Abstract
Airway remodeling plays an important role in the development of airway hyperresponsiveness in asthma. Muscarinic agonists such as carbamylcholine increased cyclic GMP (cGMP) levels in bovine tracheal smooth muscle strips, via stimulation of NO-sensitive soluble guanylylcyclase (NO-sGC), which is an enzyme highly expressed in the lungs. cGMP production, by activation of a NO-sGC, may contribute to airway smooth muscle relaxation. To determine whether the bronchoconstriction observed in asthma is accompanied by changes in this NO-sGC activity, we used a well-established murine model, ovalbumin-airway smooth muscle cells (OVA-ASMCs) of allergic asthma to evaluate such hypothesis. Histologic studies of trachea specimens showed the existence of inflammation, hyperplasia and tissue remodeling in OVA-ASMCs. Interestingly, cultured OVA-ASMCs showed lower GC basal activity than CONTROL-ASMCs. Also, we found that both OVA-ASMCs and CONTROL cells exposed to carbamylcholine and sodium nitroprusside and combinations of both drugs increased cGMP levels, which were inhibited by 1H-[1,2,4]oxadiazolo[4,3-] quinoxalin-1-one. All the experimental evidence suggests that NO-sGC activity is reduced in isolated ASMCss from experimental asthma murine model.
Highlights
Asthma is a chronic inflammatory disease that involves a reversible obstruction of the airways.[1]
Our results showed that NO-sensitive soluble guanylyl cyclase (sGC) activity is decreased in ASMCs from a well-established murine model of allergic asthma associated with rat sensitized and challenged with OVA
We found that all ASMCs exposed to a NO-donor compound as SNP and muscarinic agonist as carbamylcholine increased cyclic GMP (cGMP) intracellular levels, which were inhibited by ODQ, suggesting that sGC is the main guanylyl cyclase enzyme responsible for cGMP production in these ASMCs
Summary
Asthma is a chronic inflammatory disease that involves a reversible obstruction of the airways.[1]. These elements together are responsible for reversible obstruction of the airways and the clinical expression of asthma.[1,2,3] This chronic inflammatory process leads to structural changes in the bronchial wall, involving hypertrophy and hyperplasia of smooth muscle cells of airways (ASMCs)[2,3,4,5] as described above. “synthetic phenotype” exhibits increased mitogenic activity, and reduced staining for contractile proteins and more organelles biosynthesis.[13] Studies on phenotype modulation of smooth muscle cells led to the hypothesis that the phenomenon of “phenotypic plasticity” is not a simple artifact of cell culture but rather the ASMCs “in vivo” express a certain range of phenotypes. ASMCs either “in situ” or in culture should not be considered exclusively contractile or synthetic, but there is a balance between a heterogeneous population of synthetic and contractile cells.[13]
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