**2. Fibrosis: Some General Aspects**

The term fibrosis describes a pathological situation defined by the overgrowth, hardening, and excessive scarring that can affect nearly all tissues [54]. The scarring process is mainly characterized by the replacement of normal parenchymal tissue by connective tissue. The process is initiated by neutrophilic inflammation, which can result from various stimuli, such as mechanical injury, infections, autoimmune attacks, toxins, or radiation. Mechanistically, this process aims to eliminate the initial cause of injury and preserve the function of the affected organ [55].

The primary inflammatory response is well-orchestrated and requires engagement of the local vascular system and components of the immune system, as well as the systemic coordination of endocrine and neurological mediators [54]. This interconnection is driven by a variety of soluble factors (chemokines, cytokines). During acute inflammation, resident immune cells (e.g., macrophages, dendritic cells, MCs) are the most important in the initial phase. These cells are equipped with pattern recognition receptors (PRRs) playing a crucial role in the detection of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [54,55]. These receptors differ in their ligand recognition and defined subsets can identify a broad range of proteins, nucleic acids, or glycans [56,57]. After ligand recognition, these receptors induce various cellular responses resulting in the release of different inflammatory mediators that in turn provoke the typical five cardinal clinical signs of inflammation, namely *rubor* (redness), *calor* (heat), *tumor* (swelling), *dolor* (pain), and *functio laesa* (loss of function).

If this first-line defense is insufficient to eliminate the disease-causing agent and inflammation persists, various immune cells, such as macrophages and T-lymphocytes, are triggered to produce high quantities of cytokines and enzymes, which subsequently provoke more lasting damage. As a consequence, parenchymal cell death occurs, which is associated with an uncontrolled release of pro-fibrogenic mediators that in turn lead to activation of a pro-fibrogenic cell population with the capacity to synthesize large quantities of ECM components [58]. In this regard, members of the TGF-β family of cytokines are of fundamental importance, acting as a common master switch. TGF-β strongly promotes the synthesis of collagen and fibronectin in both epithelial and mesenchymal cells and further suppresses the process of inflammation [58]. Other important soluble mediators triggering the process of fibrogenesis are members of the platelet-derived growth factor (PDGF) family and connective tissue growth factor (CTGF). While PDGFs are highly competent mitogens and chemoattractants for fibrogenic cells, CTGF contains structural features serving as TGF-β binding domains, thereby enhancing its biological activity or sequestering other members of the TGF-β gene family, such as bone-morphogenetic proteins (BMPs), which usually act as opposing factors for TGF-β [59]. In concert with TGF-β, these mediators increase the number and activity of myofibroblasts (MFBs) and their progenitors, thereby promoting fibrogenesis in a variety of organs including skin, heart, kidney, pancreas, lung, liver, and others. Strikingly, the population of cells capable of synthesizing ECM consists of resident pro-fibrogenic cells, such as hepatic stellate cells (HSCs) and portal myofibroblasts, progenitors invading the inflamed tissue, and cells that become activated and acquire fibrogenic features [55]. These cells are preserved between different organs. The final ECM-producing cell type, the myofibroblast, can originate from cellular subsets including resident fibroblasts, mesothelial cells, circulating fibrocytes, epithelial cells, endothelial cells, pericytes, vascular smooth muscle cells, Gli1<sup>+</sup> perivascular mesenchymal stem cell-like cells, and other more specialized cells that are present within different organs or tissue. In kidney, these are, for example, podocytes found in the lining of the Bowman's capsules in the nephrons or tubular epithelial cells that might also acquire migratory properties and transit into a myofibroblast-like phenotype capable of synthesizing ECM components [55].
