Cyclosporin A increases the pulmonary eosinophilia induced by inhaledAspergillusantigen in mice

Abstract

SUMMARYWe evaluated the effects of anti-inflammatory drugs in a murine model of allergic bronchopulmonary aspergillosis(ABPA). Mice instilled with 100 iigof Aspergi/lu.v fumigatu.s antigen (intranasally, 3 days a week for 3 weeks) developed pulmonary lesions, characterized by a perivascular and pcribronchial eosinophil infiltration, a bronchoaiveoiar Iavage (BAL) eosinophilia, and elevated levels of tolal IgE, total igGI and A. fumigatus-spccific IgGl, Under the same conditions, groups of mice receiving a daily dose of 2 mg/kg dexamcthasone showed decreased numbers oi' eosinophils and lolal cells in BAL, had less numerous eosinophils in their pulmonary infiltrates, and had lower levels ofserum and BAL fluid total IgE, total IgGl and A. fumigatu.s-spec\fic IgGl. Conversely, groups of mice pretreated with an immunosuppressive agent, cyclosporin A (CsA)at adoseof 5()mg/kg, three times per week, developed pulmonary lesions with enhanced lung cosinophilic influx and increased total IgE levels, both in serum and in BAL lluid. These findings show thai dexamelhasone polenlly prevents the murine immunopathologic response to A. fumigatus. The eflect of CsA on this inflammatory response was paradoxical, insofar as it suggests an activation ofthe T helper 2 subset, which Lip-rcguiales cosinophii recruitment and IgK production.Keywords Aspergitlus fumigaius pulmonary eosinophilia dexamcthasonc cyclosporin A total and specific hypergammaglobuUnaemia ABPA

Potentiation ofin vitrosynthesis of human IgE by cyclosporin A (CsA)

“…and CsA has been reported to enhance murine IgE production both in vivo [9] and in vitro [10]. More recently, CsA has been shown to increase pulmonary eosinophilia induced by inhaled Aspergillus antigen in mice [11] and markedly potentiate both splenomegaly and hyper-IgE production in a 'Th2-Iike' murine chronic graft-vfri»i-host (GVH) response [12].…”

Increased expression of intercellular adhesion molecule-1 (ICAM-1) in a murine model of pulmonary eosinophilia and high IgE level

“…Eosinophils may act as effector cells through the release of certain pro-inflammatory mediators, and as modulator cells through the production of cytokines such as IL-3, IL-5, TNF, GM-CSF, etc. [2][3][4][5]. In Af-challenged mouse lung tissue, the eosinophil and T lymphocyte count was significantly increased.…”

“…Its receptor on leucocytes is the ,'i-1 iniegrin, very late anligen-4 (VLA-4). Lymphocytes, monocytes and eosinophils have been shown to bind to VCAM-1 [4]. Eosinophils can express VLA-4, and a MoAb against this integrin has been shown to specifically inhibit eosinophil but not neutrophil adhesion to IL-I-stimulated human umbilical vein endotheiial cells [24].…”

“…Induction of ABPA Induction of ABPA was performed as previously described [4]. Briefly, the mice were lightly anaesthetized with diethyl ether, and 50^1 of A. fumigaius antigen (100/ig in dry weight) (Af group) or 50 ^1 saline (Sa group) were administered to the tip of the nose and inhaled involuntarily.…”

“…It can damage tissues by the release of granule-associated basic proteins, eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil peroxidase and eosinophil-derived neurotoxin, and oxygen radicals, and can modulate the inflammatory process by producing mediators and cytokines, such as leukotriene C4, platelet-activating factor (PAF), IL-1, IL-3, IL-5, IL-6, GM-CSF, transforming Correspondence: Michel Laviolettc, Centre de Pneumologie, Hopilal Laval, 2725 Chemin Sle-Foy, Ste-Foy, Quebec, Canada GIV 4G5. growth factor-alpha (TGF-a), TGF-/3 and tumour necrosis factor (TNF) [2][3][4][5].…”