Concentration mgmL

Figure 5 Effect of disodium cromoglycate (DSCG) on IgE production by T cell-depleted, B cell-enriched populations of cells in the presence of IL-4 (50 mg/mL) and anti-CD40 mAb (5 mg/mL). Cells were cultured at a concentration of 106cells/mL for 10 days with different concentrations of DSCG. Supernatants were harvested after 10 days and IgE levels were measured by radioimmunoassay. Results represent mean ± SE net synthesis IgE (pg/mL) of five experiments.

Both cromolyn and nedocromil inhibit histamine and PGD2 release from human mast cells; block activation of human eosinophils; inhibit activation, chemotaxis, and mediator release from neutrophils; inhibit IgE antibody function from mononuclear cells; inhibit the Sm to Se switch; inhibit TNF-a release; and reduce mRNA for TNF-a from rat peritoneal cells (Table 1, Fig. 6) (27, 36-42).

When atopic asthmatic patients are stimulated with Dermatophagoides farinae, cromolyn has been shown to inhibit the production of IL-5 and IFN-g by sensitized human peripheral blood mononuclear cells (43). A significant decrease in TNF-a and IL-5 was reported in sensitized human lung specimens from atopic patients (43). In addition to IL-5, Oh et al. (44) reported that DSCG reduced secretion of IL-4 and IL-13 in PBMC from atopic patients. In bronchoalveolar lavage (BAL) and nasal lavage fluid, cro-molyn reduced the increase in neutrophils, myeloperoxidase, soluble intercellular adhesion molecule-1 (ICAM-1), IL-6, and TNF-a (46) (Fig. 7). In patients with bronchopulmonary dysplasia (BPD), cromolyn was reported to decrease TNF-a and IL-8 in lung lavage fluid (45,46). Shin et al. (34) reported significant inhibition of TNF-a release in the rat mast cell line RBL-2H3 pretreated with DSCG prior to antigen challenge.

In 1969, Kennedy reported a reduction in sputum eosinophils with cromolyn treatment compared to placebo (48). More recently bronchial biopsy specimens had a reduction in EG2+ eosinophils, AA1+ mast cells, and CD4+, CD8+, CD3+, and CD68+ lymphocytes in patients treated with 12 weeks of cromolyn (49) (Fig. 8). Furthermore, a reduced expression of ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) were seen on bronchial epithelium and vascular endothelium after treatment with cromolyn (49).

CS has been beneficial in the treatment of aspirin-sensitive asthma (ASA) subjects. Amayasu et al. (50) reported that ASA patients treated with cromolyn for one week resulted in an improvement in asthma symptoms, and demonstrated a significant decrease in blood and sputum eosinophils and sputum eosinophilic cationic protein (ECP) levels compared with placebo. Furthermore, there was an improvement in bronchial hypersensi-tivity in almost all patients.

In addition to their effects on mast cells, cromolyn and nedocromil inhibit the expression of membrane receptors for complement (C3b) and IgG (Fc) in human neutrophils (8). Both medications have been reported to inhibit activation of human neutrophils by platelet-activating factor (PAF) or zymosan-activated serum (51). Cromolyn treatment decreases oxygen radical production in guinea-pig alveolar macrophages in response to zymosan in a concentration-dependent manner by 72% (52). The combination medication reproterol (p2-agonist) and DSCG is used in Europe for the treatment of asthma. The combined reproterol and DSCG showed a significant inhibition of histamine release compared to another p2-agonist (salbutamol) in rat mast cells (53).

Table 1 Immunologic Effects of Cromolyn and Nedocromil

Action (Ref.) Cromolyn Nedocromil

Inhibit PGD2 release from human mast cells (36) ✓ ✓

Inhibit TNFa release and decrease mRNA for TNFa ✓

from peritoneal rat mast cells (37) Inhibit production of IL-5 from human PBMCs (43) ✓

Reduce the increase in neutrophils, myeloperoxidase, ICAM-1, IL-6, TNFa in BAL and nasal lavage fluid (46)

Decrease TNFa and IL-8 in lung lavage fluid of BPD ✓

patients (47)

Decrease in IL-6 in human airway macrophages (166) ✓

Decreases lysosomal enzyme release from human ✓

alveolar macrophages (56) Decreases oxygen radical release from human ✓

monocytes (56)

Block activation of human blood eosinophils (27,39) ✓ ✓

Inhibits release of pre-formed (granule-associated) ✓

newly generated eicosanoid medications (51,54) Blocks chemotactic response of eosinophils to PAF ✓

