Keywords: Idiopathic pulmonary fibrosis, Management, Pulmonary
hypertension, Sotatercept
Introduction
Recent understanding of Idiopathic pulmonary fibrosis (IPF) states that
IPF is progressive disease of the lung interstitium that is mainly
represented by fibrous remodeling of the alveoli as well as gradual loss
of pulmonary function that is irreversible. The process is thought to be
an accumulation of extracellular matrix (ECM) over a long term.
Permanent inhibition of oxygen transfer occurs due to this accumulation,
which causes the symptom known as shortness of breath [1]. This
problem is seen to develop from the fibrous proliferation and remodeling
of tissue due to the faulty signaling and function of alveolar
epithelium and fibroblasts of the interstitium. Other factors that have
been implicated in the disease pathogenesis included cell-signaling
pathways activation by tyrosine kinases such as vascular endothelial
growth factor (VEGF). More growth factors include fibroblast growth
factor (FGF) and platelet-derived growth factor (PDGF). [2,3]
The major characteristics of the disease are cough and dyspnea which
both have a bad impact on the patients in terms of quality of life
[4,5] in addition to its effect on life expectancy, with a 3 years
median survival when left untreated [6]. What defines IPF is the
histopathological and radiological features of lung tissue described as
extensive deposition of the ECM that leads to changes in lung
architecture, increased alveolar wall thickness, and dilated bronchi
[7]. Cases of suspected IPF can be assessed by chest high-resolution
CT scan [8,9]. IPF has been found to be the most prevalent type of
interstitial lung diseases constituting about 17%–37% of all
interstitial lung diseases [10] which makes it mandatory to look for
the best treatments possible for the disease. For many years, the
management of patients with IPF was only symptomatic and for decades
now, the only way to cure IPF is lung transplantation, but in the last
decade, multiple drugs have been undergoing clinical trials aiming at
better outcomes in IPF patients. Until recently, only two of them have
been validated and proven effective in slower progression of IPF,
nintedanib and pirfenidone, while other management modalities are still
being tested for their effectiveness. In our study, we aim to address
the present and future therapeutic agents that reduce pulmonary fibrosis
by inhibiting or reducing fibroblast activity or intercept with cell
signaling pathway. We aim to provide healthcare professionals with
valuable insights to inform their clinical practice and inspire further
research in the field of IPF management.
Antifibrotic agents
Pirfenidone
A drug with antifibrotic properties used now for IPF is known as
Pirfenidone or PFD, is taken orally [11]. This drug is a synthetic
molecule that is small with a characteristic of rapid absorption in the
gastrointestinal tract and an estimated 3 hours half-life [12]. Its
metabolism is mainly by cytochrome P450, which occurs in the liver and
most of it is excreted in the form of 5-carboxy-pirfenidone in urine
(80%) or in feces (20%). PFD was found to have two effects on the
body, antifibrotic and anti-inflammatory effects [13]. PFD has an
inhibitory effect on the proliferation of fibroblasts as well as the
synthesis of collagen which is done through interfering with the
signaling of transforming growth factor-β, or (TGF-β), and other growth
factors, like basic fibroblast growth factor and platelet-derived growth
factor (PDGF) [14,15]. It has been shown that PFD is a strong
inhibitor of fibronectin and the production of α-smooth muscle actin
(α-SMA) which is known to have a role in fibro-myofibroblast transition,
when set with TGF-β. PFD has the ability to inhibit TGF-β mediated
fibrotic changes in human fetal lung fibroblasts [16,17].
PFD has also shown its anti-inflammatory effect following
allergen-induced pre-sensitization, decreasing airway responsiveness,
inflammatory cytokines, and cells in the bronchoalveolar fluid
[18,19]. Another study revealed that PFD might have the potential to
reduce the generation of pro-inflammatory cytokines by stopping the
action of p38 MAP Kinase in B lymphocytes, introducing a new potential
in PFD for lung fibrosis, as migration and activation of fibroblasts can
occur due to the inflammatory process started by B-cell-derived
cytokines [20]. While the ASCEND study examined PFD therapy for 52
weeks, the CAPACITY studies assessed its effectiveness and safety for a
minimum of 72 weeks. Adverse effects of PFD were found to be mostly
photosensitivity, nausea, skin rash, gastrointestinal upset, and
anorexia. Serious adverse effects included irregular liver function,
facial palsy, dizziness and hepatocellular tumor [21].
The approved dose of pirfenidone that is recommended in Asia is 1800 mg
per day, while 2403 mg per day is acceptable in Europe and the US
[22]. A study was conducted to evaluate the efficacy of lowered
doses of PFD in which the results showed that patients managed with a
lower dose of PFD had the same clinical outcomes compared to other
patients taking the standard-doses of PFD and so, minimizing the dose
could be helpful to maintain the therapeutic efficacy while managing the
adverse effects at the same time[22].
Nintedanib
Nintedanib or NDB is taken orally, and has antifibrotic activity by the
inhibition of tyrosine kinase receptors like FGFR, PDGFR, and VEGF
receptor، and thus inhibiting the signaling pathways of FGF, PDGF, and
VEGF which play a pivotal role in the pathogenesis of this disease
[23,3]. NDB also has Anti-inflammatory activities although still
needs full comprehension. Studies showed that it acts by the inhibition
of mediators, including IL-2, 4, 5, 10, 12p70,13, and IF-γ by
mononuclear cells in the peripheral blood or T-cells in the human body
[24]. NDB was first developed for anti-tumor purposes and was of the
first drugs labeled as FDA approved for IPF in the EU and USA along with
PFD, after the success of INPULSIS and INSTAGE trials (NDB showed
effectiveness in decreasing the decline in FVC) [25-28].
A 150 mg of NDB twice daily dose can provide a therapeutic effect close
to the maximum NDB effect regardless of disease condition or demographic
baselines for most patients with IPF [29].
Adverse effects of the drug were mainly diarrhea, nausea,
nasopharyngitis, cough, and vomiting [30]. As the elimination of the
drug is primarily (>90%) biliary/fecal, with a negligible
role of renal excretion [31], a lowered dose of 100 mg BID for
patients with mild hepatic problems or patients experiencing adverse
effects is advised [30].
Potential and Futuristic Drugs in the Management of
Idiopathic Pulmonary Fibrosis
Saracatinib
Saracatinib is a specific, strong inhibitor of the Src kinases that was
first developed for anti-tumor purposes[32]. Saracatinib has
demonstrated that it inhibits the induced increase in the activity of
Src kinase in fibroblasts by TGF-β[32]. Saracatinib’s efficacy in
treating IPF patients is currently under investigation by a Phase 1b/2a
clinical trial (STOP-IPF), as the safety profile is now already
established. Saracatinib inhibits sRC causing a decrease in the
signaling pathway of VEGF, FGF, PDGF, and EGF further decreasing RAS
activation, finally leading to the inhibition of the proliferation of
fibroblasts as well as its differentiation (figure 1).