PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells

Abstract

Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrowderived MCs (bmMCs), human LAD2-and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3 −/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease.

Mechanisms of Allergen Immunotherapy in Allergic Rhinitis

“…Following the allergen cross-linking of adjacent IgE molecules, the mediator release from intracytoplasmic granules in the airway is orchestrated by phosphodiesterase 3 which mediates intracellular signaling of cGMP and cAMP [47]. The contents released include histamine, tryptase, cysteinyl leukotrienes and prostaglandin D2 [43,47]. Notably, overexpression of CD300c, which acts in a co-stimulatory manner for IgE-dependent basophil activation, is seen in patients with AR [48].…”

(Oral) enoximone in asthma

“…Enoximone is a selective PDE-3 inhibitor; it causes an increase in cyclic adenosine monophosphate (cAMP) and in cyclic guanosine monophosphate (cGMP) in the cell, inhibiting entry of calcium ions, resulting in relaxation and subsequent bronchodilatation. Recently published papers show that enoximone has anti-inflammatory properties due to its effect on pro-inflammatory cytokines and inhibits primary human mast cell degranulation , thus reducing inflammation [ 7 , 8 ]. It also improves the mucosal barrier function, preventing vascular leakage, causing, in underlying cases, oedema, and is effective in reducing granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6 and tumour necrosis factor (TNF)-α production of epithelial cell cultures that boost an allergic immune response.…”

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia

“…20 SARS-CoV-2 may interfere with GPCR signaling pathways to dysregulate ion and fluid transport within the lungs. 33 Furthermore, PDE3-inhibitors prevent mast cell degranulation 26 and subsequent release of pro-inflammatory mediators (e.g. histamine, bradykinin, and LTs), which have been reported to contribute to SARS-CoV-2induced inflammation.…”