Blocks survival of eosinophils in presence of IL-5 ✓

Inhibits release of ECP from eosinophils (168) ✓

Decreases the release of TNFa, IL-8, soluble ICAM-1 ✓

from human bronchial epithelial cells (169) Inhibits GMCSF and IL-8 (170,171) ✓

Inhibits cell surface ICAM-1 expression (172) ✓

Inhibits release of cytotoxic mediators from platelets ✓

taken from patient with ASA (173) Inhibits urinary LTE4 in ASA patients (174) ✓

Inhibits generation of TBX2 and IP3 from thromboxane stimulated patients (175) Inhibits activation, chemotaxis, and mediator release ✓ ✓

from neutrophils (56,176-179) Inhibit IgE antibody function from mononuclear cells ✓ ✓

Inhibits allergen-induced and mitogen induced ✓

proliferation and IL-2 release from mouse lymphocytes (180)

Figure 6 Effect of cramolyn sodium on immunoglobulin E (IgE) production by T cell-depleted, B cell-enriched populations of cells (106cells/mL) in the presence of interleukin-4 (IL-4, 50U/mL) and anti-CD40 monoclonal antibody (mAb, 5 mg/mL). Results represent mean ± SE for net synthesis of IgE (pg/mL) from five experiments. Source: From Ref. 41.

Figure 6 Effect of cramolyn sodium on immunoglobulin E (IgE) production by T cell-depleted, B cell-enriched populations of cells (106cells/mL) in the presence of interleukin-4 (IL-4, 50U/mL) and anti-CD40 monoclonal antibody (mAb, 5 mg/mL). Results represent mean ± SE for net synthesis of IgE (pg/mL) from five experiments. Source: From Ref. 41.

Figure 7 Effect of concentration of tumor necrosis factor alpha (TNF-a) in BAL fluid after two weeks of treatment with cramolyn sodium (n — 16) or placebo (n — 16) before (b) and after (a) exposure to swine dust; median values and 25th to 75th percentiles. Difference between groups is significant (p — 0.0003). Source: From Ref. 46.

Figure 7 Effect of concentration of tumor necrosis factor alpha (TNF-a) in BAL fluid after two weeks of treatment with cramolyn sodium (n — 16) or placebo (n — 16) before (b) and after (a) exposure to swine dust; median values and 25th to 75th percentiles. Difference between groups is significant (p — 0.0003). Source: From Ref. 46.

Figure 8 Effect of cromolyn sodium (CS) on individual cell counts of EG2+ eosinophils, NP 57+ neutrophils, and AA1+mast cells expressed as number of cells per square millimeter of lamina propria in bronchial mucosa before and after treatment with CS. Symbol: !, mean values. Abbreviation: NS, not significant. Source: From Ref. 49.

Figure 8 Effect of cromolyn sodium (CS) on individual cell counts of EG2+ eosinophils, NP 57+ neutrophils, and AA1+mast cells expressed as number of cells per square millimeter of lamina propria in bronchial mucosa before and after treatment with CS. Symbol: !, mean values. Abbreviation: NS, not significant. Source: From Ref. 49.

A study in human lung mast cells demonstrated that CS is a weak inhibitor of histamine release when given 15 minutes before allergen challenge. CS effectiveness is inversely related to the intensity of immunologic stimulation (8). At a concentration of 1000 mM, cromolyn inhibits histamine release by 25% and PGD2 release by 85%. Since PGD2 is a potent bronchoconstrictor, this may be an important effect of cromolyn. Church et al. (8) reported that the inhibitory effects of cromolyn on human mast cells are increased with a longer preincubation time. However, human skin mast cells are unresponsive to cromolyn, which is further supported by previous observations that cromolyn does not inhibit mast cell degranulation or the wheal and flare response in vivo.

Nedocromil and cromolyn have been shown to inhibit the release of preformed (granule associated) and newly generated eicosanoid mediators from activated eosinophils. These specific proteins are eosinophil granule-associated peroxidase and eosinophilic cationic protein (54). In rat mono-cytes and peritoneal macrophages, as well as in human monocytes and alveolar macrophages, nedocromil has been reported to inhibit FceR2-mediated activation (55,56). Bruijnzeel et al. (57) reported that nedocromil blocked the chemotactic response of eosinophils to PAF and leukotriene B4 (LTB4). In the human airway, nedocromil has been reported to decrease IL-6 and lysosomal enzyme release from alveolar macrophages (7). In addition, nedocromil reduces histamine and tryptase release five minutes after allergen challenge in bronchial segments of allergic asthmatic patients. This is accompanied by a reduction of eosinophils in BAL fluid 48 hours after challenge (58). A longer-term study comparing 16 weeks of treatment with nedocromil versus regular albuterol showed a reduction in the number of activated eosinophils in those patients treated with nedocromil on bronchial biopsy (59). Furthermore, nedocromil decreases the release of TNF-a, IL-8, and soluble ICAM-1 from human bronchial epithelial cells (7).

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