Found 25 results
Review
23 October 2024The Notch3 Pathway in Organ Fibrosis
Fibrosis occurs in many organs, including the lung, heart, skin, liver or kidney, and is characterized by progressive tissue scarring in response to repetitive or chronic non-resolving injury, ultimately leading to organ failure and death. It is, in fact, a major cause of morbidity and mortality worldwide, being estimated to account for 45% of deaths in the world. Despite this fact, little progress has been made therapeutically, and fibrosis remains a major clinical and therapeutic challenge. Although significant advances in our understanding of cellular and molecular mechanisms driving tissue fibrosis have been made, the lack of an efficient treatment reflects the limited insight into the pathophysiological mechanisms underlying the initiation and progression of the fibrotic process. Thus, there is an urgent need for better understanding of tissue fibrosis and repair mechanisms that later lead to the development of new therapeutic approaches to fight fibrosis. The Notch pathway is a highly conserved signaling pathway that has been linked to tissue fibrosis in many organs and promises to open new therapeutic opportunities. This manuscript reviews the relevance of Notch signaling in the development and progression of tissue fibrosis in several organs with a special focus on the Notch3 pathway due to the unique features of this receptor.
Review
14 October 2024Sex and Gender Differences in Liver Fibrosis: Pathomechanisms and Clinical Outcomes
The accumulation of extracellular matrix proteins is the hallmark of liver fibrosis associated with all chronic liver disease (CLD) types. Liver fibrosis results from repeated bouts of liver injury, which trigger the wound-healing response, ultimately disrupting the normal hepatic architecture. Over time, fibrosis can progress to cirrhosis, portal hypertension, liver failure, and hepatocellular carcinoma, worsening patient outcomes. Biological modifiers, such as sex and socio-cultural constructs like gender, influence the development of liver fibrosis through various genetic, hormonal, immunological, metabolic, and lifestyle-related factors, including alcohol consumption, diet, sedentary behavior, and hormonal therapy. Moreover, liver fibrosis is significantly modulated by age, reproductive status, and the etiology of CLD. This review aims to summarize the most well-characterized pathomechanisms underlying sex and gender differences in hepatic fibrogenesis as well as liver-related complications (cirrhosis, portal hypertension, hepatic encephalopathy, liver failure, and hepatocellular carcinoma) and extra-hepatic correlates of liver fibrosis (sarcopenia, cardiovascular disease, diabetes, chronic kidney disease, and dementia) across various types of CLD due to viral-related, autoimmune, drug-induced and metabolic etiologies. Understanding these disease modifiers and their mechanisms is crucial for developing innovative treatment strategies and precision medicine approaches in this field.
Review
10 September 2024A Review of the Current Landscape of Anti-Fibrotic Medicines
Fibrosis is defined as the excessive accumulation and disorganized deposition of extracellular matrix components, affecting any organ in the human body. Fibrotic diseases of the vital organs such as lung, heart, kidney and liver can be chronic, progressive, irreversible and fatal. Although fibrotic diseases account for 45% of the mortality in the Western world, the available treatment options are limited in numbers, efficacy and safety. There is certainly a lack of progress in developing novel anti-fibrotics even though the market size for fibrotic diseases is estimated to be ~$30B and several pharmaceutical companies have active R&D programmes in this field. We reviewed the current efforts in developing novel anti-fibrotic medicines focusing on lung, heart, kidney, liver and skin fibrosis. Our analysis revealed an estimated 83% attrition rate from Phase 2 to Phase 3 trials across the five fibrotic diseases. The possible reasons for the slow pace and high attrition rates in developing new anti-fibrotics are discussed and potential solutions are proposed.
