Fibrosis, also known as fibrotic scarring, is a pathological wound healing that leads to considerable tissue remodeling and the formation of permanent scar tissue. There are many different types of fibrosis, including idiopathic pulmonary fibrosis, cirrhosis, cardiac fibrosis, renal fibrosis and more. The prevalence of idiopathic pulmonary fibrosis estimates in the USA varied between 14 and 27.9 cases per 100,000 population using narrow case definitions, and 42.7 and 63 per 100,000 population using broad case definitions (Nalysnyk et al, 2012). Ramatroban (Elpidazo) is a promising treatment for fibrosis which affects the lives of millions of people.
Prostaglandin D2/DP2 Receptor Antagonism
DP2 agonism has been shown to exacerbate allergic asthma and atopic dermatitis (Brightling et al, 2020; Simon et al, 2004; Aceves et al, 2009; Kouro et al, 2009; Gourh et al, 2009). The activation of the PGD2/DP2 axis has been shown to lead to pro-inflammatory events including eosinophil activation and migration, release of the type 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13 from T helper 2 (Th2) cells and innate lymphoid cells type 2 (ILC2), and increased airway smooth muscle mass via recruitment of mesenchymal progenitors in the airway smooth muscle bundle (Brightling et al, 2020). Type 2 cytokines have broad effects on the cells and tissues of the inflammatory pathways. IL-5 is upregulated in allergic rhinitis, atopic dermatitis, scleroderma, and idiopathic pulmonary fibrosis thus leading to eosinophilia (Gandhi et al, 2017; Brunner et al, 2017). IL-4 and IL-13 have in important role in the pathogenesis of chronic sinusitis with nasal polyps and atopic dermatitis, and eczema-like features (Akhurst et al, 2012). ILC2 and Th2 activation via the DP2 receptor leads to the release of IL-13, which upregulates MDSCs (Trabanelli et al, 2017). Continuing on this downstream pathway, MDSCs are major producers of transforming growth factor-β (TGF-β) (Salminen et al, 2019). TGF-β, in turn leads to further activation of MDSCs, thereby forming a "vicious cycle" (Lee et al, 2018). TGF-β plays a major role in fibrosis, including but not limited to systemic sclerosis, scarring, focal segmental glomerulosclerosis, myelofibrosis, idiopathic pulmonary fibrosis, diabetic kidney disease induced fibrosis, skin fibrosis, and Marfan’s syndrome (Meng et al, 2016). For example, TGF-β1 is an important key factor in the transition phase from salivary gland chronic inflammation to fibrotic disease (Zhang et al, 2020). Ramatroban will block the effect of DP2 mediated activation of ILC2 cells or any type 2 response or cytokine release.
PGD2 can also inhibit TGF-β-induced collagen secretion via intracellular cAMP accumulation through the DP1 receptor (Ayabe et al, 2013). Additionally, DP1 agonism was found to reduce lung fibrosis by inhibiting basal and TGF-β- induced fibroblast proliferation (van den Brule et al, 2010). Ramatroban is not a DP1 antagonist, but blocking the DP2 receptor with ramatroban may increase PGD2 bioavailability and subsequent agonism of the DP1 receptor (Ishizuka et al, 2006). Therefore, ramatroban will, in part, mitigate and/or prevent the pro-fibrotic role of TGF-β in fibrotic disease states and conditions.
SLE and Scleroderma
Systemic scleroderma is a progressive, rare disease that causes fibrosis not only in the skin but also in tissues throughout the body, including the heart, lungs and kidneys. Pulmonary disease is a complication that has a particularly high incidence, and interstitial pneumonia has been reported as a major cause of death in patients with systemic scleroderma. Currently, there is no curative treatment for systemic scleroderma, only symptomatic treatment of skin and lung symptoms.
