Inhibitory Effects of Nedocromil Sodium on the in Vitro Induced Migration and Leukotriene Formation of Human Granulocytes1

Bruijnzeel, P. L. B.; Warringa, R. A. J.; Kok, Paul T.M.; Hamelink, M. L.; Kreukniet, J.

doi:10.2165/00003495-198900371-00004

Cited by 15 publications

(10 citation statements)

References 15 publications

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“…Nedocromil sodium is a pyranoquinoline dicarboxyline acid which has been demonstrated to have some beneficial effects in various models of asthma, including human airway response to hyperosmolar challenge [488], PAF-mediated bronchoconstriction [489], early and late responses to allergen challenge in asthmatics [490,491], and eosinophil recruitment in humans [491]. Besides its inhibitory action on mast cells, neutrophils, monocytes and platelets [492][493][494][495][496], nedocromil sodium has been shown to block various eosinophil functions, including secretion of granule proteins [497], eosinophil chemotaxis [498,499], surface antigen expression [500], leukotriene C 4 secretion in response to various agents [499,501] as well as density change, damage to airway epithelium [502,503] and other cytotoxic mechanisms [498,500]. Hence, these inhibitory effects of nedocromil on eosinophil function suggest that it may be effective in eosinophil-related disease, such as asthma.…”

Section: Xanthines and Selective Phosphodiesterase Inhibitorsmentioning

confidence: 99%

Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II)

Kroegel¹,

Warner²,

Jc³

et al. 1994

Eur Respir J

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The second part of this review on eosinophils focuses on biological cell functions and surveys the various deleterious mechanisms involved in the eosinophil-dominated inflammatory reaction. It discusses the possible pathogenic role of eosinophils in several eosinophil-related diseases, such as parasitic infections, interstitial lung disorders and bronchial diseases, graft rejection, vasculitic granulomatous disorders, pleural effusion, and bronchogenic tumours.The final section of the article highlights the possible recent pharmacological and future therapeutic approaches in modifying eosinophil recruitment and function. Eur Respir J., 1994, 7, 743-760 This paper is published as a follow-on to "Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part I)"* (Eur Respir J, 1994; 7: 519-543). Biological cell functionsThe eosinophil mediates its effector functions through various distinct cellular mechanisms, namely nonoxidative, oxidative, and humoral mechanisms ( fig. 7). Nonoxidative mechanismsAs mentioned previously, the three basic proteins as well as eosinophil peroxidase (EPO) have toxic properties independent of molecular oxygen species. For instance, major basic protein (MBP) [323], eosinophil cationic protein (ECP) [324] and EPO in the presence of hydrogen superoxide and a halide [99] kill helminthic parasites in vitro. In addition, these proteins are toxic for tumour cells and/or mammalian cells [325], including human pulmonary parenchyma and interstitial matrix [326,327], cultured human lung epithelial cells [328], and guinea-pig respiratory epithelium [252, 253,329]. Furthermore, it has been demonstrated that MBP damages human bronchial epithelium, which consists of desquamation and destruction of ciliated cells [329]. Finally, release of their granule proteins by plateletactivating factor (PAF)-activated intact eosinophils has been shown to imitate the characteristic pathological findings of airway epithelium in asthma [330].In addition to their cytotoxic action, eosinophil cationic proteins at certain subtoxic concentrations also stimulate other inflammatory cells. For instance, MBP and ECP have been shown to degranulate platelets [305], induce histamine release from mast cells and basophils [240, 245,331], as well as superoxide anion generation and lysosomal enzyme release by human neutrophils [264].Finally, eosinophil proteins may affect airway muscle function and hyperresponsiveness. Recent reports investigating the effects of direct intratracheal instillation of purified eosinophil granule proteins on pulmonary function and airway responsiveness in primates [281,332] have shown that MBP induces a dose-related increase in airway responsiveness to inhaled methacholine. In the same model, both MBP and EPO caused a transient bronchoconstriction immediately after instillation, that resolved within 1 h. Interestingly, other eosinophil granular proteins failed to effect airway responsiveness or pulmonary function.Mode of action. The mode of action of these basic proteins is n...