Review
16 July 2024Mitochondrial Damage and Epithelial-Mesenchymal Transition as Major Triggers of the Development of Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a type of interstitial pneumonia with an unknown cause that progresses gradually, primarily affecting the elderly. The presence of fibrosis has significant implications for individuals with reduced lung compliance, resulting in decreased quality of life and limited survival. Although the exact mechanism remains unclear, researchers have investigated various factors, such as senescent telomerase replication and abnormal lung stem cell differentiation, to understand the root cause. Extensive research has consistently shown that IPF is closely linked to the dysfunction of alveolar epithelial cells. Current scientific studies on IPF cover a range of aspects including oxidative stress, endoplasmic reticulum stress, mitochondrial damage, and iron-induced apoptosis. By examining these mechanisms, a comprehensive model has been developed that explains the process of IPF. Oxidative stress is identified as the primary trigger, followed by mitochondrial damage as a central component, leading to the mesenchymal transformation of alveolar epithelial cells as the ultimate outcome. This model is expected to serve as a valuable reference for understanding the mechanism of IPF and guiding future drug development efforts.
Article
30 April 2024Arrestin beta 1 Regulates Alveolar Progenitor Renewal and Lung Fibrosis
The molecular mechanisms that regulate progressive pulmonary fibrosis remain poorly understood. Type 2 alveolar epithelial cells (AEC2s) function as adult stem cells in the lung. We previously showed that there is a loss of AEC2s and a failure of AEC2 renewal in the lungs of idiopathic pulmonary fibrosis (IPF) patients. We also reported that beta-arrestins are the key regulators of fibroblast invasion, and beta-arrestin 1 and 2 deficient mice exhibit decreased mortality, decreased matrix deposition, and increased lung function in bleomycin-induced lung fibrosis. However, the role of beta-arrestins in AEC2 regeneration is unclear. In this study, we investigated the role and mechanism of Arrestin beta 1 (ARRB1) in AEC2 renewal and in lung fibrosis. We used conventional deletion as well as cell type-specific deletion of ARRB1 in mice and found that Arrb1 deficiency in fibroblasts protects mice from lung fibrosis, and the knockout mice exhibit enhanced AEC2 regeneration in vivo, suggesting a role of fibroblast-derived ARRB1 in AEC2 renewal. We further found that Arrb1-deficient fibroblasts promotes AEC2 renewal in 3D organoid assays. Mechanistically, we found that CCL7 is among the top downregulated cytokines in Arrb1 deficient fibroblasts and CCL7 inhibits AEC2 regeneration in 3D organoid experiments. Therefore, fibroblast ARRB1 mediates AEC2 renewal, possibly by releasing chemokine CCL7, leading to fibrosis in the lung.
Review
26 February 2024Mechanisms of Fibroblast Activation during Fibrotic Tissue Remodeling
Fibrosis can occur in almost every organ system. It can occur in single organs, such as in idiopathic pulmonary fibrosis (IPF), or affect multiple organs as in systemic sclerosis (SSc). Fibrotic diseases are recognized as major cause of morbidity and mortality in modern societies due to the dysfunction or loss of function of the affected organs. This dysfunction is caused by progressive deposition of extracellular matrix proteins released by activated fibroblasts. Activation of fibroblasts and differentiation into myofibroblasts is required for physiological tissue remodeling, e.g, during wound healing. Disruption of regulatory mechanisms, however, results in chronic and uncontrolled activity of fibroblasts and myofibroblasts. Intensive research during the past years identified several core pathways of pathophysiological relevance, and described different fibroblast subsets based on their expression profile in fibrotic tissue. Herein, we discuss the molecular changes in fibroblasts leading to persistent activation during fibrotic tissue remodeling with a focus on lung fibrosis and SSc.
Meeting Report
20 February 2024The Cellular and Metabolic Bases of Organ Fibrosis: UNIA Workshop 2023 in Baeza, Spain
Fibrosis is defined by scarring and tissue hardening caused by excess deposition of extracellular matrix components, mainly collagens. A fibrotic response can occur in any tissue of the body and is the final outcome of an unbalanced reaction to inflammation and wound healing induced by a variety of insults, including persistent infections, autoimmune reactions, allergic responses, chemical exposure, radiation, and tissue injury. The accumulation of extracellular matrix proteins replaces the living tissue and disrupts the architecture leading to organ malfunction. Fibrosis remains a major clinical and therapeutic challenge and has been estimated to account for 45% of deaths in the developed world. While major advances regarding mechanistic knowledge on the underlying cell biology alterations in fibrosis have helped to characterize the main phases and mediators involved, this knowledge has not yielded significant progress in treatment. Only recently, the metabolic features associated to fibrosis have begun to emerge. This information, likely representing only the tip of the iceberg, suggests that metabolic derangement is a key culprit in the pathophysiology of fibrogenesis. The Workshop on The Cellular and Metabolic Bases of Organ Fibrosis, International University of Andalusia, Baeza, Spain, October 8–11, 2023 aimed to discuss the current knowledge and novel perspectives on the mechanisms contributing to the development of fibrosis in different organs and tissues, with particular focus on new methodological developments in metabolomics and therapeutic strategies.
