Abstract
We aimed at evaluating the anti-asthmatic effect of cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3 (FOR811A), a nitrosyl-ruthenium compound, in a murine model of allergic asthma. The anti-asthmatic effects were analyzed by measuring the mechanical lung and morphometrical parameters in female Swiss mice allocated in the following groups: untreated control (Ctl+Sal) and control treated with FOR811A (Ctl+FOR), along asthmatic groups untreated (Ast+Sal) and treated with FOR811A (Ast+FOR). The drug-protein interaction was evaluated by in-silico assay using molecular docking. The results showed that the use of FOR811A in experimental asthma (Ast+FOR) decreased the pressure-volume curve, hysteresis, tissue elastance, tissue resistance, and airway resistance, similar to the control groups (Ctl+Sal; Ctl+FOR). However, it differed from the untreated asthmatic group (Ast+Sal, p<0.05), indicating that FOR811A corrected the lung parenchyma and relaxed the smooth muscles of the bronchi. Similar to control groups (Ctl+Sal; Ctl+FOR), FOR811A increased the inspiratory capacity and static compliance in asthmatic animals (Ast+Sal, p<0.05), showing that this metallodrug improved the capacity of inspiration during asthma. The morphometric parameters showed that FOR811A decreased the alveolar collapse and kept the bronchoconstriction during asthma. Beyond that, the molecular docking using FOR811A showed a strong interaction in the distal portion of the heme group of the soluble guanylate cyclase, particularly with cysteine residue (Cys141). In summary, FOR811A relaxed bronchial smooth muscles and improved respiratory mechanics during asthma, providing a protective effect and promising use for the development of an anti-asthmatic drug.
Highlights
Asthma is a respiratory condition characterized by intense inflammation and hyperreactivity of the airways, leading to a significant increase in mucus secretion and respiratory resistance [1]
The animals were allocated to four experimental groups (n = 10 each): untreated control receiving saline solution (Ctl+Sal); control treated with FOR811A (Ctl+FOR); untreated asthmatic receiving saline solution (Ast+Sal); asthmatic treated with FOR811A (Ast+FOR)
These findings showed that this metallocompound changed the pressure-volume curve (PV) curve in asthmatic condition (Ast+FOR), making it similar to that observed in the control groups (Ctl+Sal; Ctl+FOR)
Summary
Asthma is a respiratory condition characterized by intense inflammation and hyperreactivity of the airways, leading to a significant increase in mucus secretion and respiratory resistance [1]. Granulocytes–eosinophils, lymphocytes, macrophages, and mast cells–are activated triggering contraction of the airway smooth muscle, in addition to microvascular leakage and mucus secretion [2, 3]. SS-agonists, anti-inflammatories, and inhaled bronchodilators [7, 8] are examples of drugs available to control the disease. Severe cases [9] are more difficult to control because said drugs may not be responsive, even at high doses [6, 10], which justifies the need for effective therapeutic alternatives
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