Effect of Inhaled Cyclosporin on the Rat Airway: Histologic and Bronchoalveolar Lavage Assessment

Abstract

Airway inflammation plays a pivotal role in asthma. Over the last 10 years, evidence has accumulated for the potential role of lymphocytes in airway inflammation. Since cyclosporin A (Cyc-A) can profoundly influence lymphocyte activation, it is appropriate to consider this drug as a novel antiasthmatic. The effect of inhalation of low doses of Cyc-A on airway inflammation remains unclear. The purpose of this study was to investigate the bronchoalveolar lavage (BAL), peripheral blood cell profiles, and lung biopsy specimens in Cyc-A-pretreated rats. Twenty-nine rats (8 controls, 10 ovalbumin sensitized, and 11 Cyc-A inhaling and ovalbumin sensitized) were included in the study. A commercial intravenous Cyc-A solution was given as a single dose of 20 mg/kg 1 h prior to inhalation of ovalbumin via nebulizer. The total number of BAL cells significantly increased in rats inhaling Cyc-A when compared with ovalbumin-sensitized rats (2.37 ± 2.34 × 10⁶/ml and 1.01 ± 0.49 × 10⁶/ml respectively, p < 0.05). There was a significant increase in the percentage of lymphocytes (14.5 ± 8.5 versus 27.4 ± 7.4%, p < 0.03), a nonsignificant increase in the percentage of eosinophils (0.8 ± 1.0 versus 3.0 ± 4.6%), and a significant decrease in the percentage of polymorphonuclear leukocytes (9.4 ± 6.9 versus 3.4 ± 3.8%, p < 0.01) and macrophages (75.4 ± 5.1 versus 50.2 ± 11.8%, p < 0.02) in BAL in the ovalbumin-sensitized group as compared with controls. Differential cell counts revealed a higher percentage of neutrophils and macrophages in the BAL of Cyc-A-pretreated rats than in that of the ovalbumin-sensitized group (26.3 ± 26.8 versus 3.4 ± 3.8%, p < 0.01 and 66.1 ± 7.7 versus 50.2 ± 11.8%, p < 0.02). There was a nonsignificant decrease of lymphocytes and eosinophils in the Cyc-A-pretreated group when compared with the ovalbumin-sensitized group (27.4 ± 7.4 versus 21.1 ± 12.4 and 3.0 ± 4.6% versus 2.4 ± 2.6%). The peripheral blood total white blood cell count decreased in the ovalbumin-sensitized and Cyc-A-pretreated groups as compared with the control group (2,520 ± 1,098/mm³, 3,591 ± 2,251/mm³, and 5,975 ± 2,787/mm³, respectively, p < 0.01). In addition, peripheral eosinophilia was detected in the Cyc-A-pretreated group when compared with controls and the ovalbumin-sensitized group (6.9 ± 4.7, 2.4 ± 1.1, and 2.6 ± 2.4%, respectively, p < 0.01). Light-microscopic examination of the airways revealed prominent eosinophilia in tracheal, bronchial, and bronchiolar sections in the ovalbumin-sensitized group: counts were 1.8 ± 2.3/HPF, 10.3 ± 11.4/HPF, 63.3 ± 45.0/HPF, respectively. Cyc-A resulted in a decrease of the eosinophil counts/HPF to 0/HPF in trachea (p < 0.05), to 4.3 ± 9.4/HPF in bronchi (p < 0.02), to 19.4 ± 38.4 in bronchioles (p < 0.004).In conclusion, the present study supports the theory that locally administered inhaled low-dose Cyc-A is effective on inflammatory cells of sensitized airways and peripheral cells. It may therefore be useful in elucidating the inflammato...

Comparative evaluation of anti-inflammatory properties of thymoquinone and curcumin using an asthmatic murine model

“…Inflammatory changes were expressed as scores of eosinophils, this semiquantitative scale was from 0 to 3 (0 = no, 1 =mild, 2 =moderate, 3 = marked) for each cell type. The total inflammation score for each animal was calculated as the mean of the scores for 6 lungs [9]. Also plasma cells in lung tissue were assessed by giving a score using the same semiquantitative scale.…”

Cyclosporin a Reduces Airway Mucus Secretion and Mucociliary Clearance in Rats

“…3 Cyclosporin A (CsA) is one of the most important immunosuppressants used in lung transplantation. [4][5][6] Although the molecular events have not yet been completely defined, some studies indicate that CsA blocks the initial stages of lymphocyte activation, 7,8 inhibiting the production of interleukin-2 and other lymphokins. 9,10 Theoretically, the mechanism of action of CsA includes an influence on cytoplasmatic calcium, which is an essential component for normal cellular function.…”

A cyclosporin A/maltosyl- -cyclodextrin complex for inhalation therapy of asthma

“…However, the oral medication of asthmatic patients with CsA is limited because of systemic side-effects [1]. In order to avoid this risk, the direct administration of CsA to the lung has been investigated in animals [2]. Generally, nebulisation of a liquid formulation of CsA has been used for the inhalation of CsA [3].…”

“…The liquid formulations of CsA aerosol for delivery to the lung are solutions of the drug that contain organic solvents and surfactants, such as ethanol, polyethylene glycol, propylene glycol or Cremophor EL [3]. Although the nebulising CsA solution for an intravenous application containing ethanol and caster oil as the vehicle is able to attenuate eosinophil and lymphocyte infiltration into the airway lumen, neutrophilia in the bronchoalveolar lavage (BAL) fluid is induced by the irritant properties of the ingredients of commercial products, such as castor oil or ethanol in ovalbumin (OA)-sensitised rats [2]. Therefore, the liquid formulation of CsA aerosol is limited due to its local irritant potency.…”