Article
01 February 2024Molecular Regulation of Transforming Growth Factor-β1-induced Thioredoxin-interacting Protein Ubiquitination and Proteasomal Degradation in Lung Fibroblasts: Implication in Pulmonary Fibrosis
Thioredoxin-interacting protein (TXNIP) plays a critical role in regulation of cellular redox reactions and inflammatory responses by interacting with thioredoxin (TRX) or the inflammasome. The role of TXNIP in lung fibrosis and molecular regulation of its stability have not been well studied. Therefore, here we investigated the molecular regulation of TXNIP stability and its role in TGF-β1-mediated signaling in lung fibroblasts. TXNIP protein levels were significantly decreased in lung tissues from bleomycin-challenged mice. Overexpression of TXNIP attenuated transforming growth factor-β1 (TGF-β1)-induced phosphorylation of Smad2/3 and fibronectin expression in lung fibroblasts, suggesting that decrease in TXNIP may contribute to the pathogenesis of lung fibrosis. Further, we observed that TGF-β1 lowered TXNIP protein levels, while TXNIP mRNA levels were unaltered by TGF-β1 exposure. TGF-β1 induced TXNIP degradation via the ubiquitin-proteasome system. A serine residue mutant (TNXIP-S308A) was resistant to TGF-β1-induced degradation. Furthermore, downregulation of ubiquitin-specific protease-13 (USP13) promoted the TGF-β1-induced TXNIP ubiquitination and degradation. Mechanistic studies revealed that USP13 targeted and deubiquitinated TXNIP. The results of this study revealed that the decrease of TXNIP in lungs apparently contributes to the pathogenesis of pulmonary fibrosis and that USP13 can target TXNP for deubiquitination and regulate its stability.
Review
21 December 2023TANGO1 Dances to Export of Procollagen from the Endoplasmic Reticulum
The endoplasmic reticulum (ER) to Golgi secretory pathway is an elegantly complex process whereby protein cargoes are manufactured, folded, and distributed from the ER to the cisternal layers of the Golgi stack before they are delivered to their final destinations. The export of large bulky cargoes such as procollagen and its trafficking to the Golgi is a sophisticated mechanism requiring TANGO1 (Transport ANd Golgi Organization protein 1. It is also called MIA3 (Melanoma Inhibitory Activity protein 3). TANGO1 has two prominent isoforms, TANGO1-Long and TANGO1-Short, and each isoform has specific functions. On the luminal side, TANGO1-Long has an HSP47 recruitment domain and uses this protein to collect collagen. It can also tether its paralog isoforms cTAGE5 and TALI and along with these proteins enlarges the vesicle to accommodate procollagen. Recent studies show that TANGO1-Long combines retrograde membrane flow with anterograde cargo transport. This complex mechanism is highly activated in fibrosis and promotes the excessive deposition of collagen in the tissues. The therapeutic targeting of TANGO1 may prove successful in the control of fibrotic disorders. This review focuses on TANGO1 and its complex interaction with other procollagen export factors that modulate increased vesicle size to accommodate the export of procollagen.
Article
28 November 2023Translational Studies Reveal the Divergent Effects of Simtuzumab Targeting LOXL2 in Idiopathic Pulmonary Fibrosis
The composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the cross-linking of collagen, which promotes fibroblast to myofibroblast differentiation. We examined the role of lysyl oxidase (LOX)-like 2 in lung progenitors and fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab). Primary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties. LOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis. Consistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.
