6.1 Roflumilast and lung inflammation
Clinical trials reported that oral administration of roflumilast could suppress airway inflammation and improve lung function of COPD patients. In addition, it is documented to be effective in reducing the frequency of disease exacerbations when given as add-on to inhaled therapy in patients with moderate or severe COPD (Shen et al., 2018). As regards asthmatic patients, roflumilast could also significantly increase the forced expiratory volume in 1 s (FEV1) and improved airway inflammation (Bateman et al., 2006).
The anti-inflammatory mechanisms of roflumilast can be contributed to its PDE4 inhibiting activity; leading to an increase in cAMP concentration and signaling within the epithelial airway and inflammatory cells. The action which in turn will enable roflumilast to suppress the expression of pro-inflammatory cytokines as IL-6 and TNF-α (Feng et al., 2017). Moreover, another study of cigarette smoke-induced pulmonary inflammation in guinea pigs showed that roflumilast could effectively reduce the numbers of neutrophils, lymphocytes and eosinophils in bronchoalveolar lavage fluid (Fitzgerald et al., 2006).
For COPD patients, roflumilast was represented to exert a significant role in reducing eosinophil cell counts within their bronchial biopsy samples and sputum (Rabe et al., 2018), in addition to its direct suppressing effect on neutrophils function and their ROS production. As a result of elevating cAMP level, roflumilast could inhibit neutrophil chemotaxis and degranulation. cAMP could directly activate protein of Epac1, which in turn could suppress neutrophil migration as well as oxidative burst. Furthermore, cAMP could also activate protein kinase A (PKA) in neutrophils, leading to a decline in their phagocytic activity (Dunne et al., 2019).
Some in-vivo and in-vitro studies revealed that roflumilast can potently reduce the endothelial permeability and suppress the leukocyte–endothelial cell interactions through altering the expression of adhesion molecules and attenuating the upregulation of PMNL surface CD11b, that may be stimulated either by fMLP or platelet-activating factor (PAF). The action that could inhibit neutrophils adhesion to endothelial cells (Sanz et al., 2007). Additionally, results fromin-vitro studies of human neutrophils showed that roflumilast could prevent the release of neutrophil elastase, matrix metalloproteinase and myeloperoxidase, inhibiting neutrophil function (Jones et al., 2005)
A synergistic effect of roflumilast with other anti-inflammatory agents such as corticosteroids or long-acting β2-agonists have been demonstrated (Kawamatawong, 2017). It was concluded that roflumilast-N-oxide (RNO), the active metabolite of roflumilast, could enhance the anti-inflammatory effect of dexamethasone in airway smooth muscle cells in-vitro (Patel et al., 2017). At the same time, roflumilast was reported to reverse the corticosteroid-associated insensitivity towards neutrophils in COPD patients (Milara et al., 2015b). As well, other study revealed the great value of roflumilast in restoring the glucocorticoid sensitivity in glucocorticoid-resistant patients through blocking the downregulation of glucocorticoid receptor alpha (GRα), which was known to be responsible for glucocorticoid resistance (Reddy et al., 2020).