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).