinophilia in sensitised guinea pigs [61]. In addition, in asthmatic patients and in allergen-challenged sheep and guinea pigs, (pretreatment with) inhaled heparin was found to inhibit AHR to various contractile agonists [62][63][64][65][66]. 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].…”

Section: +mentioning

confidence: 95%

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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Section: +mentioning

confidence: 95%

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

Maarsingh¹,

Bossenga²,

Bos³

et al. 2009

Eur Respir J

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“…More recently, there have been several reports documenting protective effects of i.v. or inhaled heparin on cutaneous weal and flare responses or on allergen-or exercise-induced asthma [10][11][12][13]. It has been suggested that these non-anticoagulant actions of heparin are more likely to be related to modulation of mediator release rather to a direct effect on end organ receptor sites involved in these reactions.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation

Baram

Rashkovsky

Hershkoviz

et al. 1997

Clinical and Experimental Immunology

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SUMMARYThere has been substantial evidence that suggests that heparin may modulate various aspects of immune function and inflammation in addition to its well known anticoagulant activity. In this regard heparin was found to suppress cell-mediated immune responses or asthmatic reactions to allergen challenge. In the present study we analyse the effects of low molecular weight heparin (LMWH) on mast cell degranulation and cytokine production in vitro and on the elicitation of IgE-mediated mast celldependent late cutaneous allergic inflammation in vivo. We have established that LMWH preferentially inhibited tumour necrosis factor-alpha (TNF-a) and IL-4 production without having any significant effect on mast cell degranulation. These effects have been observed in mast cells derived from three different origins that were activated by either immunological or non-immunological stimuli. We have shown that there is inhibition of TNF-a production (and not neutralization of activity), as elimination of the drug after a short preincubation and addition of LMWH to rTNF-a had no effect on TNF-a-mediated cytotoxic activity. These results were also confirmed by ELISA. In vivo, s.c. injection of the LMWH inhibited the leucocyte infiltration associated with the late cutaneous response which followed passive cutaneous anaphylaxis (PCA) reaction, without affecting mast cell numbers or degranulation. These data suggest that LMWH may have an inhibitory role in mast cell-mediated allergic inflammation, and thus might be considered as a possible therapeutic modality.

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“…It has been suggested that heparin was released to decrease eosinophil recruitment into allergic inflammatory sites and to minimise the degree of tissue damage resultant of cationic proteins derived from the leucocyte. 4 These effects may be the underlying mechanism in the reduction of exercise-, histamineand allergen-induced bronchoconstriction. 6 These preliminary results indicate significantly decreased endogenous heparin levels in the asthmatic patient, thereby potentially decreasing anti-inflammatory effects.…”

Section: Resultsmentioning

confidence: 99%

“…3 The anti-allergic activity of inhaled heparin was found to be independent of its anticoagulant properties, where an inverse relationship between the molecular weight of heparin and antiallergic activity exists. 4 In patients with a history of exerciseinduced asthma, inhaled heparin did not affect respiratory parameters, partial thromboplastin time or heart rate, and prevented post-exercise bronchoconstriction. In addition, no changes to bronchoconstrictor responses to histamine were noted.…”

mentioning

confidence: 88%

Endogenous heparin levels in the controlled asthmatic patient

Davids¹,

Ahmed²,

Oberholster³

et al. 2010

S Afr Med J

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Levels of circulating endogenous heparin in patients with diseases associated with inflammatory processes, such as asthma, are still unknown. Since heparin displays antiinflammatory properties, it is expected that the inhibitory effects on inflammatory mediators are reduced at low levels of endogenous heparin. 1 We present evidence supporting the hypothesis that asthmatic patients have lower levels of circulating endogenous heparin than healthy individuals have.Since 1955, endogenous plasma heparin has been demonstrated to be a normal constituent of blood, with concentrations ranging from 153 to 177 mIU/ml, and its levels were found to be independent of gender or age.2 Discrepancies in the concentrations of endogenous heparin reported by various research groups are thought to result from the different quantitative methods or isolation procedures used.

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Effect of Inhaled Heparin on Methacholine-Induced Bronchial Hyperreactivity

Cited by 33 publications

References 21 publications

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

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

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation

Endogenous heparin levels in the controlled asthmatic patient

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