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.
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.
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.
