Organ Fibrosis
Organ fibrosis is a pathological process characterized by the excessive accumulation of extracellular matrix (ECM) proteins, leading to the scarring and hardening of tissues. This condition can affect various organs, including the liver, lungs, kidneys, and heart, and is often the result of chronic inflammation or injury. In the developed world, organ fibrosis is a significant health concern, contributing to nearly 45% of all deaths due to its association with chronic diseases such as liver cirrhosis, idiopathic pulmonary fibrosis (IPF), and chronic kidney disease. The incidence and prevalence of organ fibrosis are on the rise, driven by factors such as aging populations, increased rates of metabolic disorders, and chronic infections. In general, organ fibrosis and resulting organ failure are estimated to be responsible for at least a third of all disease-related deaths worldwide. In addition to being a major social burden, organ fibrosis also represents an immense economic burden for all nations’ healthcare systems. Despite its widespread impact, effective treatments for organ fibrosis remain limited, with current therapies primarily focused on slowing disease progression rather than reversing fibrosis. This highlights the urgent need for novel therapeutic strategies that can address the underlying mechanisms of fibrosis and improve patient outcomes.
Pulmonary Fibrosis
All pulmonary fibrosis (PF), including idiopathic pulmonary fibrosis (IPF), is characterized by a progressive phenotype, rapidly leading towards devastating consequences for patients and their families. PF relentlessly generates severe loss of lung function, impaired quality of life and often poor survival prognosis.
Understanding Idiopathic Pulmonary Fibrosis (IPF)
Idiopathic Pulmonary Fibrosis (IPF) is a rare, chronic, and progressive lung disease of unknown origin, in which progressive lung scarring occurs in the supporting framework (interstitium) of the lungs, significantly impacting both the physical and emotional well-being of patients. Characterized by the irreversible loss of lung function due to fibrosis, IPF manifests as worsening symptoms such as persistent cough, dyspnea, and a severely impaired quality of life.
For many years, IPF was considered a principally inflammatory disease, given the increase in inflammatory cells in the lungs. However, a growing body of evidence indicates that IPF is an epithelial-driven disease whereby an aberrantly activated lung epithelium produces mediators of fibroblast migration, proliferation and differentiation into active myofibroblasts. These myofibroblasts secrete exaggerated amounts of extracellular matrix (ECM) that subsequently remodel the lung architecture.
Despite recent therapeutic advancements, current IPF treatments primarily focus on slowing disease progression rather than reversing it, leading to a poor prognosis with a median survival of just 2-3 years if left untreated. As a result, the disease imposes a considerable burden on healthcare systems and contributes to significant socioeconomic costs.
Challenges in Diagnosing and Treating IPF
Lung transplantation remains the only definitive treatment for IPF but is accessible to only a minority of patients. Most patients rely on antifibrotic therapies combined with various supportive and palliative treatments. However, these therapies merely slow down the progression of the disease rather than offer a cure. The accurate diagnosis of IPF is crucial yet challenging, often requiring the observation of specific clinical characteristics along with confirmation through high-resolution chest imaging or, in some cases, lung biopsy. The lack of precise diagnostic procedures can lead to the inclusion of patients under a broad, non-specific case definition, thereby complicating the understanding of the disease’s true prevalence and incidence.
Epidemiology and the Global Impact of IPF
Estimating the epidemiology of IPF is complex due to variations in data sources and definitions used in studies. For instance, estimates derived from claims databases can differ drastically depending on whether specific or non-specific case definitions are applied. Furthermore, epidemiological studies can be misleading if they do not consider factors such as age, sex, and other risk factors. The average age of IPF patients is around 65-70 years, with incidence rates increasing with age. Additionally, IPF affects males more than females, and several risk factors, including smoking, exposure to metal or wood dust, and genetic predispositions, have been linked to the development of the disease.
Globally, the number of IPF patients (3 million in 2017) is on the rise, potentially due to an aging population, increased disease awareness, and improved diagnostic tools. However, substantial heterogeneity exists between studies estimating the incidence and prevalence of IPF, owing to diagnostic challenges, updated criteria, and methodological differences. This variability impacts the overall understanding of the global burden of IPF, making it critical to re-evaluate published data regularly. A detailed understanding of IPF’s incidence and prevalence is essential for therapeutic development and healthcare system planning, particularly in light of the disease’s significant socioeconomic impact.
