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).