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Section: Xanthines and Selective Phosphodiesterase Inhibitorsmentioning

confidence: 99%

Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II)

Kroegel¹,

Warner²,

Jc³

et al. 1994

Eur Respir J

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“…It is known that the antiallergic drug cromolyn sodium blocks the release of histamine from mast cells [8,9]. There is also evidence that cromolyn sodium may have effects on inflammatory cells such as neutrophils [10][11][12]. Despite its wide use, however, the mechanism(s) of action of cromolyn sodium has not been established [8,9].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic aspects of cromolyn sodium action on the alveolar macrophage: Inhibition of stimulation by soluble agonists

Holian¹,

Hamilton²,

Scheule³

1991

Agents and Actions

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Despite wide use of the drug cromolyn sodium, its mechanism of action remains unknown. The alveolar macrophage plays a major role in the regulation of the inflammatory responses of the lung which may contribute to asthma. Since the biochemical mechanism by which agonists stimulate the alveolar macrophage to produce superoxide anion has been described, the effects of cromolyn sodium on this process were examined. Cromolyn sodium (0.5-4 mM) reversibly blocked macrophage stimulation by formyl peptide and leukotriene B4, but not by phorbol diester and concanavalin A. Cromolyn sodium inhibition was not calcium dependent and could be reversed by increasing the dose of agonist. Cromolyn sodium did not elevate intracellular cAMP, nor did the characteristics of inhibition resemble those observed using cAMP to inhibit agonist stimulation. However, cromolyn sodium did block agonist-mediated stimulation of the phosphatidylinositol (PI) pathway. Taken together, the present results suggest that one site of action of cromolyn sodium may be at the GTP-binding protein of the PI pathway.

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“…NS inhibits the release of 15-HETE from human stimulated-bronchial epithelial cells [42], Controversial results have been reported on human blood eosinophils. Some authors have shown that NS inhibits LTC4 release from A23187-stimulated eosinophils [26]. This inhibitory effect was not observed by Burke et al [43], However, in these two studies no details were given about patients and no comparisons of AP and HS were carried out.…”

Section: Discussionmentioning

confidence: 89%

“…Previous studies showed that NS significantly decreased LTC, generation by eosinophils [26] and LTB4 and 5-HETE generation by alveolar macrophages [30] at concentrations of 10"' and KL1 mol/l, re spectively. Thus, the PMN suspension was preincubated for 5 min at 37°C with or without NS (10"4 mol/l).…”

Section: Cell Stimulation and Ns Incubationmentioning

confidence: 85%

“…In addi tion to protecting against bronchoconstriction after aller gen challenge and exercise-induced asthma in man [24], NS also reduces the bronchial reactivity of asthmatics dur ing the pollen season [25], NS was previously found to de crease LTC4 generated by stimulated eosinophils [26], Thus, the aim of the present study was to determine whether NS was able to decrease LTB4 and 5-HETE syn thesis in A23187-stimulated PMN.…”

Section: Introductionmentioning

confidence: 89%

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Arachidonate 5-Lipoxygenase Metabolism in Human Neutrophils from Patients with Asthma: In vitro Effect of Nedocromil Sodium

Radeau

Chavis

Godard

et al. 1992

Int Arch Allergy Immunol

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Among the cells which participate in amplification of the local inflammatory reaction in asthma, neutrophils (PMN) are pro-inflammatory cells that can generate inflammatory mediators and arachidonic acid derivatives in particular. In asthmatic patients (AP) with attacks, the capacity of blood PMN to produce 5-lipoxygenase metabolites was investigated and compared to the response in healthy subjects (HS). PMN from 6 AP and from 6 HS were stimulated by calcium ionophore A23187 and arachidonate 5-lipoxygenase metabolites were analyzed by reverse-phase HPLC. LTB₄, 6-trans LTB₄, ωOH-LTB₄ and 5-HETE were identified. In AP, total LTB₄ synthesis was enhanced as compared to synthesis with PMN in HS. But the total 5-HETE synthesis by PMN from AP was decreased. Thus, the inflammatory potential of PMN from AP was enhanced in comparison to HS. The anti-inflammatory effect of nedocromil sodium (NS) was studied in the 5-lipoxygenase metabolism of arachidonic acid. NS (10^––⁴ mol/l) inhibited total LTB₄ synthesized by PMN in AP but not in HS. We conclude that NS affects leukotriene synthesis only in cells with enhanced inflammatory potential.

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Inhibitory Effects of Nedocromil Sodium on the in Vitro Induced Migration and Leukotriene Formation of Human Granulocytes1

Cited by 15 publications

References 15 publications

Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II)

Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II)

Mechanistic aspects of cromolyn sodium action on the alveolar macrophage: Inhibition of stimulation by soluble agonists

Arachidonate 5-Lipoxygenase Metabolism in Human Neutrophils from Patients with Asthma: In vitro Effect of Nedocromil Sodium

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