Understanding Liver Fibrosis and Its Challenges
Chronic liver diseases represent a significant global health burden, accounting for approximately 2 million deaths annually worldwide. These diseases stem from various underlying causes, including viral infections (Hepatitis B and C), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), as well as autoimmune and genetic disorders. A key feature of chronic liver disease is the development of liver fibrosis, which plays a central role in determining both the quality of life and prognosis for affected individuals. Liver fibrosis is marked by the progressive accumulation of extracellular matrix (ECM), which disrupts the normal architecture of the liver, impairs liver function, and significantly increases the risk of hepatocellular carcinoma (HCC). Furthermore, liver fibrosis leads to chronic portal hypertension, a major contributor to clinical complications such as fluid accumulation (hydropic decompensation), bleeding events, and hepatic encephalopathy. As a result, liver cirrhosis, a severe form of fibrosis, is currently the 11th leading cause of death globally and the fourth most common cause of death among adults in Central Europe.
The Mechanisms Behind Liver Fibrosis
Liver fibrosis is driven by the body’s response to chronic liver injury, whether due to toxic, metabolic, or viral factors. Damage to hepatocytes (liver cells) triggers an inflammatory response, leading to the infiltration of immune cells and the activation of hepatic stellate cells (HSCs). These HSCs undergo trans-differentiation into collagen-producing myofibroblasts, which are responsible for the excessive production of ECM. Normally, in response to short-term injury, this fibrotic process is balanced by anti-fibrotic mechanisms that inactivate or induce apoptosis in myofibroblasts, leading to scar resolution. However, in chronic liver disease, this balance is disrupted, resulting in the persistent activation of proliferating, contractile, and migrating myofibroblasts, which leads to the excessive deposition of ECM and the progression of fibrosis.
Challenges in Treating Liver Fibrosis
The progression of liver fibrosis is primarily regulated by non-parenchymal cells (NPCs), including Kupffer cells and other immune cells. Hepatocyte apoptosis and the release of damage-associated molecular patterns (DAMPs) not only directly activate HSCs but also recruit and activate lymphocytes and macrophages. These immune cells further promote HSC trans-differentiation and myofibroblast activation by producing pro-inflammatory and pro-fibrogenic cytokines. However, distinct macrophage subpopulations also play a role in fibrosis resolution by expressing matrix metalloproteinases (MMPs), which break down ECM. The complexity of liver fibrosis is further compounded by a network of cytokine-induced signaling pathways, including Transforming Growth Factor Beta (TGF-β), Platelet-Derived Growth Factor (PDGF), the NLRP3 inflammasome-Caspase1 pathway, and WNT/β-catenin signaling. These pathways are central to the activation of HSCs and the progression of fibrosis.
Given the intricate and multifaceted nature of liver fibrosis, developing effective therapies remains a significant challenge. Current treatment options are limited, and the successful reversal of fibrosis requires novel approaches that can target multiple aspects of the disease simultaneously. The need for such innovative therapies is underscored by the general, etiology-independent mechanisms that drive fibrosis development across different chronic liver diseases.
Epidemiological studies show that chronic kidney disease (CKD) affects more than 10% of the world’s population. With renal disease progression, the final common pathway is kidney fibrosis. Kidney fibrosis is a complex and progressive condition characterized by the excessive accumulation of extracellular matrix (ECM) components, leading to the scarring and hardening of kidney tissue. This pathological process often results from chronic kidney disease (CKD), where ongoing injury and inflammation trigger the activation and proliferation of myofibroblasts. These cells, originating from various sources such as fibroblasts, pericytes, and possibly bone marrow-derived cells, are central to the development of fibrosis due to their role in producing ECM proteins like collagen.
The activation of these myofibroblasts is largely mediated by cytokines and growth factors released by damaged renal epithelial cells, infiltrating immune cells, and other stromal cells. Transforming growth factor-beta (TGF-β) is one of the most potent pro-fibrotic cytokines, driving myofibroblast activation and ECM production. Other factors, such as platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and inflammatory mediators like the NLRP3 inflammasome, also play significant roles in the fibrotic response by perpetuating inflammation and fibrosis. The continuous activation of these signaling pathways leads to a vicious cycle of tissue injury, inflammation, and fibrosis, ultimately resulting in the irreversible loss of kidney function. This underscores the urgent need for novel, targeted therapies that can effectively interrupt the fibrotic process at multiple levels, ultimately preventing or reversing kidney fibrosis.