Systemic sclerosis is often considered a Th2 cytokine disease with increased type 2 cytokines, including IL-4, IL-5, and IL-13 (Gourh et al, 2009; Mavalia et al, 1997). CCR5/DP2 ratio is low in systemic scleroderma and even more so in systemic scleroderma with interstitial lung disease, indicating increased Th2 polarization (Boin et al, 2008). Furthermore, eosinophilia is a common feature of systemic sclerosis and often circulating levels of eosinophil cationic protein are markedly increased (Gustafsson et al, 1991). IL-4 induces adherence of human eosinophils and basophils to the endothelium by upregulating adhesion molecules, including VCAM-1, ELAM-1, and ICAM-1 (Schleimer et al, 1992). IL-5 is also known to upregulate eosinophil numbers and is critical in regulating expression of genes involved in the growth, survival, and effector function of eosinophils (Takatsu et al, 2008). In fact, IL-5 upregulation in allergic rhinitis, atopic dermatitis, scleroderma, and idiopathic pulmonary fibrosis thus leading to eosinophilia (Brightling et al, 2020; Simon et al, 2004; Aceves et al, 2009; Kouro et al, 2009; Grouh et al, 2009). Therefore, blocking the maladaptive type 2 immune response with ramatroban via the DP2 receptor may mitigate inflammation and promote recovery.
Despite hypoxia and vascular injury, there is a severe dysregulation of angiogenesis in systemic sclerosis (Cantatore et al, 2017). It has been proposed oxidative stress leads to generation of 8-isoprostane which activates TP receptors leading to inhibition of VEGF-induced migration of endothelial cells and thereby inhibition of angiogenesis (Tsou et al, 2015). It is notable that the role of TP receptor agonism remains controversial with some reports concluding that the TP receptor promotes angiogenesis while others conclude that the TP receptor inhibits angiogenesis (Ashton et al, 2004; Nie et al, 2000). Therefore, TP receptor agonism and subsequent RhoA activation may lead to decreased angiogenesis in scleroderma, which can be reversed with a TP receptor antagonist such as ramatroban.
Sepsis and Septic Shock
Neutrophil extracellular traps (NETs) protect against infection, in particular by large pathogens, but they are also implicated in the pathology associated with a growing number of immune-mediated conditions (Papayannopoulos et al, 2017). When neutrophil extracellular traps (NETs) circulate at high levels in the blood, they can trigger the occlusion of small vessels, leading to damage in the lungs, heart, and kidneys (Barnes et al, 2020; Cedervall et al, 2015; Fuchs et al, 2010; Thalin et al, 2019; Martinod et al, 2014). For example, in severe coronary artery disease, complexes of NETs are elevated, and NET levels positively associate with thrombin levels, which predict adverse cardiac events (Borissoff et al, 2013). Some conditions and diseases that contain NET formation include, but not limited to, preeclampsia, small vessel vasculitis, systemic lupus erythematosus, lupus nephritis, cystic fibrosis, ARDS, and even COVID-19. In mouse models of septicemia, intravascular NETs form microthrombi that obstruct blood vessels and cause damage to the lungs, liver, and other organs. Autopsy samples collected from septic patients show that NETs infiltrate microthrombi (Jiménez-Alcázar et al, 2017). In animal model of endotoxic shock in male rats all rats died within 48 hours after endotoxin challenge. Endotoxin shock mice had systemic hypotension, damage of the gastric mucosa consisting of hemorrhagic infiltrates, depressed phagocytosis, increased blood levels of TNF-α, TxB2, and 6-keto-PGF1α, reduced white blood cell count, and enhanced myeloperoxidase activity in the ileum, heart and lungs. Administration of ramatroban, 30 min before endotoxin challenge, increased the survival rate by 45%. Ramatroban also reduced hypotension, decreased TNF-α levels in serum, enhanced phagocytic activity, and lowered myeloperoxidase activity in the ileum, heart, and lung. Gastric alterations were also significantly reduced with ramatroban pre-treatment (Altavilla et al, 1994).
Community Acquired Pneumonia
Pneumonia is a type of lung infection. It can cause breathing problems and other symptoms. In community-acquired pneumonia (CAP), you get infected in a community setting. It doesn’t happen in a hospital, nursing home, or other healthcare center.