Mechanisms of epithelial damage: are there parallels between bullous skin diseases and asthma?

Dhami, D.; Shute, Janis K.

doi:10.1111/j.1365-2222.1994.tb02735.x

Cited by 6 publications

(1 citation statement)

References 31 publications

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“…Moreover, eosino–phils are believed to be of major importance in other inflammatory diseases such as connective tissue diseases of unknown origin, e.g. bullous dermatoses and hypereosino–philic syndromes [3, 4, 5]. Tissue damage and propagation of inflammation are thought to be mediated by the interaction between Th2–like T cells [6], antigen–presenting cells [7] and eosinophils [8, 9].…”

Section: Introductionmentioning

confidence: 99%

The CC Chemokine Receptor Antagonist Met–RANTES Inhibits Eosinophil Effector Functions

Elsner

Petering²,

Kimmig³

et al. 1999

Int Arch Allergy Immunol

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Eosinophils play an important role in allergic diseases such as allergic asthma, rhinoconjunctivitis and atopic dermatitis. Recruitement of eosinophils to the side of inflammation, the release of reactive oxygen species, leading to tissue damage, and the propagation of the inflammatory response are mediated by chemokines. Thus, the applicability of agents able to inhibit or antagonize chemokine–induced eosinophil activation seems to be of interest in the treatment of allergic diseases. Therefore, the effect of the CC chemokine antagonist, Met–RANTES, on its effect on human eosinophil effector functions in response to RANTES, MCP–3 and eotaxin was investigated. Met–RANTES had no intrinsic activity on [Ca²⁺]_i transients in eosinophils and was able to dose–dependently inhibit [Ca²⁺]_itransients in eosinophils following stimulation with RANTES, MCP–3 and eotaxin. Besides its effect on [Ca²⁺]_i transients, Met–RANTES dose–dependently inhibited actin polymerization in eosinophils and the release of reactive oxygen species following stimulation with RANTES, MCP–3 and eotaxin. The results of this study lead to the conclusion that Met–RANTES is an effective and powerful compound to antagonize effector functions of human eosinophils following stimulation with RANTES, MCP–3 and eotaxin and is therefore a promising therapeutic approach to prevent the invasion and destructive power of eosinophils in allergic diseases.

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Section: Introductionmentioning

confidence: 99%

The CC Chemokine Receptor Antagonist Met–RANTES Inhibits Eosinophil Effector Functions

Elsner

Petering²,

Kimmig³

et al. 1999

Int Arch Allergy Immunol

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Human eotaxin represents a potent activator of the respiratory burst of human eosinophils

et al. 1996

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Increased numbers of eosinophils are found in parasitic infections, autoimmune diseases and allergic diseases such as allergic asthma. They are activated by distinct cytokines and chemokines leading to the immigration in the inflamed tissue and mediate tissue damage by releasing reactive oxygen species. Here, the effect of the recently cloned CC chemokine human eotaxin was investigated for its ability to affect different eosinophil effector functions and compared to the CC chemokines MCP-3 and RANTES. Human eotaxin induced chemotaxis of human eosinophils in a dose-dependent manner. The range of efficacy of the CC chemokines compared to the well-known chemotaxin C5a was eotaxin = RANTES > MCP-3 = C5a. In addition, eotaxin induced rapid and transient actin polymerization, a prerequisite for cell migration, in eosinophils in the same range of efficacy as observed for chemotaxis. To investigate whether eotaxin was able to activate the respiratory burst of eosinophils, release of reactive oxygen species was measured by lucigenin-dependent chemiluminescence. Eotaxin induced production of significantly high amounts of reactive oxygen species at a concentration between 10 ng/ml and 500 ng/ml. Surprisingly, the effect of eotaxin was comparable to the well-known eosinophil activator C5a. The range of efficacy of the CC chemokines compared to C5a in the activation of the respiratory burst was eotaxin = C5a > MCP-3 > RANTES. Production of reactive oxygen species was inhibited by pertussis toxin, staurosporin, genestein and wortmannin. Furthermore, eotaxin induced transient increases in intracellular calcium concentration ([Ca2+]i) in human eosinophils. Therefore, pertussis toxin-sensitive Gi-proteins, protein kinase C, tyrosine kinase, phosphatidylinositol-3-kinase and transient increases in [Ca2+]i are involved in the signal transduction of eosinophils following stimulation with eotaxin. In summary, this study reveals the importance of the CC chemokine eotaxin as a potent activator of the respiratory burst, actin polymerization and chemotaxis. Eotaxin, therefore, plays an important role not only by attracting eosinophils to the site of inflammation but also by damaging tissue by its capacity to induce the release of reactive oxygen species.

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The CC chemokine antagonist Met‐RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3

et al. 1997

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Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by chemokines. Thus, agents that would be able to inhibit or antagonize chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a chemokine receptor antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through chemokine receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.

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Mechanisms of epithelial damage: are there parallels between bullous skin diseases and asthma?

Cited by 6 publications

References 31 publications

The CC Chemokine Receptor Antagonist Met–RANTES Inhibits Eosinophil Effector Functions

The CC Chemokine Receptor Antagonist Met–RANTES Inhibits Eosinophil Effector Functions

Human eotaxin represents a potent activator of the respiratory burst of human eosinophils

The CC chemokine antagonist Met‐RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3

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